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The controversy being created about the origins of the virus that causes COVID-19 – Frontline

Posted: July 6, 2021 at 2:07 am

The famous question about whether the world as we know it arose from evolution or creation was settled long ago in favour of evolution and against religious bigotry. But the old debate resurfaced, only in a different garb, during the pandemic. The question is posed thus: did the SARS-CoV-2 virus, which causes COVID-19, naturally evolve from bats through an intermediary to humans or was it engineered in a laboratory in Wuhan, the capital of Hubei Province, and leaked accidentally or intentionally?

COVID-19, perhaps one of the most virulent pandemics in the past 100 years, has exposed the frailties of public health systems in many countries, as evidenced by the massive loss of lives and livelihoods across the world. But it has also shown the power of science and technology, especially the open and quick sharing of data and results. Obversely, the ensuing infodemic has brought with it a tide of misinformation, chiefly the manufactured controversies on whether the SARS-CoV-2 virus evolved naturally or was deliberately or artificially created by Chinese scientists who then caused its spread intentionally or otherwise.

Here, we argue that the virus, which appears so perfect and complexly suited to infecting humans and for transmission amongst them, is most likely of natural evolutionary origin. Various statements and articles speculating that the virus was created by design and released through laboratory leaks appear to lack scientific credibility and border on conspiracy theories. The push by some scientists and governments for investigations, in the name of biosafety monitoring, into a possible laboratory leak from the Wuhan Institute of Virology (WIV) appear to be driven by paranoia or a Chinaphobia.

Nearly two centuries ago, Charles Darwin said in his Origin of Species: To suppose that the eye with all its inimitable contrivances .could have been formed by natural selection, seems, I freely confess, absurd in the highest degree. When it was first said that the sun stood still and the world turned round, the common sense of mankind declared the doctrine false .Reason tells me, that if numerous gradations from a simple and imperfect eye to one complex and perfect can be shown to exist, ...then the difficulty of believing that a perfect and complex eye could be formed by natural selection, though insuperable by our imagination, should not be considered as subversive of the theory.

Also read: On the political economy of pandemics

Viruses are opportunistic and take advantage of unusual situations and the weaknesses of their hosts. In most cases, humans invite viral pathogens upon themselves by invading and occupying biological spaces to the detriment of other animals, thereby also presenting viruses with greater opportunities to infect them. The precise path that leads a particular virus jumping from its reservoir population to humans is mostly fortuitous, difficult to determine and, in some instances, has remained inconclusive.

The influenza pandemic that started in 1918, which was popularly called the Spanish flu though the origin was not in Spain but in Haskell County, Kansas, United States, infected about 500 million people and resulted in the death of possibly 50 million. It is now known to have been caused by the virus H1N1 with genes of avian origin, although the exact origin has still not been conclusively established. It is thought to be of zoonotic origin from birds because since then there have been several similar influenza virus pandemics: in 1958 (H2N2), 1968 (H3N2) and 2009 (H1N1 pdm09). Interestingly, H1N1 pdm09 was also called swine flu because it contained a sequence segment similar to the Eurasian swine influenza virus from 1992. It is estimated that 0.001 per cent to 0.007 per cent of the worlds population died of respiratory complications associated with the H1N1 pdm09 virus infection in the first 12 months of the virus circulation. Where did that virus jump from? No intermediate host has been identified. Thankfully, there was no laboratory leak conspiracy theory for that episode.

A highly pathogenic avian influenza (HPAI), A(H5N1) was first detected in humans in 1997 during an outbreak among poultry in Hong Kong. H5N1 has continued to circulate and been detected at various times, for instance in 2003 and 2014. It has been found that low pathogenicity avian influenza viruses (LPAIVs) are generally asymptomatic in their natural avian hosts. LPAIVs can evolve into highly pathogenic forms, which can affect avian and human populations with devastating consequences. The acquisition of multiple amino acids with positively chargeable side chains such as lysine (K) and arginine (R) in the haemagglutinin cleavage site creates what is called a polybasic motif because of the presence of exchangeable hydrogens in the side chains. Thus, for example, the polybasic motif (RERRRKKR) can be cleaved by proteases such as furin in the human host. This leads to the switch to a HPAI virus from LPAIV precursors facilitating viral entry into cells. Proteolytic cleavage regulates numerous processes in health and disease.

Also read: COVID-19: No endgame in sight

The ubiquitously expressed protease furin cleaves a plethora of proteins at polybasic recognition motifs. Mammalian substrates of furin include cytokines, hormones, growth factors and receptors. A viral pathogen generally needs to bind to a receptor in human cells in order to make its entry. The receptor binding decides the type of cells the virus infects. Receptor binding is often enhanced by proteolytic cleavage of the viral protein that binds. Since the virus can reproduce and make the proteins it needs only after entry into cells, it makes use of the proteases in the host. So, not surprisingly, numerous viral pathogens exploit the ubiquitous nature of furin to enhance their virulence and spread. A furin cleavage site occurs in SARS-CoV-2, and its occurrence is the centrepiece of the conspiracy theories, the so-called smoking gun if you will.

Acquired immune deficiency syndrome (AIDS), which was first reported in 1981 from New York City, has killed about 35 million plus people so far. A retrovirus, now termed human immunodeficiency virus type 1 (HIV-1), was subsequently identified as the causative agent of what has since become one of the most devastating infectious diseases to have emerged in recent history. The zoonotic origin of HIV-1 was unclear for more than a decade and was discovered by pure luck and some hard work.

The HIV-1 is similar in sequence and genomic organisation to viruses found in chimpanzees (simian immunodeficiency virus, or SIVcpz). However, there was a low prevalence of SIVcpz infection in wild-living animals. Moreover, chimpanzees were present in geographic regions of Africa, but AIDS was not initially seen there. This along with the differences between HIV-1 and SIVcpz cast doubts on chimpanzees as a natural host and reservoir for HIV-1. It was then suggested that another, as yet unidentified, primate species could be the natural host for SIVcpz and HIV-1. The link was finally established in 1999. A chimpanzee (named Marilyn) of the subspecies Pan troglodytes troglodytes had been caught in the wild in Africa and then exported as an infant to the U.S. for research. She had not received any blood contaminated with HIV. But, during a sero-survey in 1985 amongst 98 chimpanzees, Marilyn showed a high level of antibodies to HIV-1. She died shortly afterwards giving birth to stillborn twins. A polymerase chain reaction analysis in 1999 of the spleen and lymph node tissues retrieved from frozen samples showed the presence of the virus now called SIVchzptt, which is the closest relation to HIV-1, and confirmed its zoonotic origin.

Also read: India's vaccination policy: A U-turn and a spin

Interestingly, the HIV-1 envelope protein initiates infection by mediating the fusion of the viral envelope with the cell membrane. For this to occur, the envelope protein has to be cleaved by host proteases such as furin at a polybasic motif in a loop connecting two regions. In fact, in an attempt to bolster the conspiracy theory that SARS-CoV-2 was man-made, claims have been made that Dr Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), holds patents of an HIV component used to create COVID-19.

The severe acute respiratory syndrome (SARS) pandemic of November 2002 to July 2003, which was caused by a coronavirus now called SARS-CoV, affected about 8,000 people in more than 30 countries. In May 2003, sampling of 25 animals in a wet market in Hong Kong showed the presence of a coronavirus in three masked palm civets, one racoon dog and two Chinese ferret badgers with 99.8 per cent of its sequence identical to the human SARS-CoV. Subsequently, serological and epidemiological surveys pointed to traders of palm civets having been infected with SARS-like viruses earlier. Studies in 2004 suggested that a small proportion of healthy individuals in Hong Kong had been exposed to SARS-CoV-related viruses at least two years before the SARS outbreak reached Hong Kong in mid February 2003.

In 2005, two groups of researchers demonstrated that bats were natural reservoirs of SARS-like viruses. There is now evidence to suggest that there are four possible routes of transmission of SARS-CoV: animal-to-human, animal-to-animal, human-to-human and human-to-animal. Studies with animals showing infectivity to SARS-CoV have shown that inter-species contact and cross-species virus transmission (i.e. spillover) are essential and sufficient to cause epidemic emergence. Sustained transmission and virus adaptation within the spillover species determine the magnitude and scope of subsequent disease outbreaks. For example, SARS-CoV uses the angiotensin-converting enzyme (ACE2) as a receptor for its spike protein to bind to and gain entry into human cells. The spike protein also gets cleaved by a host protease (not furin), which enables the binding and fusion of the viral envelope with the cell membrane. It was found that the spike protein in the virus isolated from human patients in the 2002-03 outbreak bound more efficiently to the ACE2 receptor than the virus isolated from palm civets or from humans with mild cases in 2004. It took about three years after the outbreak of SARS-CoV to establish all this.

Also read: COVID-19: Perils of vacuous claims

However, a study in 2012 isolated a SARS-like coronavirus that was able to utilise ACE2 in humans, civets and in Chinese horseshoe bats for cell entry. This virus (bat SL-CoV-WIV1) offers strong evidence that SARS-CoV originated from a bat reservoir and suggests that an intermediate host may not have been required to facilitate adaptation to human ACE2. Curiously, in 2009 an article in the journal Proceedings of National Academy of Sciences of the United States of America revealed that a group at Cornell University engineered SARS-CoV to introduce a furin cleavage polybasic site to study the proteolytic activation of SARS-CoV.

In November 2012 came the first case of the disease that since May 2013 has been called the Middle East respiratory syndromes (MERS), which is caused by the MERS coronavirus (MERS-CoV). The outbreak started in the Middle East and has now spread to about 24 countries, affecting people and causing deaths, albeit in comparatively smaller numbers than COVID-19. In June 2014, it was found that the sequence of the virus from a man who became sick with MERS and that isolated from the camel he was tending were nearly identical. It was concluded that the camel was the intermediate host from which the virus could have jumped to humans. But a 2015 study showed that transmission from camels to humans is rare. This raises questions about whether the camel was really the intermediate animal for transmission. MERS-CoV does not use ACE2 as the receptor but binds to dipeptidyl peptidase 4 (DPP4). However, it has a furin cleavage site similar to that in SARS-CoV-2, which helps in its infection.

In China, on December 29, 2019, local hospitals in Wuhan using the surveillance mechanism for a pneumonia of an unknown aetiology that was established in the wake of the 2003 SARS outbreak identified the first four cases of COVID-19, which were all associated with the seafood wholesale market in Wuhan. On December 31, the Chinese Centre for Disease Control and Prevention dispatched a rapid response team to Wuhan to accompany the Hubei provincial and Wuhan city health authorities who were conducting an epidemiological and aetiological investigation. Scientists of the WIV made the sequence of the virus available to the international community through a manuscript that was submitted to the journal Nature on January 20, 2020. The paper was published online on February 3. It showed that the sequence of the virus from human patients was 94.4 per cent identical to SARS-CoV and 96.2 per cent identical to the virus from bat samples (RaTG13) collected previously from caves in Yunan.

Also read: COVID and other diseases: An Animal Farm perspective

On February 11, the International Committee on Taxonomy of Viruses named the virus SARS-CoV-2 because of its close relationship to SARS-CoV. The World Health Organisation (WHO) called the disease COVID-19 to distinguish it from the earlier SARS. The disease rapidly spread to many countries, and the WHO declared it a pandemic on March 11. The virus was shown to use the ACE2 receptor for binding and cell entry and was aided by cleavage by protease transmembrane serine protease 2 (TMPRSS2). A furin protease cleavage site not seen in SARS-CoV was found in this virus, and the cleavage at this site enables the entry of the virus into the cell.

To date, the disease has caused 177.5 million cases and 3.8 million deaths worldwide, and 1.99 million sequences from infected cases have been made publicly available. These sequences have shown the evolutionary changes that are happening in the virus. No other virus or disease in history has been subject to such close scrutiny and public discussion, thanks to the sharing of data and findings facilitated by modern communication, including social media channels. The first reports of the virus and disease were from China, which is becoming a major player in the world economy and is threatening to surpass existing powerhouses. The fact that the WIV specialises in coronaviruses, and has allegedly been engaged in collaborative work with U.S. institutions on gain of function research because of the prevalence of these viruses in the region, gave rise to conspiracy theories spread by right-wing governments and scientists.

At the beginning of 2020, several scientists/virologists were of the opinion that the question of whether the virus was the result of natural evolution should be answered in the affirmative. But because of the elections in the U.S., President Donald Trump needed an enemy to blame and attack in order to distract attention from his poor handling of the pandemic despite prior warnings from the U.S. Centres for Disease Control and Prevention. When the horrifying images of people being buried in New York were splashed in the media, he chose to call the virus a China virus. He even declared that he had found the cure in the form of hydroxychloroquine. But in the beginning, a few reputed scientists even declared the disease an ordinary influenza. Later, the vicious nature of the pandemic became clear, and the whole world had to look for solutions that would work in the temporary short term as well as the permanent long term.

Once the U.S. elections were over, the new President brought in measures to help the vulnerable sections and to ramp up vaccinations. Now the question about the origin of the virus, which scientists were working on anyhow, became politicised to align with the new policy to challenge the emerging force of China. The discredited conspiracy theory that the virus was a bioweapon engineered at a laboratory in Wuhan is now brought out as new wine in old bottles with the claim it leaked from that same laboratory.

Also read: COVID-19: Vaccine follies

So what evidence has been marshalled in support of the contending conjectures and what should be done now? Coronaviruses are not new. They have been around for at least a few decades. Jemma Geoghegan, the well-known virologist from New Zealand who was prominent in her countrys prompt COVID-19 response, said: SARS-CoV-2, the virus that causes the COVID-19, is closely related to other viruses that exist in nature. This virus is likely to have taken a path similar to SARS in 2003, viz., from animals to humans. Jemma Geoghegan explores the role that size, structure and mode of transmission of viruses play in the prediction of whether a virus will infect humans and cause a pandemic. She explained that prediction was difficult because of the vast number of viruses and said it was simply impossible to predict... whether a newly discovered animal virus could jump into humans and cause a pandemic. She also mentioned that five coronaviruses have emerged in the past and the intermediary animal responsible for COVID-19 remains unclear. Farm animals such as rabbits could be a possible intermediary for many viruses, but more studies are required to establish this conclusively. Ninety-six per cent of the genome sequence of SARS-CoV-2 is common to that found in bat coronaviruses. That the spike protein of SARS-CoV-2 can bind effectively to human cells is most likely a result of natural selection rather than manipulation in a laboratory. The backbone of the virus seems to be linked to bats and pangolins and is quite different from anything available in laboratories.

The genome of SARS-CoV-2 shows thousands of differences from its closest relative, according to Jonathan Stoye, group leader of the Retrovirus-Host Interactions Laboratory at the Francis Crick Institute in the United Kingdom. Now the changes that have been observed in the nucleotide sequence of the SARS-CoV-2 genomes sequenced so far clearly indicate that it is highly improbable for modifications that span such a large evolutionary distance to have taken place in a laboratory. This therefore suggests that the variations happened in animals, either bats, which form the reservoir for coronaviruses, or an intermediary animal in the wild, which is yet to be discovered.

The most important supposed villain in this is said to be the spike glycoprotein, which helps the virus bind to the specific ACE2 receptor. A cleavage of the spike protein by the host proteases, one of which is furin, helps facilitate the entry. This was the smoking gun the science correspondent Nicholas Wade attributed to the Noble laureate David Baltimore. While Wade used this information and spun stories beyond what is known, Baltimore himself withdrew from Wades surmises. In an article in Current Science (June 10, 2021), Prof. P. Balaram developed Wades arguments and gave further impetus to the improbable thesis that the virus was manipulated/engineered in the WIV and leaked. This scenario was also the favourite among the conspiracy theorists initially. However, U.S. scientists immediately responded that nature was responsible for the virus reaching humans through an intermediary via slow evolutionary processes. Moreover, many viruses use the furin cleavage site, and it is not unique to SARS-CoV-2. An analysis of all coronavirus sequences published in the journal Stem Cell Research in December 2020 showed that furin cleavage sites in spike proteins naturally occurred independently multiple times in coronaviruses.

Also read: Misplaced optimism as COVID numbers go down

A recent report in the journal Cell showed the great diversity of viruses in least horseshoe bats, or Rhinolophus pusillus (https://doi.org/10.1016/j.cell.2021.06.008 ). It showed that apart from the previously reported coronavirus sample, RaTG13, two others, RpYN06 and RmYN02, had similarities over the whole genome. A bioRxiv reprint in March 2021 used the available 1,58,118 public seasonal genome sequences of hCoV, SARS-CoV-1, SARS-CoV-2 and MERS-CoV and noted that the current sampled diversity of seasonal coronaviruses had emerged over a 70-year-period, punctuated by the emergence of new lineages at intervals ranging from 5 to 20 years.

Interestingly, in July 2020, a group published an analysis of the more than 45,000 SARS-CoV-2 sequences from infected people then available, which showed the mutations and deletions that happened in the furin cleavage site, and concluded that the furin cleavage site might not be essential for SARS-CoV-2 to enter human cells in vivo. This shows that the virus in its passage through human cells is capable of losing the furin cleavage site. So it is not a site that is essential to virus infection, and this makes the case for the artificial insertion of this sequence to create a new virus much less appealing. A study published in PLOS Biology in March 2021 showed that the bat virus closest to SARS-CoV-2, RmYN02 (sharing an ancestor from about 1976), arose from a recombination within coronaviruses in bats and shares genetic features similar to SARS-CoV-2. This suggests the possibility that SARS-CoV-2 could have evolved in bats and directly jumped to humans without the need for an intermediate animal.

Although it is possible to conclude that there may be an undiscovered facilitating intermediate species, the results support the premise that the progenitor of SARS-CoV-2 was capable of efficient human-to-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, that created a relatively generalist virus capable of infecting many hosts. Thus, finding the closest relative to SARS-CoV-2 could then be a matter of screening diverse bat populations. This really warns us against jumping the gun, whether it is smoking or not, and concluding that SARS-CoV-2 does not have a natural origin. A letter published in Science on May 14 said: We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data. A proper investigation should be transparent, objective, data-driven, inclusive of broad expertise, subject to independent oversight, and responsibly managed to minimise the impact of conflicts of interest.

Also read: India needs to spread its bets on vaccines: Dr Satyajit Rath

But a couple of months earlier, The Lancet published a letter emphatically dismissing conspiracy theories and saying that sharing of data is being threatened by disinformation and rumours. This issue of sharing data and information has become more about political sloganeering, in which some scientists too have joined in, than about science. Scientists from various countries have analysed the genomes of SARS-CoV-2 and come to the conclusion that this virus originated in the wild as did many other pathogens. The presidents of the U.S. national academies of sciences, engineering and medicine have backed this and warned that conspiracy theories create only fear, rumours and prejudice and jeopardise the global fight against the virus. They said they supported the call from the WHO Director General to promote scientific evidence and unity over misinformation and conjecture.

The problem with conspiracy theories is that they usually provide one point of speculative evidence that forms the basis for further speculative theorising. Essentially, they all turn to one final definitive source to rest their case. In this case, Nicholas Wades publication of his speculative thesis in Bulletin of the Atomic Scientists has been used to spread the canard that the pandemic was caused by negligence or deliberate action in Wuhan.

Incidentally, Wades book A Troublesome Inheritance: Genes, Race and Human History (2014) drew sharp criticism from 130 scientists for its racist overtones. They said in a letter to The New York Times: Wade juxtaposes an incomplete and inaccurate account of our research on human genetic differences with speculation that recent natural selection has led to worldwide differences in I.Q. test results, political institutions and economic development. We reject Wades implication that our findings substantiate his guesswork. They do not. We are in full agreement that there is no support from the field of population genetics for Wades conjectures. In the past, many people have criticised him for misreporting their remarks in his articles.

No doubt more data is needed on the nature of studies at the WIV. The institute is one of international standing where research work is carried out in collaboration with scientists from the U.S., Europe, Australia, Japan and India (the National Centre for Biological Sciences, or NCBS) with funding from these countries. It is one of the two laboratories in China to have a biosafety level of 4 (the highest level). Even the U.S. Department of Defence has funded programmes at the institute. It is only natural that researchers from these countries would demand a high degree of transparency about safety procedures at the WIV, including the recording of accidents and the corrections undertaken. The WIV has a high level safety procedures that is not matched even by the Indian Department of Atomic Energyfunded NCBS. There has even been a collaboration on the bat viruses from Nagaland involving scientists from the NCBS. A needless controversy has now been created about whether proper approvals were obtained from the Indian Council of Medical Research, the Ministry of External Affairs, and so on, for such studies. This is because the issue has deliberately been politicised with the intention of derailing international scientific collaborations with entities based in China.

Also read: The B.1.617 variant of COVID-19 that emerged in India is spreading to South Asia and beyond

To this end, conspiracy theorists have attempted to link Dr Fauci, the face of the COVID-19 response in the U.S., to the laboratory leak theory. His office provided a research grant of $6,00,000 for five years (which the NIH eventually halted) to an American organisation, EcoHealth Alliance, working with the WIV. Dr Fauci received an email on April 18, 2020, from the zoologist Peter Daszak thanking him on behalf of the staff of EcoHealth Alliance for rejecting the laboratory leak theory. Actually, Dr Fauci did not reject it but only claimed it was less likely compared with the zoonotic origins theory. Republican senators in the U.S. introduced a Bill to remove Dr Fauci, who has advised several Presidents across parties, from his post.

Harping on conspiracies vitiates the atmosphere to the point where research involving international collaboration, particularly on virus mutations and the required responses, becomes increasingly difficult. In an article in Forbes magazine, Ethan Siegel lists out the strident remarks that have been made about the virus, which cannot, in the language of the scientific method, even be termed hypotheses: 1. It was a bioweapon developed in Wuhan. 2. Dr Fauci was directly involved in funding the programme in the laboratory that created the virus 3. Dr Shi Zhengli, the bat woman, was the brains behind the research to unleash the virus 4. Some kind of banned/unregulated research in gain of function was being done to modify a coronavirus, which resulted in the virus that causes COVID-19. All these are extraordinarily improbable compared with the hypothesis that the disease has zoonotic origins.

But the international collaboration the pandemic has brought about among scientists, virologists, medical professionals and public health administrators is extraordinary. They will eventually agree that Darwin still rules the world of cell biology.

S. Krishnaswamy is a retired professor of biotechnology earlier from Madurai Kamaraj University, Tamil Nadu. T.R. Govindarajan is a retired professor of physics from the Institute of Mathematical Sciences, Chennai.

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The controversy being created about the origins of the virus that causes COVID-19 - Frontline

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Kelly lauds $21 billion state budget bill, vetoes $500,000 …

Posted: June 6, 2021 at 1:45 am

TOPEKA Gov. Laura Kellys enthusiasm when signing a new $21 billion state government budget couldnt be dampened with the lone veto of an earmark for research using stem cells to search for a treatment of severe COVID-19 cases.

Im proud of this bipartisan, fiscally responsible budget that demonstrates what lawmakers can get done when we work together, Kelly said. This budget includes increased funding for disability services, the criminal justice system, mental health services and higher education.

She said the appropriations would deliver critical services so that Kansans, businesses and local governments continue with the COVID-19 recovery.

The House voted 98-21 to approve Senate Bill 159, while the Senate voted 26-12 on the bills behalf. Its possible the Legislature would attempt to override the governor Wednesday when convened for the final day of the annual session, but there remained sharp division between legislators who believe the state was spending too little or too much.

I refuse to give more of my hard-earned money to government that has an endless appetite for spending with no true results for the great people of Kansas, said Rep. David French, a Lansing Republican among House members opposed to the bill.

The budget for the fiscal year starting July 1 and signed into law Friday raised state spending by $17 million to provide salary increases for employees in the Kansas court system and to add 70 new court services officers.

The Legislature rejected proposals to provide across-the-board pay raises for state workers, with some lawmakers declaring it unfair to give increases to state employees who didnt lose jobs during the pandemic. Kelly recommended state employees get a 2.5% salary bump.

Is the irony lost on anyone else that the very judges salaries that we are increasing as a good job are the same judges that have stepped all over our toes with massive education funding? said Rep. Tatum Lee-Hahn, a Ness City Republican irritated by previous court rulings that state aid to K-12 schools was unconstitutionally low. This is a huge reason we cannot get control of our states budget.

Topeka Rep. Vic Miller, one of the few Democrats to vote against the budget, did so for a reason contrary to Lee-Hahns position. Miller said he voted no because the rest of state employees were also deserving of a pay raise.

The law did authorize issuance of bonds to finance the $120 million renovation of Docking State Office Building next to the Capitol and $65 million in bonds for construction of a Kansas Department of Health and Environment lab in the Topeka area.

The measure funneled $53 million to public and private universities and colleges for scholarships, staff recruitment and economic development. The extra funding was designed to comply with federal requirements on higher education institutions receiving federal COVID-19 aid.

The bill directed $3.6 million at the Board of Indigents Defense Services to boost the rate paid attorneys. It included $3 million to support implementation in Kansas of the nationwide 988 hotline for people to connect with mental health or suicide prevention counselors.

Kelly vetoed a provision setting aside $500,000 for the University of Kansas Medical Center to conduct clinical trials for a COVID-19 treatment using stem cells derived from umbilical cords. Critics said the modest level of funding to the Midwest Stem Cell Therapy Center would make the project not realistic or even feasible, because a typical clinical trial could cost 20 times the amount appropriated.

Given those realities and the proven effectiveness of COVID-19 vaccines and treatments that are now widely available, we should focus our efforts on increasing the number of Kansans who are vaccinated so that we can prevent infections, severe illnesses and deaths, Kelly said.

Sen. Mike Thompson, R-Shawnee, said he was disappointed the governor undermined research on COVID-19. He said $500,000 was enough to support a clinical trial involving 10 people.

There is currently no treatment available for COVID-19 patients who have developed the most severe symptoms, including pneumonia, said Thompson, among Republicans critical of Kellys handling of the pandemic. There is an urgent need for a medical intervention beyond supportive therapy for these patients.

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[Full text] Binding of the SARS-CoV-2 Spike Protein | HMER – Dove Medical Press

Posted: April 15, 2021 at 1:47 am

Introduction

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and its damaging effects on both health and economics worldwide. Transmission and pathology of the virus appears to be mediated through the respiratory system via interaction of the viral spike protein with the ACE-2 receptor13 differentially presented on various cells within the respiratory system.4,5 Expression of ACE-2 has been reported on lung alveolar epithelial cells, enterocytes of the small intestine, circulatory endothelial cells, arterial smooth muscle cells,6 adipose tissue, bone marrow, duodenum, endometrium, heart, kidney, testis, and thyroid7 suggesting a potential direct effect of COVID-19 on those tissues. Additionally, infection with COVID-19 has been associated with significant liver injuries and altered liver function tests.8

Alterations in liver function have been attributed to secondary effects of cytokine cascade, hypoxia, underlying liver disease,911 or infection of ACE-2 positive cholangiocytes.12 There have also been reports of coronavirus particles in hepatocytes without a defined mechanism for infection.13

In a recent report studying the receptome of spike binding, ACE-2 was confirmed as the primary receptor for the spike protein via the binding domain (RBD) on the spike 1 portion of the molecule and the N-terminal-domain as the sites critical for virushost interaction.14 Additionally, the report described binding of the spike protein with ectopically expressed ASGR1 and KREMEN1 in transfected non-liver cells. The results strongly suggested the existence of additional entry points into cells for the SARS-CoV-2 virus via the spike protein. Differences in primary infection sites and clinical manifestations of SARS-CoV and SARS-CoV-2, both utilizing ACE-2 as the primary site of cellular infection, suggested that other cellular receptors may be involved in SARS-CoV-2 host interactions.14

E12 TERT-immortalized multi-lineage progenitor cells (MLPC) derived from human umbilical cord blood have been differentiated into immortalized AT2-like cells (AT2) (manuscript submitted) and fused directly with primary human hepatocytes to create immortalized hepatocyte-like cells (HLC).15 The resultant E12 AT2-like cells expressed the characteristics of small airway epithelial cells associated with alveolar type 2 cells and not alveolar type 1 cells. The E12/PHH fusion cells (HLC) expressed the characteristics of fully mature and highly differentiated hepatocytes.15

This report studied the interactions of the SARS-CoV-2 spike protein with potential receptors on human cord blood-derived MLPC differentiated AT2, HLC and primary human hepatocytes (PHH) by confocal analysis. The characteristics of spike protein binding were examined using biotinylated spike proteins and blockade of binding by un-labeled spike proteins, spike protein-directed neutralizing antibodies and an antibody directed against the hepatocyte surface membrane asialoglycoprotein receptor 1 (ASGr1). The results suggested that binding and inhibition analyses can be used to assess the potential mechanisms of viral host cell interactions with a myriad of different target cells in the body, but also to assess therapeutics designed to inhibit that binding.

Immortalized AT2 and HLC could provide accurate and reproducible tools to study the differential virushost interactions between these targets of COVID-19 infection and aid in the development of therapeutics designed to inhibit binding and infection by the SARS-CoV-2 virus. In addition, the potential binding of spike protein to the ASGr1 on hepatocytes suggested a mechanism of viral entry via the clathrin-coated pit receptor-mediated pathway and direct injury to the liver.16,17

MLPC are multi-potent non-hematopoietic stem cells isolated from human umbilical cord blood.15 Umbilical cord blood was collected as part of an FDA submission to market PrepaCyte-CB, a product to de-bulk cord blood for cryo-banking and transplantation. IRB approval of the studies was conducted by the University of Minnesota, the Saint Louis Cord Blood Bank and by Quorum Review Protocol #800, March 3, 2005. The cord blood samples were collected by the American Red Cross Cord Blood Program (Saint Paul, Minnesota) and Ridgeview Medical Center (Waconia, MN). Donations were collected with donor consent for research use only.

Briefly, isolated leukocytes were incubated overnight in MSCGM (PT-4105, Lonza, Walkerville, MD) after which non-adherent cells were removed. Cells were cultured in MSCGM until 8090% of cells had a fibroblastic morphology. These cells were transfected with the gene for TERT, as previously described15 and were cloned by limited dilution. The E12 clone was selected for both immortality and differentiating potential. The E12 MLPC, expanded and cryopreserved for over 14 years, were used as undifferentiated control cells and as the source of cells for the development of the AT2-like cells and the fusion partner in the development of MLPC/hepatocyte hybrid cells.15 For confocal analysis, E12 cells (106/mL in MSCGM, 200 L per well) were plated in non-coated 16 well chamber slides (Nalge, Nunc International, Rochester, NY) and allowed to attach overnight before use in the analysis.

AT2-like cells were developed from the differentiation of E12 MLPC. Briefly, E12 cells (3 x 105 cells/mL) in MSCGM were added to non-coated tissue culture vessels and allowed to attach overnight. Medium was then exchanged with SAGM (SAGM, Lonza, Walkerville, MD, cat # 3118) and allowed to culture for 814 days with 3 medium changes per week. Upon achieving 70% confluence, cells were harvested by treatment with Tryp-LE (12605028, Life Technologies, Grand Island, NY) allowed to dissociate from the culture vessel and used for confocal analysis, as a positive control for binding spike proteins and ACE-2 expression. Cells (106/mL in SAGM, 200 L per well) were plated in non-coated 16 well chamber slides and allowed to adhere overnight prior to confocal analysis.

Hepatocyte-like fusion cells were created by the fusion of E12 MLPC with primary human hepatocytes, as previously described.15 Equal numbers of E12 MLPC and primary hepatocytes were fused using 50% polyethylene glycol in RMPI + 0.01% EDTA. Resultant cells were plated into collagen-coated 75 cm2 tissue culture flasks and were cultured for 7 days in RPMI + 20% FBS. After 7 days, non-fused PHH were no longer viable and did not contribute to the HLC cell lines. HLC were examined for hepatocyte-specific markers including albumin and urea production. HLC were demonstrated to express markers and production consistent with fully mature and well-differentiated hepatocytes. HLC (106/mL in hepatocyte expansion medium, 200 L per well) were plated in collagen-coated 16 well chamber slides and were allowed to adhere overnight prior to confocal analysis. Hepatocyte expansion medium consisted of Williams Medium E supplemented with 2% fatty acid-free BSA (Sigma, A7030), 1% ITS solution (Lonza, 17838Z), 5mM hydrocortisone 21-hemisuccinate (Sigma, H2270) and glutamax (35050, Gibco) supplemented with FGF basic (20 ng/mL) (233-FB), FGF-4 (20 ng/mL) (7460-F4), HFG (40 ng/mL) (294-HG), SCF (40 ng/mL) (255-SC), Oncostatin M (20 ng/mL) (295-OM), BMP-4 (20 ng/mL) (314-BP), EGF (40 ng/mL) (236-EG) and IL-1 (20 ng/mL)(201-LB) all from R&D Systems (Minneapolis, MN).

Cryo-preserved primary human hepatocytes and media were obtained from Zenotech (Kansas City, KS). Cells were thawed with OptiThaw medium and enumerated with OptiCount medium in a standard hemacytometer. Hepatocytes were diluted to a final concentration of 106 cells/mL of OptiPlate medium and were plated in collagen-coated 16 well chamber slides at 200 L per well. After 4 hours of plating, the medium was changed to OptiCulture medium to allow overnight attachment and spread of cells prior to confocal analysis.

Cells were prepared for staining with antibodies and binding of spike proteins by fixing the cells in 1% formaldehyde for 1 hour. Cells were then washed x 2 with PermaCyte permeabilization medium (WBP-1000, CMDG, St. Paul, MN). All staining took place in the presence of PermaCyte. Cells were incubated with an unlabeled primary antibody (100 ng) for 30 minutes at room temperature. ACE-2 (labeled with alexa 594, FAB9332T), albumin (MAB1456) and asialoglycoprotein receptor 1 (MAB4394) antibodies were obtained from R&D Systems (Minneapolis, MN). Unbound antibody was removed by washing with PermaCyte and the cells were counterstained with a secondary antibody specific for mouse (A-11005) antibody labelled with Alexa 594 dye (Life Technologies, (Eugene, OR)). Marker expression was confirmed by positive staining when compared to cells stained with antibody isotype controls (QTC1000, CMDG, St. Paul, MN). The nuclei of the cells were visualized by staining with DAPI.

The binding of SARS-CoV-2 spike and spike 1 proteins was analyzed by confocal microscopy using biotinylated spike proteins. Cells were prepared as described above. Cells were labelled with 250 ng of either biotinylated spike (RBD) (SPD-C8E9, ACROBiosystems, Newark, DE) or biotinylated spike 1 protein (SIN-C82E8, ACROBiosystems) for 30 minutes. Unbound spike proteins were removed by washing cells twice with PermaCyte medium. Bound spike proteins were visualized by secondary staining with streptavidin-alexa 594 (S11227 Life Technologies). Cells were counterstained with DAPI to visualize the nuclei.

Specificity of biotinylated spike proteins binding to the cells was confirmed by blockade of binding by a 5 molar excess of unlabeled spike protein. Cells were prepared as per the confocal analysis of antibody binding. Cells were incubated with 1.25 g of unlabeled spike protein (ACROBiosystems, SPD-S52H6) or spike 1 protein (ACROBiosystems, S1N-C52H3) for 1 hour. Without washing the unbound unlabeled spike protein, biotinylated spike and spike 1 proteins were added to the cells and incubated for 30 minutes. Cells were washed twice with PermaCyte medium to remove any unbound proteins. Bound biotinylated spike proteins were observed by secondary labeling with streptavidin-alexa 594. Cells were counterstained with DAPI to visualize the nucleus.

The effects of antibodies on the binding of the spike proteins to the cells were examined using two commercially available neutralizing antibodies obtained from ACROBiosystems (SAD-S35) and Novatein Biosystems (PR-nCOV-mABS1, Boston, MA) and the ASGr1-specific antibody (R&D Systems). One g of either neutralizing antibody was preincubated with the spike protein for one hour prior to the addition of the mixture to the cells prepared as described for binding of the spike proteins. The ASGr1 antibody (300 ng) was preincubated with cells prior to the addition of the spike protein. Visualization of the binding of biotinylated spike protein was accomplished by secondary staining with streptavidin-alexa 594. The nuclei of the cells were visualized with DAPI.

Cells were analyzed on the Olympus Fluoview 1000 confocal microscope. The confocal images in Figures 14 are representative of at least 3 studies done on different days.

Figure 1 Biotinylated spike and spike 1 protein binding to E12 differentiated AT2-like cells and inhibition by unlabeled spike protein and neutralizing antibodies. Bound biotinylated spike proteins were visualized by sequential labeling with streptavidin-alexa 594. Cells positive for binding are shown by red fluorescence. Blue nuclei were visualized by counterstaining with DAPI. (A) Binding of biotinylated spike protein (containing RBD). (B) Inhibition of biotinylated spike protein binding by co-incubation with a 5 molar excess of unlabeled spike protein (RBD). (C) Binding of spike 1 protein. (D) Inhibition of biotinylated spike protein binding by preincubation with a neutralizing antibody from ACROBiosystems. (E) Lack of binding inhibition by neutralizing antibody from Novatein Bio. (F) Inhibition of biotinylated spike 1 binding by unlabeled spike (RBD) protein.

Abbreviation: RBD, receptor-binding domain.

Figure 2 Expression of ACE-2, ASGr1 and serum albumin. Undifferentiated E12 MLPC data are shown in (AD). E12 HLC fusion cell results are presented in (EH). Primary human hepatocytes (PHH) are shown in (IL). Cells were incubated with unlabeled primary antibody and sequentially stained with secondary antibody labeled with alexa-594. Positive binding is shown by red fluorescence. Blue nuclei were visualized by DAPI counterstaining. Figures (A, E and I) were stained with isotype control antibodies. Figures (B, F and J) were stained with antibody specific for ACE-2. Figures (C, G and K) were stained with antibody specific for the asialoglycoprotein receptor 1 (ASGr1). Figures (D, H and L) were stained with antibody specific for serum albumin.

Figure 3 Undifferentiated E12 MLPC confocal microscopy is shown in (AD). E12 HLC fusion cell data are presented in (E-H). Primary human hepatocytes (PHH) are shown in (IL). Positive binding is indicated by red fluorescence. Blue nuclei were visualized with DAPI counterstaining. Figures (A, E and I) were labeled with Sav-594. Figures (B, F and J) were labeled with biotinylated spike protein followed by sequential staining with streptavidin-alexa 594. Figures (C, G and K) were labeled with biotinylated spike 1 protein followed by sequential staining with streptavidin-alexa 594. Figures (D, H and L) biotinylated spike protein binding was blocked by a 5 molar excess of unlabeled spike protein (RBD) followed by sequential staining with streptavidin-alexa 594.

Figure 4 Inhibition of biotinylated spike binding by neutralizing antibodies to spike 1, spike and ASGr1. E12 HLC fusion cell data are shown in (AD). Primary human hepatocytes (PHH) are shown in (EH). Positive binding of biotinylated spike proteins is shown by red fluorescence. Blue nuclei are visualized by counterstaining with DAPI. Figures (A and E) confocals show the inability of a 5 molar excess of unlabeled spike 1 protein to block the binding of biotinylated spike protein. Figures (B and F) show inhibition of binding of biotinylated spike protein by neutralizing antibody from ACROBiosystems. Figures (C and G) show binding inhibition of biotinylated spike protein by neutralizing antibody from Novatein Bio. Figures (D and H) demonstrate inhibition of any detectable binding of biotinylated spike protein by antibody specific for the hepatocyte membrane ASGr1.

In a parallel study that surveyed the differentiation of E12 MLPC to AT2-like cells, it was demonstrated that AT2-like cells were positive for markers associated with AT2 cells (surfactant protein C, ACE2, TM4SF1, HT2-280), negative for markers associated with AT1 cells (AGER, caveolin 1 and aquaporin) and positive for markers not unique to AT2 cells but known to be expressed on AT2 cells (CK19, CD26 and EpCAM). These results were identical to primary small airway epithelial cells. Both cell types were also shown to bind spike and spike 1 proteins. Biotinylated spike proteins could be blocked by unlabeled spike protein (RBD). Pre-incubation with neutralizing antibodies prevented the binding of biotinylated spike protein by the ACROBiosystems neutralizing antibody, but not the Novatein antibody. Expressions of ACE-2, spike protein binding and inhibition were repeated for this study to confirm the involvement of the ACE-2 receptor (Figure 1).

The expressions of ACE-2, ASGr1 and albumin in control E12 MLPC, HLC and PHH were studied by antibody staining. E12 MLPC were shown to be negative for ACE-2, ASGr1 and albumin expression. In contrast, ASGr1 and albumin were shown to be strongly expressed by both HLC and PHH. ACE-2 was not detectible in either cell type (Figure 2).

The ability of E12 MLPC, HLC and PHH to bind spike and spike 1 proteins was studied using biotinylated spike proteins. E12 MLPC were unable to bind either spike or spike 1 proteins. HLC and PHH were able to bind spike protein but not spike 1 protein. The binding of biotinylated spike protein could be blocked by pre-incubation with unlabeled spike protein (Figure 3). The binding of biotinylated spike protein could not be blocked by spike 1, but could be blocked by ACROBiosystems and Novatein neutralizing antibodies and also an antibody directed against the ASGr1 (Figure 4).

It is critical to elucidate the mechanisms of virus/host interactions of the SARS-CoV-2 for the development of therapeutics designed to inhibit the binding and internalization of the virus to a myriad of cell types. The overarching strategy for the development of vaccines or therapeutics has involved the interaction between the S1 portion of the viral spike protein and the ACE-2 cellular receptor found in the respiratory tract and in various other tissues.47 Differences in transmission, pathology and organ involvement between SARS-CoV and SARS-CoV-2 (both dependent upon ACE-2 binding) suggested that additional receptors may contribute to the attachment and internalization of the SARS-CoV-2 virus14 in both the respiratory lungs and other organ systems.

The potential infection of tissues that are ACE-2 negative has spurred the search for additional receptor interactions of the spike protein. Some of these potential spike protein receptor targets include neuropilin-1,18 ASGR1 and KREMEN1.14 The observation of SARS-CoV-2 particles in hepatocytes8 and the robust expression of ASGr1 receptors and neuropilin-1 on hepatocytes suggested that altered liver function associated with COVID-19 infection may be directly caused by infection with the virus and mediated by binding to one or both receptors.

We investigated the potential virus: receptor interactions via the spike protein using fluorescent confocal microscopy and biotinylated spike (RBD) and spike 1 proteins. In a parallel study, E12 MLPC were differentiated to AT2-like cells (manuscript submitted). These cells expressed markers associated with AT2 cells (surfactant protein C, ACE2, TM4SF1, HT2-280), negative for markers associated with AT1 cells (AGER, caveolin 1 and aquaporin) and positive for markers not unique to AT2 cells but known to be expressed on AT2 cells (CK19, CD26 and EpCAM). These results were identical to primary small airway epithelial cells. The binding of biotinylated spike proteins and specific blocking by unlabeled protein and neutralizing antibodies confirmed that the primary interaction of spike protein with AT2-like cells and primary small airway epithelial cells was via the S1 portion of the protein with the ACE-2 receptor. We repeated those studies in support of our findings with the HLC and PHH. The differential inhibition of spike protein binding with two different antibodies suggested that viral neutralization could result from mechanisms other than direct inhibition of S1 (RBD) binding to ACE-2.

The characteristics of SARS-CoV-2 interactions with hepatocytes were studied by observing the binding of biotinylated spike (RBD) and spike 1 proteins to HLC and PHH using the undifferentiated E12 as a known negative control. It was observed that HLC and PHH were both negative for ACE-2, precluding that as a potential site of viral binding. This was confirmed by the inability of the cells to bind S1 protein. The binding of biotinylated spike protein and blockade by unlabeled spike protein on HLC and PHH suggested that the binding was specific, and via a mechanism distinct from ACE-2. The complete inhibition of spike binding by an antibody directed against the ASGr1 is strongly suggestive that ASGr1 is a binding site for the spike protein on hepatocytes. Interestingly, blockade of spike binding by both neutralizing antibodies on HLC and PHH was distinct from AT2 cells where inhibition occurred solely with the antibody that was directed against the RBD. This is suggestive of neutralizing activity that can occur outside the RBD.

Utilization of multiple cell types to study the interactions of spike protein binding will help identify additional receptor pathways for infection with COVID-19. They could also provide a powerful tool to aid in the development of therapeutics against multiple sites on the spike protein or receptors of the host cells. With the existent emergence of new variants and mutations of the SARS-CoV-2 exhibiting enhanced transmissibility, it is especially important to expand our repertoire of cellular models to investigate the effects of the mutations on the binding characteristics of the virus to host cells. The availability of immortalized cells with the stable characteristics of human alveolar type 2 cells and mature well-differentiated hepatocytes could provide an accurate and reproducible tool to effectively study the various virushost interactions via spike proteins by providing potential viral receptors that are segregated according to cell type. We believe that AT2 and HLC provide such a tool.

Dr Daniel P Collins reports personal fees from BioE, LLC, during the conduct of the study. In addition, Dr Daniel P Collins has a patent Composition for an in vitro culture medium to maintain and expand stem cell-derived hepatocyte-like cells pending, as well as,a patent Methods to develop immortalized hybrid hepatocyte-like cells, also pending. The authors report no other conflicts of interest in this work.

1. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA. 2020;117(21):1172711734. doi:10.1073/pnas.2003138117

2. Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215220. doi:10.1038/s41586-020-2180-5

3. Premkumar L, Segovia-Chumbez B, Jadi R, et al. The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci Immunol. 2020;5(48):eabc8413. doi:10.1126/sciimmunol.abc8413

4. Hikmet F, Mar L, Edvinsson , et al. The protein expression profile of ACE2 in human tissues. Mol Sys Biol. 2020;16(7):e9610. doi:10.15252/msb.20209610

5. Sungnak W, Huang N, Bcavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681687. doi:10.1038/s41591-020-0868-6

6. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS corona virus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631637. doi:10.1002/path.1570

7. Wang D, Eraslan B, Weiland T, et al. A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol Syst Biol. 2019;15(2):e8503. doi:10.15252/msb.20188503

8. Wang Y, Liu S, Liu H, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol. 2020;73(4):807816. doi:10.1016/jhep.2020.05.002

9. Desai N, Neyaz A, Szabolcs A, et al. Temporal and spatial heterogeneity of host response to SARS-CoV pulmonary infection. Nat Comm. 2020;11(1):6319. doi:10.1038/s41467-020-20139-7

10. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):10331034. doi:10.1016/S0140-6736(20)30628-0

11. Chu H, Chan JF, Wang Y, et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clin Infect Dis. 2020;71(6):14001409. doi:10.1093/cid/ciaa410

12. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv. 2020. doi:10.1107/2020.02.03.931/766

13. Lozano-Sepulveda SA, Galan-Huerta K, Martnez-Acua N, Arellanos-Soto D, Rivas-Estilla AM. SARS-CoV-2 another kind of liver aggressor, how does it do that? Ann Hepatol. 2020;19(6):592596. doi:10.1016/j.aohep.2020.08.062

14. Gu Y, Cao J, Zhang X, et al. Interaction network of SARS-CoV-2 with host receptome through spike protein. bioRxiv. 2020. doi:10.1101/2020.09.09.28/508

15. Collins DP, Hapke JH, Aravalli RN, Steer CJ. Development of immortalized human hepatocyte-like hybrid cells by fusion of multi-lineage progenitor cells with primary hepatocytes. PLoS One. 2020;15(6):e234002. doi:10.1371/journal.pone.0234002

16. DSouza AA, Devarajan PV. Asialoglycoprotein receptor mediated hepatocyte targeting strategies and applications. J Control Release. 2015;203:126139. doi:10.1016/j.jconrel.2015.02.022

17. Huang X, Leroux JC, Castagner B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjug Chem. 2017;28(2):283295. doi:10.1021/acs.bioconjchem.6b00651

18. Daly JL, Simonetti B, Klein K, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science. 2020;370:861865. doi:10.1126/science.abd3072

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[Full text] Binding of the SARS-CoV-2 Spike Protein | HMER - Dove Medical Press

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IN8bio announces first-in-human Phase 1 trial Update from The University of Kansas Cancer Center using INB-100, IN8bio’s Gamma Delta T-cell product…

Posted: December 4, 2020 at 11:51 am

NEW YORK, Dec. 03, 2020 (GLOBE NEWSWIRE) -- IN8bio, Inc., a clinical-stage biotechnology company focused on developing innovative allogeneic, autologous and genetically modified gamma-delta T cell therapies for the treatment of cancers (IN8bio or the Company), today announced an upcoming presentation that provides an update of the ongoing Phase I clinical trial of their product candidate INB-100 at the 62nd American Society of Hematology Annual Meeting & Exposition (ASH), which will take place virtually from December 5 to 8, 2020. INB-100 is designed for the treatment of patients with leukemia undergoing hematopoietic stem cell transplantation with haploidentical donors.

The poster and accompanying narrated slide presentation is titled, First-in-Human Phase I Trial of Adoptive Immunotherapy with Ex Vivo Expanded and Activated gamma delta T-Cells Following Haploidentical Bone Marrow Transplantation and Post-BMT Cyclophosphamide and reviews the study design and provides a brief update on enrollment and patient status.

The company reported that, as of abstract submission, three female subjects with acute leukemia had been enrolled in the INB-100 Phase 1 trial, of whom two had been dosed, and that no treatment-related adverse events had been recorded. The trial is continuing to enroll and treat patients. The abstract for the presentation can be found at https://ash.confex.com/ash/2020/webprogram/Paper142876.html.

The poster and slide presentation are jointly authored by the scientific and physician investigators from IN8bio and The University of Kansas Cancer Center (KU Cancer Center), and will be presented by the studys Principal Investigator, Dr. Joseph McGuirk, Schutte-Speas Professor of Hematology-Oncology, Division Director of Hematological Malignancies and Cellular Therapeutics and Medical Director, Blood and Marrow Transplant at KU Cancer Center.

This preliminary data report from KU Cancer Center with our allogeneic product candidate, INB-100, demonstrates the absence of significant GvHD in these initial patients, said William Ho, Chief Executive Officer of IN8bio. This suggests that gamma delta T-cells delivered as an off-the-shelf allogeneic cell therapy may be well tolerated and have significant potential to treat patients with serious and life-threatening cancers.

Dr. McGuirk, commented, Potentially curative stem cell transplants using partially matched donors -- called haploidentical transplants have greatly expanded access to stem cell transplantation. The infusion of donor-derived gamma delta T-cells from the stem cell donor, offers the hope of diminishing this risk of relapse and curing more patients.

About IN8bioIN8bio is a clinical-stage biotechnology company focused on developing novel therapies for the treatment of cancers, including solid tumors, by employing allogeneic, autologous and genetically modified gamma-delta T cells. IN8bios technology incorporates drug-resistant immunotherapy (DRI), which has been shown in preclinical studies to function in combination with therapeutic levels of chemotherapy. IN8bio is currently conducting two investigator-initiated Phase 1 clinical trials for its lead gamma-delta T cell product candidates: INB-200 for the treatment of newly diagnosed glioblastoma, which is a difficult to treat brain tumor that progresses rapidly, and INB-100 for the treatment of patients with acute leukemia undergoing hematopoietic stem cell transplantation. For more information about the Company and its programs, visit http://www.IN8bio.com.

Forward Looking StatementsCertain statements herein concerning the Companys future expectations, plans and prospects, including without limitation, the Companys current expectations regarding the curative potential of its product candidates, constitute forward-looking statements. The use of words such as may, might, will, should, expect, plan, anticipate, believe, estimate, project, intend, future, potential, or continue, the negative of these and other similar expressions are intended to identify such forward looking statements. Such statements, based as they are on the current expectations of management, inherently involve numerous risks and uncertainties, known and unknown, many of which are beyond the Companys control. Consequently, actual future results may differ materially from the anticipated results expressed in such statements. Specific risks which could cause actual results to differ materially from the Companys current expectations include: scientific, regulatory and technical developments; failure to demonstrate safety, tolerability and efficacy; final and quality controlled verification of data and the related analyses; expense and uncertainty of obtaining regulatory approval, including from the U.S. Food and Drug Administration; and the Companys reliance on third parties, including licensors and clinical research organizations. Do not place undue reliance on any forward-looking statements included herein, which speak only as of the date hereof and which the Company is under no obligation to update or revise as a result of any event, circumstances or otherwise, unless required by applicable law.

Contact:IN8bio, Inc.Kate Rochlin, Ph.D.+1 646.933.5605info@IN8bio.com

Investor Contact:Julia Balanova+ 1 646.378.2936jbalanova@soleburytrout.com

Media Contact:Ryo Imai / Robert Flamm, Ph.D.Burns McClellan, Inc.212-213-0006 ext. 315 / 364Rimai@burnsmc.com/rflamm@burnsmc.com

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IN8bio announces first-in-human Phase 1 trial Update from The University of Kansas Cancer Center using INB-100, IN8bio's Gamma Delta T-cell product...

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Incysus Therapeutics Announces Name Change to IN8bio, Inc. – GlobeNewswire

Posted: August 28, 2020 at 8:55 am

NEW YORK, Aug. 24, 2020 (GLOBE NEWSWIRE) -- Incysus Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on delivering innovative gamma-delta () T cell immunotherapies for the treatment of cancer, today announced that it has changed its name to IN8bio, Inc. (IN8bio or the Company). The Companys new name reflects its novel approach to cell therapy, focused on the development of gamma-delta T cells for anti-cancer therapies. These powerful immune cells possess properties of both innate and adaptive immune cells and can serve as a functional bridge between the two systems to impact tumor killing.

IN8bio was founded to develop novel immunotherapies to treat cancer. Our new name, IN8bio, reflects that focus, commented William Ho, President, Chief Executive Officer and co-founder of IN8bio. As we continue to treat patients in our ongoing clinical programs, we are focused on delivering the next generation of innovative cancer therapies.

IN8bio is using autologous, allogeneic and genetically modified gamma-delta T cells to address the high unmet need in both solid and liquid tumors. IN8bio entered the clinic in 2020 with two Phase 1 clinical trials which are currently enrolling patients. In February 2020, IN8bio initiated enrollment in a Phase 1 clinical trial of gamma-delta T cell immunotherapy in leukemia patients undergoing allogeneic stem cell transplantation. That trial, the first clinical trial of an expanded and activated allogeneic gamma-delta T cell immunotherapy, is being conducted with its partners at the University of Kansas Cancer Center. Additionally, in February 2020, IN8bio initiated enrollment in a Phase 1 clinical trial of patients with newly diagnosed glioblastoma, which is a difficult to treat brain tumor that progresses rapidly. This trial is being conducted at the ONeal Comprehensive Cancer Center at the University of Alabama at Birmingham. IN8bios proprietary Drug Resistant Immunotherapy (DRI), which is being used in the glioblastoma trial, is the first genetically engineered gamma-delta T cell therapy to be administered to patients.

About IN8bioIN8bio is focused on delivering novel immunotherapies for the treatment of cancer. By using allogeneic and genetically modified gamma-delta () T cells, IN8bios technology addresses certain challenges that immunotherapies face targeting cold, low mutation cancers. IN8bios immuno-oncology programs include activated and gene-modified adoptive cellular therapies that are designed to protect cells from chemotherapy and may allow novel combinations of drugs to disrupt the tumor microenvironment and increase immunogenicity. IN8bios first clinical program is targeted to address leukemia in patients who are undergoing hematopoietic stem cell transplant (HSCT) and its second program is targeted to the treatment of newly diagnosed glioblastoma in combination with chemotherapy. For more information about the Company and its programs, visit http://www.IN8bio.com.

Forward Looking StatementsCertain statements herein concerning the Companys future expectations, plans and prospects, including without limitation, the Companys current expectations regarding its business strategy, product candidates, and clinical development process and timing, constitute forward-looking statements. The use of words such as may, might, will, should, expect, plan, anticipate, believe, estimate, project, intend, future, potential, or continue, the negative of these and other similar expressions are intended to identify such forward looking statements. Such statements, based as they are on the current expectations of management, inherently involve numerous risks and uncertainties, known and unknown, many of which are beyond the Companys control. Consequently, actual future results may differ materially from the anticipated results expressed in such statements. In the case of forward-looking statements regarding investigational product candidates and continuing further development efforts, specific risks which could cause actual results to differ materially from the Companys current expectations include: scientific, regulatory and technical developments; failure to demonstrate safety, tolerability and efficacy; final and quality controlled verification of data and the related analyses; expense and uncertainty of obtaining regulatory approval, including from the U.S. Food and Drug Administration; and the Companys reliance on third parties, including licensors and clinical research organizations. Do not place undue reliance on any forward-looking statements included herein, which speak only as of the date hereof and which the Company is under no obligation to update or revise as a result of any event, circumstances or otherwise, unless required by applicable law.

Contact:IN8bio, Inc.William Ho, President & CEOwho@IN8bio.com+1 646.600.6GDTinfo@IN8bio.comwww.IN8bio.com

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Incysus Therapeutics Announces Name Change to IN8bio, Inc. - GlobeNewswire

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Seeing through a forest of SCN2A gene variation – SFARI News

Posted: February 20, 2020 at 5:45 am

On August 23, 2019, the FamilieSCN2A Foundation held their biennial SCN2A Professional and Family meeting, in Seattle, Washington. The gathering brought together 37 families of individuals with mutations in the SCN2A gene, 60 investigators, eight clinicians and five industry groups that conduct research and/or clinical work on conditions related to this genetic change. A number of SFARI scientists and staff also attended the event.

The SCN2A family meeting was one of many events that family organizations of rare, neurodevelopmental disorders organized last summer. These meetings help families connect with others similarly affected as well as professionals working to better understand these conditions and develop new therapeutics. SFARI often attends and facilitates research opportunities carried on at these events.

SCN2A is a high-confidence autism risk gene, which encodes a subunit of a sodium channel in the brain called Nav1.2. When the channel malfunctions, conditions like epilepsy and autism follow. As part of its mission to understand the genetics and neurobiological underpinnings of autism, SFARI has awarded about $3 million for research on SCN2A, and some of this research was presented at the meeting. SFARI also supports a genetics first initiative called Simons Searchlight (formerly known as Simons VIP), which enrolls people with a genetic diagnosis showing rare genetic changes associated with autism and related neurodevelopmental conditions, such as SCN2A.

Many stories that may reflect the different ways SCN2A can be disabled were told at the meeting. One child had his first seizure when he was days old, and now spends many of his days irritable and immobilized by dystonia. Another developed normally until his first seizure as a toddler, which seemed to wipe out all of his skills; his milestones are now hard won in the face of continuing seizures and an autism diagnosis. Another had a sudden regression at 1 year of age, and after a misdiagnosis and seizure medication, she goes to a school for children with autism. Still another suffered from relentless seizures, which robbed her of speech; she died last year at the age of 12.

So far, about 300 different variants of the SCN2A gene have beendocumented, and the functional consequences of many are unclear. Some researchers have developed high-throughput experiments to systematically test each of thesevariants, and to screen compounds that could normalize their function2. Another approach may use genetherapy to boostexpression of the remaining good copy of SCN2A. Either way, finding appropriate in vitro testing grounds for these SCN2A variants is essential and may help personalize treatment approaches or identify more homogeneous patient groups for drug trials.

The meeting also underscored the power of family gatherings to push the science ahead. Investigators could see multiple examples of a rare genetic condition and engage new participants in research studies such as The Investigation of Genetic Exome Research (TIGER), a project of the University of Washington that compares phenotypes of single-gene conditions. In turn, families had the opportunity to express their concerns to scientists and infuse the research proceedings with urgency.

My biggest takeaway from this years conference was the mutual inspiration between the scientists and the families, says Leah Schust, meeting organizer and executive director of the FamilieSCN2A Foundation. Her son has a mutation in SCN2A.

Meeting the researchers working on a cure for our kids motivates us to fight on, Schust says. Then the scientists all say that meeting the families inspires them to go back to their labs and work even harder.

Family focus. The family meeting helped researchers reconsider what would be meaningful clinical endpoints for potential treatments. Schust says that most researchers and industry groups had thought seizure control was the most important issue. After listening to us, they realized that quality of life, movement disorders and autonomic dysfunction are higher on our list of where we would like to see improvement, she says.

When SCN2A mutations were first linked to autism, the gene stood out because it encodes a relatively well-understood protein, unlike many of the other identified genes. Nav1.2 is a voltage-gated channel found exclusively on excitatory neurons in the brain, where it controls the flow of sodium ions into the neuron, and thus its propensity for firing action potential. Experiments have revealed detailed pictures of Nav1.2s structure3, and known drugs alter its function4.

SCN2A also stands out because of its high recurrence rate in autism: unlike other autism genes, SCN2A is mutated with somewhat regular frequency5 (Figure 1).

Just as understanding why a car wont start is critical to fixing it, researchers need to understand how these SCN2A mutations alter the Nav1.2 channel. A current model1 posits that some mutations are gain-of-function, rendering the channel too active and the brain hyperexcitable, leading to infantile epilepsy; conversely, loss-of-function mutations reduce excitability and seem associated with autism and/or intellectual disability, as well as childhood-onset (as opposed to neonatal) seizures.

Yet the functional consequences of most SCN2A mutations remain unknown, and some may not fall neatly into a loss-of-function or gain-of-function category. A way of making sense of these mutations may come from looking at the working parts of Nav1.2, said Arthur Campbell of the Broad Institute of MIT and Harvard. For example, missense SCN2A variants linked to epilepsy seem to hit the channel randomly. But when marking their location on a crystal structure model of the channel, the missense variants cluster in several places: on the voltage sensor, on the linker helix responsible for conveying voltage sensor movement to the channel pore, on an area thought to interact with the beta-subunits involved in chaperoning the channel to the right place, and on the inactivation gate, which closes the pore off from sodium ion flow. He suggested that this knowledge, combined with the structural similarities between all sodium channels, may help drug development for SCN2A-related conditions.

High-throughput systems that can assay hundreds of cells at a time are helping researchers systematically explore SCN2A mutation, explained SFARI Investigator Al George of Northwestern University. While conventional electrophysiology would require weeks of work to characterize a single SCN2A variant, Georges group uses an automated patch-clamp system that can characterize multiple variants transfected into non-neuronal cell lines in a day. Using this system, two variants associated with neonatal seizures both exhibited an exceptional willingness to activate and a slowness to inactivate, which are properties consistent with a gain-of-function interpretation.

The high-throughput set up also promises to expedite the hunt for drugs to normalize SCN2A function: George described a 384-well plate design that allows measurement of the effects of two different drugs, at four different concentrations, on the SCN2A variant and control channels simultaneously. A known drug (carbamazepine) and an experimental drug (PRX-330) shifted channel inactivation to more hyperpolarized voltages, which could help quiet channels with gain-of-function mutations.

To narrow in on potentially therapeutic compounds, Jeff Cottrell and colleagues at the Broad Institute of MIT and Harvard have come up with a two-stage screen to find small molecule activators or inhibitors of Nav1.2 channels. First, compounds are initially tested on non-neural cells transfected with Nav1.2 sodium channels and potassium channels, which enables them to spike. The cells in 384-well plates are stimulated in parallel, and voltage-sensitive dyes give a readout of spiking activity; remarkably, Cottrells system allows data collection from up to 96 wells simultaneously. Any compounds that modulate spiking would then be subjected to the second stage, in a high-throughput electrophysiology assay similar to that described by George. Compounds with helpful mechanisms would then be tested for selectivity for Nav1.2 versus other sodium channels. A selective compound would then be tested in neurons, first in vitro then in vivo. This step-wise process has identified an activating compound that makes Nav1.2 more likely to open at rest and has potent effects on action potentials in brain slices and on electroencephalogram (EEG) traces from mice engineered to carry a disabled copy of SCN2A; however, Cottrell said this particular compound is not a therapeutic candidate in part because it broadens the action potential in a way that could promote seizures. A full screen is underway, and so far has identified 378 modulators from a library of 77,000 compounds.

Beyond academia, J.P. Johnson Jr. of Xenon in Burnaby, British Columbia, discussed the companys work to create sodium channel inhibitors for treating epilepsy. To obtain selective compounds, the group targets the voltage-sensing domain because its structure is the most diverse region of sodium channels. Xenon uses a trial-and-error method to optimize sodium channel inhibitor potency and selectivity. The methodical process has yielded some interesting compounds, including both selective Nav1.6 inhibitors and dual Nav1.6 and Nav1.2 inhibitors. Both quashed spiking in mouse excitatory pyramidal neurons, which contain only Nav1.2 and Nav1.6, but they did not alter spiking in Nav1.1-containing inhibitory neurons. A Nav1.6 selective inhibitor, XEN901, is currently undergoing safety trials in humans.

Kathrin Meyer of Nationwide Childrens Hospital in Columbus, Ohio, addressed the possibility of using gene therapy to normalize malfunctioning Nav1.2 channels. Meyer has been involved in several gene-therapy trials for neuromuscular disorders, including a successful one for infant-onset spinal muscular atrophy type6. Gene therapy for brain diseases was spurred by the discovery of adeno-associated virus 9 (AAV9), which can cross the bloodbrain barrier to deliver genetic material to the central nervous system. AAV9 is small, cannot replicate, does not integrate into host DNA and seems not to cause disease in humans. In considering gene therapy for SCN2A-related conditions, Meyer emphasized an approach that adds back a working copy of the gene, thus sidestepping the need for gene editing to make mutation-specific corrections. Such a treatment would only apply to those with loss-of-function mutations.

The large size of the SCN2A gene precludes its delivery by AAV9, however. As a workaround, Meyer suggested that SCN2As mRNA transcript could be targeted in an attempt to replace only the affected area of the mRNA. So far, such strategies have not been very efficient, but there are new ideas that might address some of the difficulties. Because access to tissue samples of patients with neurological disorders is limited, the development and testing of new therapies is complicated. Meyer suggested developing gene therapies in vitro using neurons reprogrammed from skin cells of patients. This might help identify which patients would react best to a certain treatment. There is likely not a one-fit-for-all situation, she said.

SFARI deputy scientific director John Spiro underscored the need for in vitro systems, citing the organizations initiative to bank blood cells to systematically generate induced pluripotent stem cells from individuals with autism. Simons Searchlight is also a resource of many different biospecimens for researchers. So far, 186 families with SCN2A-related changes have registered, and 83 of these have completed consent, lab reports and medical histories with a large number of blood samples as well. (On the sidelines of the meeting, 18 parents, 11 of their children with SCN2A mutations, and three unaffected siblings donated blood toward this initiative.) Spiro also stressed a need to come up with more quantitative methods of phenotyping, such as wearable electronics that can monitor sleep and circadian rhythms. Data that can be collected longitudinally and at home might provide sensitive outcome measures for clinical trials.

A new role for Nav1.2 has been revealed in recent work described by SFARI Investigator Kevin Bender of the University of California, San Francisco: the channels mediate back-propagating action potentials, which travel into the dendritic trees of neurons. Mice engineered to lack one copy of SCN2A a situation that mimics people with truncating SCN2A mutations that render the resulting Nav1.2 channels useless had cortical neurons with slower action potentials, reduced dendritic excitability and immature synapses based on their shape and function7. This role for Nav1.2 was particularly important later in development: when conditional knockout mice lost an SCN2A copy later in life, their cortical neurons exhibited immature synapses, though their density remained normal. Preliminary experiments suggest that adding back a working copy of SCN2A later in life through transgenic methods or by upregulating transcription of the remaining good copy of SCN2A via CRISPR techniques can restore action potential velocity and synaptic maturity.

Bender stressed how interacting with the SCN2A family group helped focus his research on important aspects of their childrens conditions. For example, parents have noted sensory hypersensitivity in their children, leading Bender to collaborate with colleague Evan Feinberg to use an eye-tracking assay in mice to measure their visual responses. He noted that SCN2A haploinsufficient mice were more sensitive to certain visual stimuli than control mice; if the assay is robust, it could help bridge the gap between SCN2A-related phenotypes in humans and behaviors measured in mice.

As meeting attendees sorted through the new findings, therapeutic questions lingered. An important issue for any therapy, whether drug or gene, will be how early in development one will have to intervene to help someone with an SCN2A mutation. Bender noted that synaptic properties could be rescued in his mice when they were 30 days old equivalent to a 10-year-old human but these and other experiments will have to probe the time periods during which therapies will be maximally effective. To find good measures of efficacy also means understanding the full complement of conditions that beset people with SCN2A mutations. For example, though seizures afflict many, Keith Coffman of Childrens Mercy Hospital in Kansas City, Missouri, suggested that, in some cases, these represent a movement disorder rather than epilepsy. Basic descriptive knowledge like this is imperative for guiding future treatment approaches.

Another smaller SCN2A meeting is planned for this year from July 30 to August 2, in Columbus, Ohio. This will be more family focused, says Schust, and there will be opportunities to participate in research.

There is clearly a lot more work to do before all the terrific basic research that was discussed at this meeting produces meaningful results for families, but it is extremely gratifying to see how much progress has been made on so many fronts and how many new good ideas are emerging, Spiro says. And its terrific to witness firsthand the positive cycle of how families drive researchers and vice versa.

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FHSU partners with Be the Match for bone marrow registry event – hays Post

Posted: at 5:45 am

Brynn Niblock, FHSU junior in pre-med from Hoxie, swabs her cheek as part of the sign up for the Be the Match bone marrow registry Feb. 6 at Gross Memorial Coliseum.

By CRISTINA JANNEYHays Post

Usually Tiger basketball games are a time to have fun cheer the home team, eat some popcorn but students and community members at Feb. 6 game took a few minutes to stop and potentially save a life.

FHSU student health sponsored a Be the Match bone marrow registry drive.

Potential donors ages 18 to 44 answered a list of qualifying health questions on their smartphones and then swabbed their cheeks to be matched with a potential cancer sufferer in need of bone marrow transplants.

Kathy Pyke of Hays knows too the well the importance of the registry. Pyke was at Gross Memorial Coliseum the night of the drive as a volunteer handing out information to potential donors.

Her husband, Tom, was diagnosed with leukemia on March 1, 2014. Family members were tested, and they were not matches. Doctors were also unable to find a bone marrow match on the national registry. There were 6.2 million people in the registry at the time.

In lieu of a bone marrow transplant, Pyke was given donated umbilical cord blood.

Initially the treatment improved Pyke's condition. However, he ultimately died as a result of the disease on Feb. 12, 2015 at the age of 62.

Kathy said the family was rocked by Tom's illness. He was playing golf and went fishing the week before he was diagnosed with cancer.

Kathy said she wishes she could be on the registry to help another family, but her age prevents her from doing so.

"Not only for my husband," she said of the importance of the registry. "I did pray there had been a match. We stayed at the Hope Lodge that was run by the American Cancer Society in Kansas City. There were 45 apartments there and everyone there has someone who has cancer plus a caregiver in it. You just see so many lives being touched. ...

"If this is something that can help somebody, it is just an easy thing to do."

Kathy said she had a good friend who had a family member sign up for the registry, and he was able to donate to someone who had cancer in England.

Pyke said she would also like to see more hospitals participate in the cord blood bank, which is what helped her husband. At the time of Tom's illness, HaysMed was not participating in the umbilical cord blood bank.

Michelle Toogood, BSN, RN, supervisor of Hays Meds Women's andInfant Care Center/NICU, said parents wishing to participate in cord blood donation should initiate the process prior to delivery. HaysMed staff will then aid in the collection of the specimen.

"I just can't express how much people need to do this," Pyke said of signing up for the registry. "It is just so easy to swab test and they could potentially save more than one person's life. It is so easy to do and so important."

If you are identified as a match to someone suffering from cancer, you would be contacted through the registry and asked if you are willing to donate,Amanda McCord, RN at the FHSU student health center.

"Finding the perfect match is essential for people who are fighting this type of cancer," McCord said. "The closer the match the better their chances of remission and beating whatever cancer they are fighting."

There are over 70 diseases that can be treated by bone marrow transplants, according to Be the Match.

Physicians will usually look for matches among relatives first, but only 70 percent of the time are matches made from family members, McCord said.

Statistics also indicate minority patients are less likely to find matches than Caucasian patients. Be the Match is trying to boost minority participation as there are fewer minority participants in the registry at this time, McCord said.

Donating bone marrow is a little bit different for every donor, McCord said.

Most give through a Peripheral Blood Stem Cell (PBSC) donation. A machine draws blood from one arm, extracts the cells it needs, and returns the remaining blood through your other arm, according to the Be the Match website.

Others give through a marrow donation. Liquid marrow is withdrawn from the back of your pelvic bone with a needle. In this case, youll receive anesthesia and feel no pain during the procedure, the Be the Match website said.

According to Be the Match,PBSC donors may experience headaches or body aches several days before collection, but these disappear shortly after donation. Most donors feel completely recovered within a few weeks.

If you missed the Be the Match event at FHSU last week, you can contact Be the Match though its website, and the organization will send you the cheek swab kit to sign up for the registry.

The Be the Match website also has information on the donation process and a link to make monetary donations to the Be the Match program.

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Trial cancer treatment in Wichita – KAKE

Posted: December 2, 2019 at 9:43 am

WICHITA, Kan. (KAKE) -

There's a major medical break-through in the world of cancer treatment. No more chemotherapy or radiation; doctors in Wichita are using patients' own blood cells to fight off cancer, and it's working.

62-year-old David Butler's appointments at the Cancer Center of Kansas are coming to an end. It's been two long years for him - in 2017, stomach pain led doctors to discover 13 tumors inside his abdomen. Butler went through months of chemotherapy, then stem cell therapy. But the cancer kept coming back.

The news could have been grim. But not for Butler. The Cancer Center of Kansas is one of just nine facilities in the nation chosen to participate in a study using the patient's own cells to fight off the disease.

It's called Car T-cell Therapy. A patient's own immune cells are harvested, then genetically modified and inserted back into the body. Those t-cells then search out and kill the cancer. And the Car T-cell Therapy can be given as outpatient treatment, with no hospital stay required.

David Butler is now cancer-free, and his doctors are hopeful the t-cells will continue to stave off the disease.

The Cancer Center of Kansas has treated two patients, and so far so good. Once the study is finished, doctors and the drug company will go to the FDA for full approval to use the therapy to treat cancer across the country.

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Infanticide: Live Organ Harvesting Commonplace in US Abortion Mills – Church Militant

Posted: October 17, 2019 at 12:49 am

SAN FRANCISCO (ChurchMilitant.com) - Bombshell testimony from the trial of Center for Medical Progress undercover journalists David Daleiden and Sandra Merritt has revealed that infanticide is commonplace insideU.S. abortion mills.

Earlier this month, attorneys for Daleiden submitted a closing argument brief detailing that live births are occurring inside the facilitiesand that these newborns are routinely killed their organs harvested while still alive.

Describing Daleiden's research into the practice, the brief recounts that hediscovered "a mainstream media expos produced and aired in 2000 by Chris Wallace for the program '20/20.'"

From Wallace's report, Daleiden learned of Dean Alberty, who worked as a fetal tissue procurement technician inside a Planned Parenthood facilityin suburban Kansas City.

According to the brief:

From the "20/20" video he learned that Alberty had been handed whole fetuses from Planned Parenthood doctors and had harvested beating hearts. Alberty had also testified before Congress and described a live birth of twins who were actually cuddling each other. He would not harvest from them and the abortion doctor drowned them in a pan of water.

The practice was not isolated to Kansas City, Daleiden discovered.

In the course of his research, he came across the bookBeyond Abortion: A Chronicle of Fetal Experimentation, which documents experiments performed on unborn babies, as well as the removal of organs from infant abortion survivors.

In Beyond Abortion, Daleiden found an article titled "Artificial Placenta," which described "obtaining live fetuses as old as 24 weeks from unnamed abortionists and keeping them alive in a machine for study but letting them drown in the machine after obtaining data."

In the summer of 2011, he learned of a company named StemExpress, which specializes in providing "biospecimens" to researchers across the country; adeeper look at the firm revealed the scaleof tissue harvestingoccurring inside American abortion mills.

Daleiden discovered that StemExpress required "tissue procurers to service 48 universities and 8 private entities with fetal organs and tissues."

He later uncovered"a StemExpress order form with a list of organs and tissues for sale, including whole hearts, hearts with veins and arteries attached, as well as brains, livers and other organs."

He then found"aStanford study using whole human fetal hearts obtained from StemExpress which they put on a Langendorff perfusion machine."

According to the brief:

Mr. Daleiden learned through his own research and by consulting experts, including Dr. Theresa Deisher, that in order to use the Langendorff machine the heart had to either still be beating when it was placed on the machine or a beating heart had to be arrested in a relaxed state in a potassium solution and then quickly transported to the machine. ... Dr. Deisher testified that she told Mr. Daleiden that the "most horrifying aspect of the use of the remains of aborted fetuses was that some of the babies had to be alive, have beating hearts when they were harvested."

Deisher, a stem cell research scientist,testified that based on her experience with stem cell research on hearts, this was a frequent occurrence. Thebabies' hearts haveto be harvested while still beating, she explained, as otherwise the organ would have no research value because once in "contracture," the heart's cells would no longer be capable of regenerative growth.

The brief detailedadditional evidence of infanticide including testimony by a former StemExpress employee:

Mr. Daleiden continued to gather evidence for his investigation. He met Holly O'Donnell who had worked for StemExpress and told him she left after seeing a late gestated fetus. She was directed to dissect its brain. She did so. She also told him that her superior Jessica tapped the fetuses'heart and it started beating. She also told him of seeing a message stating that an intact fetus was being sent to the StemExpress facility.

Daleiden later learned that "StemExpresstechnicians had to work very closely with the abortion doctors at [Planned Parenthood] MarMonte who increased dilation on thepatients in order to obtain intact fetuses with beating hearts."

California Attorney General Xavier Becerra a self-identified Catholic is prosecuting Daleiden and Merritt for their undercover work. In his preliminary hearing closing argument, he made no effort to rebut testimony about the harvesting of infant abortion survivors' organs.

Instead, Becerra suggested that harvesting organs from newly born infants is protected by the state's abortion statutes.

The "defendants willfully misrepresent the law on homicide in California," he argued. "California law is clear that therapeutic abortion is not homicide."

Pro-life advocates counter that there is nothing "therapeutic" about harvesting beating hearts from live infants.

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Kansas Regenerative Stem Cell Seminar – Stem Cell Centers …

Posted: September 10, 2019 at 7:46 pm

1How much is the seminar?

This is a complimentary seminar. No cost and no obligation. The doctor will be reviewing the latest research on how stem cells are able to help revive and rejuvenate worn, damaged joints and tissues (such as knees, shoulders and hips). Please contact us if you have any questions!

2How much downtime should I expect after regenerative cell therapy?

Typically, there is no little to no downtime from regenerative cellular therapy.

3Is more than one treatment needed?

Not every person is the same. Obviously that possibility exists and thats why we take our patients through our advanced assessment so we can carefully determine if you are one of those special cases. It is important to understand that once a joint regenerates, there would be no need for further treatment unless a new injury occurred or over-time,that joint degenerated again.

4How much does it cost?

Every person is unique and would require a one on one consultation with a provider to see if you are a candidate. The good news is, we've made it a goal to never let price get in the way of your health. If together we find regenerative therapy is right for you, and will improve your quality of life, there are several flexible payment options available.

5What determines the outcome of my regenerative cell therapy?

Various factors will determine the outcome of your Regenerative Cell Therapy treatment, such as the extent of damage, disease and the location being treated. Most people respond well to this therapy option and experience relief from pain in just a short period of time. For instance, this therapy has been known provide full relief to patients after only one treatment.

6How are regenerative cells collected?

Our Regenerative Cell Treatment is a revolutionary breakthrough treatment option for people suffering from inflammation, reduced mobility, sports injuries, tissue and ligament damage, or chronic pain. Regenerative Cell Therapy is an injectable regenerative tissue matrix solution, that oftentimes leaves the patient feeling relief after only ONE treatment. This cutting edge treatment takes the best components from all the current non-invasive treatment options and puts them into one. This Regenerative Cell Treatment is collected from mothers who have donated their placental tissue after delivering a child by c-section birth.

7Is there anything else I can do to increase the effectiveness of my therapy?

Yes! Our treatment plans are comprehensive. Not only will we provide you with the most cutting-edge treatment options, but we will also assist you through rehabilitation. Following the custom program created for your specific needs will thoroughly increase the effectiveness.

8How long does the repair process take?

Generally, the repair process begins immediately and the good news is that it can continue to repair for up to eight additional months from the date of the initial procedure.

9Can the procedure fail?

Like any other procedure, there is no 100% guarantee. In certain cases, it is possible that you may need additional treatments or your stem cells do not have enough repair potential relative to your personal injury.

10If the regenerative cell therapy does not work can I still have surgery?

Yes. There is nothing about these procedures that would preclude you from having traditional surgery. We evaluate each case carefully, however, so if its possible to tell that the best course of action is truly conventional surgery we will advise you on that.

11Will insurance cover it

Unfortunately insurance and Medicare do not cover stem cell therapy (yet). We have made this treatment option extremely affordable because of this.

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