Category Archives: Cell Medicine

Mitochondria are structures within the cell that convert energy from food into energy the cell can use. Each cell contains hundreds to thousands of mitochondria. Although most DNA is found inside the cells nucleus, mitochondria also contain a small amount of DNA, known as mitochondrial DNA.

In the early 2000s, researchers realized that short sections of mitochondrial DNA encode small (less than 100 amino acids long), biologically active proteins, now referred to as mitochondrial microproteins. The first mitochondrial microprotein to be discovered was called humanin.

There is growing evidence that humanin and other similar mitochondrial microproteins play a role in several age-related conditions, including Alzheimers disease.

Alzheimers disease is the most common type of dementia, characterized by progressive mental deterioration. According to the CDC, as many as 5.8 million Americans were living with Alzheimers disease in 2020.

The Cohen Laboratory at the University of Southern California (USC), one of the three laboratories that independently discovered humanin in 2003, has discovered a new microprotein connected to the risk of Alzheimers disease.

Their latest research, published in the journal of Molecular Psychiatry, revealed that a mutation in the newly discovered SHMOOSE microprotein is associated with a higher risk for Alzheimers disease across four cohorts. According to the researchers, nearly 1 in 4 individuals with European ancestry have the mutated version of the protein.

Dr. Pinchas Cohen, professor of gerontology, medicine, and biological sciences and senior author of the study, told Medical News Today:

The implications are not immediate, but we believe that [relatively soon], the SHMOOSE SNP [single nucleotide polymorphism] genetic variant that is found in over 20% of Europeans may guide both the classification of individuals that are at risk for Alzheimers that may benefit from certain preventive measures and also could inform the selection of medical interventions that will become available in the near future. A bit further ahead, SHMOOSE [protein] analogues may become available as therapeutics for individuals who carry the SNP and develop dementia, in a precision medicine approach.

Brendan Miller, Ph.D., first author of the study, studied mitochondrial DNA sequences from the Alzheimers Disease Neuroimaging Initiative (ADNI) database, searching for small variations in the genes called single nucleotide polymorphisms or SNPs. He found that a mutation in one particular mitochondrial SNP (rs2853499) was associated with a greater risk of Alzheimers disease and brain atrophy.

Dr. Miller and his colleagues then discovered that the mutated SNP causes a change in a mitochondrial microprotein, which they called SHMOOSE. The researchers used a technique called immunoprecipitation to isolate the SHMOOSE microprotein from the mitochondria of nerve cells.

When they analyzed this sample using mass spectrometry, they detected and identified two unique protein fragments from the SHMOOSE microprotein. The researchers reported that this is the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date.

Having identified a microprotein associated with a higher risk of Alzheimers disease, the researchers followed up on their discovery by carrying out studies in rats and cell culture experiments.

They found that the SHMOOSE microprotein accumulates in the mitochondria of neurons (nerve cells), where it binds to the inner mitochondrial membrane protein mitofilin. The SHMOOSE microprotein appears to act on the brain by influencing mitochondrial gene expression and boosting mitochondrial oxygen consumption. The researchers noted that mutated SHMOOSE microprotein was less effective at boosting oxygen consumption and impacted gene expression differently.

Dysregulated mitochondrial associated brain energetics is one of the multiple pathways thought to be important for Alzheimers disease, Andrew Saykin, PsyD, ABCN, Professor and Director of the Center for Neuroimaging and Indiana Alzheimers Disease Research Center, told MNT.

George Perry, Ph.D., Professor and Semmes Foundation Distinguished University Chair in Neurobiology at the University of Texas at San Antonio, told MNT that this study is very important as it links risk of [Alzheimers disease] to cellular metabolism. There are numerous cell biology and biochemical studies that highlight this [] and finding genetic data further support[s] this view.

Dr. Saykin observed that with further development and validation there could be implications of this and other microproteins for early detection, longitudinal monitoring, and potentially for therapeutic targeting.

MNT also discussed the studys findings with Tal Nuriel, Ph.D., Assistant Professor of Pathology and Cell Biology at Columbia University Irving Medical Center. Dr. Nuriel told MNT that most Alzheimers disease-related gene mutations discovered in the past are either very rare variants or common variants that confer a very small risk.

He said the mutation, or variant, in the SHMOOSE microprotein appears to confer a moderate risk for Alzheimers disease and is relatively common in the population and [this] alone makes it interesting.

Dr. Nuriel added that the fact that this is a microprotein that can theoretically be administered as a therapeutic agent is valuable. He cautioned that there will be a very long road ahead before any therapy derived from this microprotein could become a reality. Importantly, its unclear whether this SHMOOSE microprotein would enter the brain if given subcutaneously or intravenously. And if it doesnt enter the brain, this would greatly limit its ability to be used therapeutically.

When asked about the next step in the research following this discovery, Dr. Cohen told MNT, Our immediate plan is to treat mice that have been engineered to develop Alzheimers disease with SHMOOSE over several months and assess the improvement in their symptoms and performance. We will also work on developing longer acting analogues of the pep[t]ide.

The researchers noted in the study that SHMOOSE is yet another microprotein of a growing number that modify mitochondrial biology. According to a recent review, thousands of DNA sequences with microprotein-coding potential are currently unverified or functionally uncharacterized.

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Alzheimer's disease risk linked to newly discovered protein mutation - Medical News Today

Weill Cornell Medicine investigators have identified definitive biological links between African ancestry and disease processes that affect an aggressive cancer type called triple-negative breast cancer (TNBC). Their analysis of TNBC tumors from a diverse patient population yielded a large set of genes whose expression differed in patients with African ancestry compared with patients with European ancestry.

In the study, published Sept. 19 in Cancer Discovery, a journal of the American Association for Cancer Research, the scientists identify the expression of 613 genes associated with African ancestry and more than 2,000 genes associated with regional African ancestry in patients with TNBC. They also describe distinct patterns of immune responses in patients of African descent that may explain patterns of disease progression and outcomes. Together, these findings provide a foundation for future research into better treatment options for this cancer, which has the worst survival outcomes of all breast cancer types.

Many people are not aware of the geographic origins of their ancestors nor how much of their DNA was inherited from each source, known as genetic ancestry. Previous studies of racial differences in TNBC analyzed data from African American patients and relied on self-reported race, said senior author Dr. Melissa B. Davis, associate professor of cell and developmental biology research in surgery and director of health equity in the Englander Institute for Precision Medicine at Weill Cornell Medicine. Our study is the first to determine each individuals ancestry not only by African descent but also by specific regions within Africa.

TNBC tumor cells have no estrogen or progesterone receptors and scant amounts of HER2/neu protein on their surface, making them challenging to treat as they dont respond to hormone therapies or anti-HER2 drugs that block cell proliferation. The subtype represents about 33 percent of breast cancer diagnoses in African countries compared with less than 20 percent in other nations. African American women have twice the risk of developing TNBC and a higher risk of mortality than white Americans of European ancestry.

For their current study, the investigators performed ancestry estimation on breast tissue samples from 132 patients and RNA sequencing on a subset of 26 cases provided by the Englander Institute of Precision Medicine at Weill Cornell Medicine; the University of Alabama at Birmingham; and The International Center for the Study of Breast Cancer Subtypes (ICSBCS), now headquartered at Weill Cornell Medicine. The ICSBCS was established in 2004 and features partners across different regions of Africa as well as the Caribbean and Central America. This study drew samples from ICSBCS founding member The Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana, as well as the Millennium Medical College St. Pauls Hospital in Addis Ababa, Ethiopia.

After identifying the expression of genes associated with African ancestry at the country and regional levels, the researchers examined the affected biological pathways and estimated proportions of immune cells in tumors. They discovered that women with TNBC with a high degree of African ancestry, primarily East Africans from Ethiopia, had significantly higher immune cell populations infiltrating tumors, than women with a lower degree of African ancestry who were mainly African Americans and West Africans from Ghana. Increased immune responses in TNBC tumors in women of regional African descent will be particularly interesting to researchers studying the benefits of immunotherapies, said lead author Dr. Rachel Martini, a postdoctoral associate in surgery at Weill Cornell Medicine.

This recent discovery gives us hope that we will continue to find answers and contribute to solutions for a disease which has long afflicted all ancestries, but shows greater burden in Africa, said Dr. Ernest Adjei, consulting pathologist at KATH. The ICSBCS provides a great platform for strong research collaborations into the future as we work together for improved outcomes in breast cancer management.

The investigators also found that several African ancestry-associated genes detected in normal breast tissue switched expressions in tumor tissue. These findings suggest that some ancestry-specific differences in gene expression may be in response to malignancies, said Dr. Martini.

Finally, the researchers examined the data by self-reported race and found some of the same pathways they had associated with ancestry. However, they also found others imprinted on tumors relating to diabetes and obesity that were not associated with ancestry. This finding suggests its essential to look at both race and ancestry when exploring disparities in TNBC development and outcomes, said Dr. Davis, who is an ethnicity scholar at the New York Genome Center and also serves as scientific director of ICSBCS. For example, we could potentially harness aspects of the diabetes or obesity pathways in tumors as targets to treat cancer patients with comorbidities.

The teams most recent findings add to a robust legacy of studies utilizing the ICSBCS biorepository that are clarifying the role of genetic ancestry related to breast cancer risk, added co-author Dr. Lisa Newman, chief of the Section of Breast Surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, professor of surgery at Weill Cornell Medicine and ICSBCS medical director and founder.

The investigators are now looking more deeply at gene expression differences to determine the master regulators of the pathways they identified and performing single cell analysis to learn more about the tumor microenvironment. We want to get to the bottom of the molecular features driving disparities in TNBC before we move our work into the clinical space, Dr. Davis said.

Excerpt from:
Biological Links Identified Between an Aggressive Breast Cancer Type and African Ancestry - Weill Cornell Medicine Newsroom

Researchers have emphasised nanotechnology as an outstanding technological trend in the last few decades, and it is characterized by the fast proliferation of electronics for applications in communication, known as nanomedicine, and environmental monitoring. Studies are now being conducted on the scientific bottlenecks that affect the lifespan of the living, particularly humans. Among these constraints are illnesses with few or no alternatives for treatment and healing. A drug delivery system (DDS) refers to an alternative diagnosis and/or therapy that has been shown in the medical fraternity [1,2]. Nanorobots are nanoelectromechanical systems (NEMS), a recently developed chapter in miniaturisation, similar to microelectromechanical systems (MEMS), which is already a multibillion-dollar business. Designing, architecting, producing, programming, and implementing such biomedical nanotechnology are all part of nanorobotics and NEMS research. Any scale of robotics includes calculations, commands, actuation and propulsion, power, data-sharing, interface, programming, and coordination. There is heavy stress on actuation, which is a key prerequisite for robotics [1]. The similarity in size of nanorobots to that of organic human cells and organelles brings up a huge variety of its possible uses in the field of health care and environmental monitoring of microorganisms. Other potential uses, such as cell healing, may be possible if nanorobots are tiny enough to reach the cells. Furthermore, it is still to be realised that the tiny sensors and actuators' square measures are necessary for the growing concept of a strongly connected ascending information technology infrastructure; the envision of artificial cells (nanorobots) that patrol the cardiovascular system, thus, detecting and destroying infections in minute quantities. This might be a programmable system with approachable ramifications in medicine, creating a revolutionary replacement from therapy to bar [1]. Chemotherapeutic substances employed in cancer treatment measure disseminates non-specifically throughout the body, where they exert an influence on both malignant and normal cells, restricting the drug quantity feasible within the growth and also resulting in unsatisfactory medication due to excessive toxic hazards of the chemotherapy drugs on normal cells of the body. It is safe to say that molecularly focused medical care has evolved as a collaborative method to overcome the lack of specificity of traditional cancer therapy drugs [3]. With the help of nanotechnology, intercellular aggregation of the drugs in cancer cells can be increased while minimising the risk of unwanted drug toxicity in normal cells by utilising various drug targeting mechanisms [4].

This review article focuses on the recent advancements, technological growth, and expansion in the field of nanorobotics and nanotechnology and its application in the discipline of bio-healthcare systems, principally for the DDS in the medication of cancer. Existing research literature and relevant studies regarding the topic of concern were read and a detailed analysis was undertaken in the indexes of PubMed, Science Direct, MEDLINE, Scopus, and Google Scholar. Hardly any language or time constraints were applied. To obtain a detailed search, more articles, synonyms, and derivatives of the phrases were employed; the following evaluation phrases were used: "drug delivery", "cancer", "neoplasms", and "cancer therapy".

Nanorobots are miniaturised machines that have the ability to perform work at par with that of current existing machines, having applications in the aspects of medicine, industry, and other areas like the development of nanomotors employed for the conservation of energy; nanorobots havealso proved to be serviceable inreducing infertility problems by acting as an engine and giving a boost to the sperm motility when attached to them [2]. Organic and inorganic nanorobots are by far the most commonly studied. Organic nanorobots, also known as bio-nanorobots, are created by combining virus and bacterium DNA cells. This type of nanorobot is less harmful to the organism. Diamond structures, synthetic proteins, and other materials are used to make inorganic nanobots, which are more hazardous than organic nanobots. To overcome this hurdle of toxicity, researchers have devised a way involving encapsulating the robot, thusdecreasing its chances of being destructed by the body's self-defence mechanism[5,6]. Scientists can gain an understanding of how to energise micro and nano-sized devices using reactionary processes if they understand the biological motors of live cells [7]. The Chemistry Institute of the Federal Fluminense University created a nano valve, which is made up of a tank covered with a shutter in which dye molecules are housed and may leave in auniform fashion whenever the cover is opened. This gadget is also natural, made of silica (SiO2), beta-cyclodextrins, and organo-metallic molecules, and shall be used in therapeutic applications [1]. Proteins are employed in certain studies to feed nanomotors that can move huge objects, as well as the use of DNA hybridisation and antibody protein in the development of nanorobots. DNA hybridisation is defined as a process by which two complementary single-stranded DNA and/or RNA molecules bond together to form a double-stranded molecule.A nanorobot can be functionalized using a variety of chemical compounds [8]. It has been investigated in nanomedicine in DDS, which operates directly on targeted cells of the human body. Researchers create devices that can administer medications to precise places while simultaneously adjusting the dose and amount of release. This DDS using nanorobots can be used to treat joint disorders, dental problems, diabetes, cancer, hepatitis and other conditions [2,9-12]. One of the benefits of this technology is the potential to diagnose and treat illnesses with minimal impact on normal tissues, minimizing the likelihood of negative effects and guiding healing and remodelling therapy at the cellular and sub-cellular levels [13,14].

New advances in medication delivery have resulted in greater quality in targeted drug delivery that uses nanosensors to detect particular cells and regulate discharges through the use of smart medicines [1]. Traditional chemotherapeutic drugs act by eliminating swiftly replicating cells, which is a primary feature of malignant cells. Most anticancer medications have a limited therapeutic boundary, often resulting in cytotoxicity to normal stem cells that proliferate quickly, such as bone marrow, macrophages, gastrointestinal tract (GIT), and hair follicles, causing adverse effects like myelosuppression (lower synthesis of WBCs, producing immunosuppression), mucositis (inflammation of the GIT lining), alopecia (hair loss), organ malfunction, thrombocytopenia/anaemia, and haematological side effects, among other things. Doxorubicin is used to treat numerous forms of cancer, including Hodgkin's disease, when it is combined with other antineoplastic medicines to minimize its toxicity [15,16]. Paclitaxel is a drug that is injected intravenously and is used to treat breast cancer. Some of the significant side effects include bone marrow suppression and progressive neurotoxicity. Cisplatin is an alkylating drug that results in the intra-DNA binding filament. Its negative effects include giddiness and severe vomiting, and it can be nephrotoxic [1]. Camptothecin is applied to treat neoplasiaby inhibiting type 1 topoisomerases, an enzyme required for cellular duplication of genetic information. Numerous initiatives have been launched with the goal of employing nanotechnology to build DDS that can reduce the negative impacts of traditional therapy. On the surface of single-walled carbon nanotubes (SWNTs), doxorubicin was layered [17]. Doxorubicin was used in metastatic tumour cells as a polymer prodrug/collagen hybrid. The use of polymeric pro-drug nanotechnology in the therapy of rapidly dividing abnormal cells is a novel advance in the field [18]. Nanotechnology is continually looking for biocompatible materials that may be used as a DDS. The nanoparticle hydroxyapatite (HA), a significant component of bone and teeth, was employed to deliver paclitaxel, an anti-neoplastic medication, and the out-turn implies that therapy should begin with hydrophobic medicines [19]. Various initiatives have been launched with the goal of employing nanotechnology to build DDS, which can reduce the negative influence of traditional chemotherapy. The limitation of conservative chemotherapeutics is that it is unable to target malignant cells exclusively. These above-listed adverse effects often result in a delay in treatment, reduced drug dose or intermittent stopping of the therapy [20]. Given the ability of nanorobots to travel as blood-borne devices, they can aid in crucial therapy procedures such as early diagnostics and smart medication administration [21]. A nanorobot can aid with smart chemotherapy for medication administration and give an efficient early dissolution of cancer by targeting only the neoplastic-specific cells and tissues and preventing the surrounding healthy cells from the toxicity of the chemotherapy drugs so being used. Nanorobots as drug transporter for timely dose administration allow chemical compounds to be kept in the bloodstream for as long as essential, giving expected pharmacokinetic characteristics for chemotherapy in the therapies for anti-cancer as shown in Figure 1 [22-25]. The clinical use of nanorobots for diagnostic, therapy, and surgery can be accomplished by injecting them via an intravenous route. The nanorobots may be getting intravenously injected into the body of the recipient. The chemotherapy pharmacokinetics comprises uptake, metabolism, and excretion, as well as a rest period to allow the body to re-establish itself ahead of the succeeding chemotherapy session. For tiny tumours, patients are often treated in two-week cycles [26]. As a primary time threshold for medical purposes, nanorobots can be used to assess and diagnose the tumour within a short span of time using proteomic-based sensors. The magnetic resonance contrast-agent uptake kinetics of a very small molecular weight can forecast the transport of protein medicines to solid tumours [27]. Testing and diagnostics are critical components of nanorobotics study. It provides speedy testing diagnosis at the initial visit, eliminating the need for a follow-up appointment following the lab result, and illness identification at an earlier stage. The demand for energy for propulsion is a restriction in the usage of nanorobots in vivo. Because small inertia and strong viscous forces are associated with less productivity and less convective motion, higher quantities of energy are required [28]. Drug retention in the tumour will decide the medication's effectiveness after nanorobots pass cellular membranes for targeted administration. Depending on its structure, medication transport pathways from plasma to tissue impact chemotherapy to achieve more effective tumour chemotherapy [27]. According to the latest research, nanotechnology, DNA production of molecular-scale devices with superior control over shape, and site-specific functionalisation assures interesting benefits in the advancement of nanomedicine. However, biological milieu uncertainty and innate immune activation continue to be barriers to in vivo deployment. Thus, the primary benefit of nanorobots for cancer medicine administration is that they reduce chemotherapeutic side effects. The nanorobot design integrates carbon nanotubes and DNA, which are current contenders for the latest types of nanoelectronics, as the optimum method [29]. As a compound bio-sensor with sole-chain antigen-binding proteins, a complementary metal oxide semiconductor (CMOS) is used for building circuits with characteristic sizes in tens of nanometres [30]. For medicament release, this approach employs stimulation elicited upon proteomics and bioelectronics signals. As a result, nanoactuators are engaged to adjust medication delivery whenever the nanorobot detects predetermined modifications in protein gradients [1,31]. Thermal and chemical signal changes are relevant circumstances directly connected to significant medical target identification. Nitric oxide synthase (NOS), E-cadherin, and B cell lymphoma-2 (Bcl-2) are some instances of fluctuating protein aggregation within the body near a medical target under diseased conditions. Furthermore, temperature changes are common in tissues with inflammation [32]. The framework integrates chemical and thermal characteristics as the most essential clinical and therapeutic recommendations for nanorobot template analysis. It also integrates chemical and thermal characteristics as the most essential diagnostic and therapeutic recommendations for nanorobot framework evaluation. The simulation in a three-dimensional real-time setting attempts to provide a viable model for nanorobot foraging within the body. One of the breakthroughs describes a hardware structure rooted in nano-bioelectronics for the use of nanorobots in neoplasia therapy [33,34]. The continuous venture in building medical micro-robots has led to the initial conceptual framework research of a full medical nanorobot until now issued in a peer-reviewed publication, "Respirocytes", detailed a theoretical unnatural mechanical red blood cell, or "Respiro-cytes", consisting of 18 billion perfectly ordered architectural atoms proficient in delivering 236 times extra oxygen to the tissues and cells of the body per unit volume than normal red blood cells [35]. Microbivores, or unnatural phagocytes, might monitor the circulation, searching for and eliminating pathogens such as bacteria, viruses, or fungi. These nanobots may use up to 200 pW continuously. This capability is employed to break down germs that have been entrapped. Microbivores have biological phagocytic defences that are either organic or antibiotic-assisted, and they can operate up to 1,000 times quicker. Even the most serious septicaemic diseases will be eliminated by microbivores within a short span of time. Because virulent microorganisms are entirely digested into harmless sugars and amino acids, which are the nanorobots sole discharge, the nanorobots reject the advanced possibility of sepsis or septic shock [36,37].

To bring in combination the required collaborative skills to produce these unique technologies, numerous conventional streams of science, such as medicine, chemistry, physics, materials science, and biology, have come together to form the expanding field of nanotechnology. Nanotechnology has a vast span of possible applications (Figure 2) [39],from improvements to current practices to the creation of entirely new tools and skills. The last few years have observed an exponential increase of interest in the topic of nanotechnology and research, which has led to the identification of novel applications for nanotechnology in medicine and the emergence of an advanced branch called nanomedicine. It includes the science and technology of diagnosing, treating, andpreventing illness, traumatic injury, and alleviating pain; conserving and enhancing human health using nanoscale architectured materials, biotechnology, and genetic engineering; eventually, complex machine systems and nanorobots, known as "nanomedicine" (Figure 3) [40,41].

In vivo diagnostics, nanomedicine might create technologies that can act within the human body to diagnose ailments earlier and identify and measure toxic chemicalsand tumour cells. In the surgical aspect,when launched into the body through the intravenous route or cavities, a surgical nanorobot controlled or led by a human surgeon might work as a semi-autonomous on-site surgeon. An inbuilt computer might manage the device's operations, such as looking for disease and identifying and fixing injury by nanomanipulation while maintaining communication with the supervising surgeon via coded ultrasonic signals [37]. By transforming mechanical energy from bodily movement, muscle stretching, or water flow into electricity, scientists were able to design a new generation of self-sustained implanted medical devices, sensors, and portable gadgets [39]. Nanogenerators generate electricity by bending and then releasing piezoelectric and semiconducting zinc oxide nanowires. Nanowires may be produced on polymer-based films, and the utilization of flexible polymer substrates may one day allow portable gadgets to be powered by their users' movement [39]. Fluorescent biological labelling, medication and gene delivery, pathogen identification, protein sensing, DNAstructure probing, tissue engineering, tumour identification, separation and purification of biological molecules and cells, MRI contrast enhancement, and phagokinetic research are among the uses. The extended duration effect of nanomedicine study is to describe quantitative molecular-scale components called nanomachinery. Accurate command and manipulation of nanomachinery in cells can lead to a more diverse and advanced gain in the interpretation of cellular processes in organic cells, as well as the creation of new technologies for disease detection and medication. The advantage of this research is the formation of a platform technology that will affect nanoscale imaging methodologies aimed to investigate molecular pathways in organic cells [40,42].

The main target of writing this review was to provide an outline of the technological development of nanotechnology in medicine by making a nanorobot and introducing it in the medication of cancer as a new mode of drug delivery. Cancer is described as a collection of diseases characterised by the unregulated development and spread of malignant cells in the body, and the number of people diagnosed every year keeps adding up. Cancer treatment is most likely the driving force behind the creation of nanorobotics; it can be auspiciously treated using existing medical technology and therapeutic instruments, with the major help of nanorobotics. To decide the prognosis and chances of survival in a cancer patient, consider the following factors: better prognosis can be achieved if the evolution of the disease is time-dependent and a timely diagnosis is made. Another important aspect is to reduce the side effects of chemotherapy on the patients by forming efficient targeted drug delivery systems. Programmable nanorobotic devices working at the cellular and molecular level would help doctors to carry out precise treatment. In addition to resolving gross cellular insults caused by non-reversible mechanisms or to the biological tissues stored cryogenically, mechanically reversing the process of atherosclerosis, enhancing the immune system, replacing or re-writing the DNA sequences in cells at will, improving total respiratory capacity, and achieving near-instant homeostasis, medically these nanorobots have been put forward for use in various branches of dentistry, research in pharmaceuticals, and aid and abet clinical diagnosis. When nanomechanics becomes obtainable, the ideal goal of physicians, medical personnel, and every healer throughout known records would be realized. Microscale robots with programmable and controllable nanoscale components produced with nanometre accuracy would enable medical physicians to perform at the cellular and molecular levels to heal and carry out rehabilitating surgeries. Nanomedical doctors of the 21st century will continue to make effective use of the body's inherent therapeutic capacities and homeostatic systems, since, all else being equal, treatments that intervene the least are the best.

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The Use of Nanorobotics in the Treatment Therapy of Cancer and Its Future Aspects: A Review - Cureus

MADISON, Wis. Kidney transplant patients like Tessa Adolph, from Rockford, Illinois, face an age-old problem to protect their new kidney and bodies after transplant surgery: how to prevent infections while also safeguarding their new kidney from damage or rejection.

In Adolphs case, the risk came from the BK virus.

At 19, she was diagnosed with Henoch-Schnlein purpura, a rare condition that causes small blood vessels in the body organs, including kidneys, to become inflamed and bleed. This transitioned into a condition called IgA nephropathy, or Bergers disease, that over time can cause kidney scarring and eventual kidney failure, she said.

People with IgA nephropathy produce too much of an antibody that the body uses to protect itself from disease-causing pathogens. In most cases, the condition develops over decades, but Adolphs condition was extremely aggressive and after two years her kidney function was down to about 7%. She had to undergo kidney dialysis for seven months while she waited for a kidney transplant.

We tried many things to treat it, even chemotherapy and I lost all my hair, but in the end, I needed a transplant, she said.

Her mom donated a kidney and through a process called paired kidney exchange, Adolph was able to get a new kidney. Then, a new problem arose, or more precisely, reawakened the BK virus.

The BK virus causes symptoms similar to a common cold, and most people are infected with this virus at a young age. The human immune system typically fights it off, but the virus continues to linger quietly in the body. The immune system usually keeps it in check, but during transplantation, medications are used to suppress the activity of the immune system to keep the body from rejecting the transplanted kidney.

While immunosuppression is necessary to protect the new organ, it comes with a tradeoff: dormant viruses like BK can start to proliferate, according to Dr. Sandesh Parajuli, transplant physician, UW Health, and associate professor of medicine, UW School of Medicine and Public Health.

We walk this balance between preventing infection and causing damage to the kidney or outright rejection, he said. But there just havent been many good options for treating BK reinfection.

Traditionally, no antiviral drugs have been effective for fighting BK reinfection, and some are even harmful to new kidneys, without much benefit, so Parajuli felt there had to be a better option, he said.

One solution was made possible by the Program for Advanced Cell Therapy, or PACT, at UW Health and the UW School of Medicine and Public Health. The program conducts clinical trials examiningcytomegalovirus reinfectionin bone marrow transplant patients and other cell therapy trials. Parajuli thought a similar path could be tried with BK.

Earlier this year, he collaborated with PACT to launch a first-of-its-kind phase 1 trial using T-cells a type of immune system cell donated from a close relative of Adolph to treat the infection. T-cells used for this procedure are collected from donor blood, and those that target BK specifically are purified for transfusion at PACTs manufacturing laboratory at University Hospital.

It takes six hours to prepare the T-cells. Once they are ready, they are infused into the patient to treat the infection.

Adolphs care team had struggled to contain her BK infection despite multiple treatments, and she eventually had to go back on antiviral drugs, she said. So, in March, Adolph decided to become the first person to enroll in the trial, using cells donated by her father.

I was like, yeah, Im down, she said. At that point, I was just tired of dealing with these things.

Like other PACT cell therapies, a significant advantage of these approaches is a very low risk of side effects other than possible injection site irritation because the treatments use the bodys own immune system to fight off the virus, according to Parajuli.

During the five-minute injection, Adolph felt a little dizzy, but experienced no lasting side effects, she said.

The goal of a phase 1 trial is to determine what dose is safe for patients to take. Establishing how well a drug or device works comes in later trial phases, Parajuli said.

In Adolphs case, the drug had an initial impact but did not effectively fight off the BK infection. However, phase 1 data are critical for future studies, and she is still glad she participated, Adolph said.

Im hoping my participation helps someone else down the road, she said.

Parajuli hopes to enroll 20 patients. Given the hundreds of kidney transplant patients UW Health cares for in a year, there will be no short supply of potential participants, he said.

The trial is free for participants, however, the cost of undertaking the trial is significant, he said.

These are incredibly expensive trials, and we are looking for assistance in the form of private donations, biotech industry support and the like, but the potential of this treatment will keep us working to make this a reality, Parajuli said. Kidney transplant patients deserve to have another option to treat BK reinfection.

A recorded interview with Parajuli is available, and he and Adolph are available for a limited number of interviews today.

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UW Health, UW-Madison School of Medicine and Public Health: Innovative clinical trial targets recurrent BK infection in kidney transplant recipients -...

Abhinav Achreja, PhD, Research Fellow at the University of Michigan Biomedical Engineering and Deepak Nagrath, Ph.D. Associate Professor of Biomedical Engineering work on ovarian cancer cell research in the bio-engineering lab at the North Campus Research Center (NCRC). Image credit: Marcin Szczepanski, Michigan Engineering

The way that tumor cells enable their uncontrolled growth is also a weakness that can be harnessed to treat cancer, researchers at the University of Michigan and Indiana University have shown.

Their machine-learning algorithm can identify backup genes that only tumor cells are using so that drugs can target cancer precisely.

Most cancer drugs affect normal tissues and cells. However, our strategy allows specific targeting of cancer cells.

The team demonstrated this new precision medicine approach treating ovarian cancer in mice. Moreover, the cellular behavior that exposes these vulnerabilities is common across most forms of cancer, meaning the algorithms could provide better treatment plans for a host of malignancies.

This could revolutionize the precision medicine field because the drug targeting will only affect and kill cancer cells and spare the normal cells, said Deepak Nagrath, a U-M associate professor of biomedical engineering and senior author of the study in Nature Metabolism. Most cancer drugs affect normal tissues and cells. However, our strategy allows specific targeting of cancer cells.

This approach is known as collateral lethalityusing information gleaned from genes that cancer cells discard to find weaknesses. The human body comes with many mechanisms designed to protect against cancer. Cancer cells themselves used to contain suppressor genes that prevent their spread. Those cells however, have a clever strategy for dealing with that; they simply delete a portion of their DNAthe part that includes those suppressor genes.

In doing so, the cells typically lose other genes that are necessary for survival. To avoid death, the cells find a paraloga gene that can serve a similar function. Usually there are one or, possibly, two genes that can step in and perform the same function to keep the cell alive.

What if you could identify the right paralog and target it in a way that shuts down its vital function for the cell?

When a direct replacement for the deleted metabolic gene is not available, our algorithms use a mathematical model of the cancer cells metabolism to predict the paralogous metabolic pathway they might use, said Abhinav Achreja, a U-M research fellow in biomedical engineering and lead author on the research paper. These metabolic pathways are important to the cancer cells and can be targeted selectively.

Study abstract: Metabolic collateral lethal target identification reveals MTHFD2 paralog dependency in ovarian cancer (DOI: 10.1038/s42255-022-00636-3)

Attacking metabolic pathways essentially shuts down the cells energy source. In examining ovarian cancer cells, U-Ms team zeroed in on one gene, UQCR11, that was often deleted along with a suppressor gene. UQCR11 plays a vital role in cell respirationhow cells break down glucose for energy in order to survive.

Disturbances in this process can lead to a major imbalance of an important metabolite, NAD+, in the mitochondria, where respiration takes place. Despite all odds, ovarian cancer cells continue to thrive by relying on their backup plan.

U-Ms algorithm correctly sorted through multiple options and successfully predicted a cell missing UQCR11 would turn to the gene MTHFD2 as its backup supplier of NAD+.

Researchers at the Indiana University School of Medicine helped validate the findings in the lab. This team, led by professor of medicine Xiongbin Lu, developed genetically modified cell and animal models of ovarian cancers with the deletions. Six out of six mice tested showed complete cancer remission.

This research was supported by funding from the National Cancer Institute, Office of the Director for the National Institutes of Health, University of Michigan Precision Health Scholars Award, and Forbes Scholar Award from Forbes Institute of Cancer Discovery.

Continued here:
Shutting down backup genes leads to cancer remission in mice - University of Michigan News

Read the Full Video Transcript

Pedro Barata: Hello and welcome. My name is Pedro Barata. I'm a GU medical oncologist and an associate professor of medicine at Tulane Medical School in New Orleans, Louisiana. It's my true pleasure to be joined today by Dr. Laurence Albiges. She's really well-known and a star in the kidney clinical arena. She's an MD/PhD medical oncologist, and currently the head of the Medical Oncology Department at Gustave Roussy in Villejuif, France. So welcome, Dr. Albiges. Thank you so much for taking the time to be with us today.

Laurence Albiges: Thank you, Pedro. Thank you for the invitation.

Pedro Barata: Absolutely. By the way, I start by congratulating you for your fantastic talk and presentation of a very important study, your phase 2 Keynote-B61 that basically explore the combination of lenvatinib with pembrolizumab as first-line treatment for patients with non-clear cell renal cell carcinoma. So again, very elegant presentation, and I was hoping we could talk a little bit about that today if that's okay with you.

Laurence Albiges: Sure. That will be my pleasure. So actually, this is a phase 2 in an area that is clearly an unmet need. Namely, what we call non-clear cell renal cell carcinoma that should not be named as such because these are different entities that are usually having a worse prognosis than clear cell, and that are really challenging to treat. And so what we've been reporting this time, and it's the first time we're presenting the data, is a phase 2, a non-randomized phase 2, that enroll patient with non-clear cell histology that never been previously treated and that were treated with a combination of pembrolizumab administered every six weeks with lenvatinib at 20 milligrams per day. So it's a combination of VEGF TKI, lenvatinib, plus immune checkpoint pembrolizumab. The primary endpoint of this study is response rate.

Pedro Barata: Fantastic. Thank you so much. And so remind us, as you were saying, which you raise a very, very good point, right? Non-clear cell behaves differently from clear cell. And we can actually go further and argue that actually within non-clear cell group, there's many different diseases that are part of these broad classification of non-clear cell. Can you remind us what type of patients were enrolled in these phase two, as far as histology goes, and then go ahead also and give us kind of the highlights, if you will, on the efficacy portion of this study.

Laurence Albiges: Sure. So that study is about a 150-patient study. What has been presented at this ESMO are the very first results with an efficacy population of 82 patient. These were patient for which we had sufficient follow-up. And with regard to your question of histology, the vast majority of those patients are papillary nccRCC carcinoma. They account for 51 patient in the efficacy population. So that's about 62% of patient. The second most frequent entity are what we call chromophobia RCC, and we know those patients are hard to treat because they tend to be less sensitive or less responding to an immune checkpoint when used as single agent. And then we had other histologies, such as translocation RCC or unclassified tumors, or even more rare tumors, such as medullary carcinoma. So these are, as you can see, a very [inaudible] patient population.

Laurence Albiges: What are the key results? Well, first, the response rate, that is achieving 47.6%. So almost one patient out of two that has objective response. The disease control rate, that is 79%. So basically, almost 80% of patient that has either partial response or stable disease or even complete response. And if you look at the response by histology [inaudible], it's very consistent across papillary and classified translocation and other tumor type. The histology where we saw the less responsive were it chromophobe tumor, as anticipated. And I think, at this point, it's important to stress that we already had data with pembrolizumab single agents that were previously reported by David McDermot. We had seen other regimen with combination with VEGF TKI, and this is the first report of lenvatinib, plus pembrolizumab in this histology of patient with non-clear cell. There was no significant signal in terms of safety. This is the regimen that we are used to handle.

Laurence Albiges: And so, therefore, there was no new safety signal. I think it's important that out of the 82 patient that were accessible for response, we could see some degree of tumor shrinkage in the vast majority of them. It was 86% of patient that had some degree of tumor shrinkage. So clearly, a combination that is active, for now, the follow-up is short. We only had 8.2 months follow-up. Nevertheless, many patients were still under treatment at the time of analysis. Therefore, we will be waiting for further follow-up and the entire patient population to be followed, to provide final analysis.

Pedro Barata: No, it is so important as you mentioned and summarized these results. It's very good news, in my opinion, promising results for patients with non-clear cell histologies. And so thank you for highlighting it so elegantly for us. And as you mentioned, so now we have data with lenvatinib, pembrolizumab. There are other combos being explored out there with proof of concept and promising results. So can you tell us what the next steps for these efforts seem to be? I mean, sounds like you're going to update with longer, with more mature follow-up, you're going to update those results and hopefully we'll see the data being consistent over time. Is any other perspectives you can share with the audience as far as next steps for the non-clear cell RCC patients?

Laurence Albiges: Yeah. Thank you. So what I'm not yet able to provide you with is the progression-free survival, given that for now, median follow-up is at 8.2 months. What we have at six months is 72.3% of patient that are progression-free at that step. So we haven't yet reached the median PFS. And of course, we don't have yet the overall survival for this patient population. I think these items are very important. As we said, these patients tend to have a poor prognostic. And so, therefore, being able to generate prospective data of combination regimen in this space is very important. So we are eagerly waiting for those longer-term follow-up to define the potential role of this combination in patient with non-clear cell.

Pedro Barata: That's fantastic. Well, Dr. Albiges, I feel like we could stay and talk about this much longer. I really appreciate your taking the time to talk to us. Again, congratulations. Very elegant presentation and I'm looking forward to actually follow-up data and also the publication, right? So again, thank you and congratulations.

Laurence Albiges: Thank you very much.

Link:
Pembrolizumab in Combination with Lenvatinib as First-Line Treatment for Non Clear Cell Renal Cell Carcinoma (nccRCC), KEYNOTE-B61 - Laurence Albiges...

The Oncologic Drug Advisory Committee voted 9 to 4 that the current benefits of poziotinib did not outweigh its risks for the treatment of patients with nonsmall cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations.1

The decision was made on day 1 of the September 22/23 ODAC Meeting by 14 voting members. The vote followed an extensive discussion about the overall risk/benefit of poziotinib 16 mg once daily with consideration of the limited response the drug has shown, short durability of response, high toxicity, inadequate dosage optimization, and the fact the confirmatory clinical trial was delayed.

A new drug application was submitted to the FDA for poziotinib as a potential treatment option for previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations. The proposed indication was supported by results from the phase 2 ZENITH20 clinical trial. The NDA was accepted by the FDA on February 11, 2022, but then raised to the ODAC.

ZENITH20 is a multicenter, multicohort, open-label phase 2 study (NCT03318939) primarily evaluating objective response rate by independent review committee (IRC) in patients with advanced or metastatic NSCLC. The secondary outcomes of the study include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), safety/tolerability, and quality of life.2

Results reported in 2021 were from 90 patients who had received a median of 2 prior lines of therapy. Poziotinib achieved an ORR of 27.8% (95% CI, 18.9%-38.2%) with partial response observed in 25 patients. The DCR achieved with poziotinib was 70.0% (95% CI, 59.4%-79.2%). Seventy-four percent of patients treated with poziotinib in the study had tumor reduction at a median shrinkage of 22%.

The agent showed a 5.1-month (95% CI, 4.2 to 5.5) median duration of response, and clinical benefit with poziotinib in the study was irrespective of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations.

The median PFS observed with the agent was 5.5 months (95% CI, 3.9-5.8) with a 5.1-month median DOR.

Safety findings from ZENITH20 showed that the grade 3 or higher treatment-related adverse events (TRAEs) observed were rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). The majority of patients in the study (76.7%) required dose reduction. Due to TRAEs, 13.3% of patients Permanently discontinued poziotinib.

I think the bottom line from this study is that it clearly does have substantial activity in the population was studied in when you consider the alternatives that are available and the lack of oral medications that are approved for these patients. I think it's unquestionably from my clinical perspective, it's a clinically meaningful activity. We have some patients that have been on the drug for years and are doing quite well on it and are very grateful that they had this oral drug available. I think this could potentially provide an important option for patients and for healthcare providers for this important unmet need. And it's worth pointing out that if this is approved, well her two mutations occur not just in lung cancer but in more than 20 Different malignancies. One would love to see then that if this is approved If we could build on those studies and look at the activity in those other tumor types as well, said John Heymach, MD, PhD, a medical oncologist, and chair of the Department of Thoracic-Head & Neck Med Onc, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.

Despite the results from ZENITH20, the FDA holds that better therapies are now available for patients with HER2 exon 20 insertion mutation-positive NSCLC.

Poziotinib, as demonstrated by the limited response rate with poor durability observed in the primary efficacy population is not improved over available therapies, explained Nicole Drezner, MD, clinical team lead in the Division of Oncology 2 at the FDA, during the FDA presentation.

For patients with nonsmall cell lung cancer, who have received both prior platinum-based chemotherapy and an immune checkpoint inhibitor, available therapy includes docetaxel in combination with ramucirumab [Cyramza] with a benchmark or are of 23%. Anti-PD-L1 therapies are considered available therapy that is not previously received and are associated with lower ORRs with more substantial durability than what is observed with chemotherapy. Trastuzumab dereuxtecan [Enhertu], a HER2- targeting antibody drug conjugate received accelerated approval last month for the treatment of patients with HER2-mutated non-small cell lung cancer as an indication which would include the patients who comprise the primary efficacy population in this application. The drug demonstrated a response rate of 58%, with a duration of response is 8.7 months, both considerably greater than what was observed with poziotinib, Drezner added.

Comparing the data from DESTINY-Lung02 (NCT04644237) which supported the accelerated approval of trastuzumab dereuxtecan to the ZENITH20 data3, Dezner noted that the ORR observed with poziotinib was low with poor durability. Further, the safety profile of poziotinib was brought into question.

The applicant states that the safety profile of poziotinib is similar to other drugs in class. However, in our assessment, poziotinib is more toxic than other tyrosine kinase inhibitors [TKIs] for lung cancer, especially at the 16-milligram dose. Eight of 10 patients experienced grades 3 to 4 adverse events. Similarly, over 80% of patients require a drug interruption and over 50% of patients needed a dose reduction, said Justin N. Malinou, MD, clinical reviewer, Division of Oncology 2 Thoracic and Head and Neck Oncology Office of Oncologic Diseases at the FDA, during the FDA presentation.

Regarding dose optimization, the FDA highlighted that dose reductions occurred within the first months of treatment. Beyond the 24-week mark, most patients were receiving a 12 mg once daily dose of poziotinib.

In FDA review of the applicants clinical pharmacology package, we identified significant areas of concern regarding the lack of dosage optimization. Given that the applicant has provided insufficient data over the clinically relevant dose range, we cannot determine if alternative dosages may provide acceptable efficacy and an improved toxicity profile. Therefore, we continue to assert that the applicant failed to adequately justify their proposed dosage of 16 milligrams once daily, said Jeanne Fourie Zirkelbach, PhD, team lead, Clinical Pharmacology Division of Cancer Pharmacology 2 Office of Clinical Pharmacology at the FDA, during the FDA presentation.

Finally, the FDA originally recommended that a confirmatory trial for poziotinib start recruitment in 2020. To date, no patients have been enrolled in the confirmatory trial. The FDA noted that it would be 4 years before results from the confirmatory trial would be available.

With Spectrum Pharmaceuticals alluding to their success and progress with poziotinib and the FDA asserting that they are unhappy with the development of poziotinib, ODAC members carried out an in-depth discussion.

A point was raised by Spectrum Pharmaceuticals was that poziotinib showed similar dose reduction and discontinuations as other approve TKIs like mobocertinib (Exkivity) and neratinib (Nerlynx). Moreover, poziotinib had the same ORR as agents like mobocertinib. However, the FDA responded that the duration of response with mobocertinib greatly exceeded poziotinib.

The applicant also mentioned that multiple sites for the confirmatory trials have been opened and will started enrolled patients in the next few weeks. But the FDA pointed out that only 3 of the sites were in the Unites States (US) and that failure to accrue patients at US sites would results in findings that are not reflective a US population.

During the open public hearing,7 out of 8 presentations were from patients who testified that poziotinib has either helped them or a family member. The patients did mentioned toxicities but noted that they were manageable.

Joshua K. Sabari,MD, a medical oncologist and assistant professor,Department of Medicine at NYU Grossman School of Medicine, as medical director, Kimmel Pavilion 12, at NYU Langone Health stated that although trastuzumab deruxtecan is now standard for HER2 exon 20 insertion mutation-positive NSCLC, some patients are not eligible to receive it. Therefore, poziotinib may be another option, according to Sabari.

ODAC member opinions varied during the discussion. Some oncologists noted that the risk-benefit profile of poziotinib was acceptable considering that toxicities related to TKIs can be managed in the clinic. One member noted that the short duration of response observed with poziotinib in ZENITH20 could be due to toxicity.

Importantly, poziotinib is an oral agent, which means patients can take their medication in an outpatient setting. One ODAC member raised the point that if toxicities associated with poziotinib required patients to come back to the clinic, it impacts. the favorability of the risk-benefit profile.

REFERENCES:

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. September 22, 2022. Accessed September 22, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-22-23-2022-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09222022

2. Le X, Cornelissen R, Garassino M, et al. Poziotinib in non-small-cell lung cancer HarboringHER2exon 20 insertion mutations after prior therapies: ZENITH20-2 Trial. J Clin Oncol. 2022;40(7): 710-718. doi: 10.1200/JCO.21.01323

3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA website. August 11, 2022. Accessed September 22, 2022. https://bit.ly/3LyWDMK

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FDA's ODAC Votes That Benefits Do Not Outweigh Risks for Poziotinib in HER Exon 20 Ins+ NSCLC - Targeted Oncology

An inspirational East Kilbride teenager studying to become a nurse is living proof that trials of new treatments for children with cancer can save lives.

Katie Currie was just three years old when diagnosed with acute lymphoblastic leukaemia.

Her parents Neil and Siobhan said they felt like their world came crashing down, as months of treatment began.

Then two years later in 2008, aged five, Katie relapsed.

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After a nationwide search for a donor whose stem cells were a match - a campaign supported by the East Kilbride News at the time - she had a stem cell transplant on September 11, 2008.

Katie began a clinical trial that Cancer Research UK helped fund for a new chemotherapy treatment called mitoxantrone, and the trial results were striking.

Mitoxantrone proved so effective that all children taking part in the trial were put on the new chemotherapy drug as soon as possible.

Now Katie, who is in remission, is sharing her remarkable story to support Childhood Cancer Awareness Month this September.

She is passionate about giving back after the treatment shes received, and that starts with studying for a degree in child health nursing at Edinburgh Napier University.

Katie, 19, said: I am living proof that clinical trials work and feel proud I took part in a trial that helped change in a positive way how some childhood cancers are treated.

I was so young when I was diagnosed that I dont remember much from then, but I do remember being in hospital and I remember the nurses.

It is surreal to think about what I went through then and how far I have come. Now Im keen to do everything I can to put something back and help the NHS.

Cancer Research UK funded scientists helped show that the drug mitoxantrone can increase survival by more than 50 per cent in children whose acute lymphoblastic leukaemia has come back after treatment.

Katie is one of around 330 young people up to the age of 25 who are diagnosed with cancer in Scotland every year.

Acute lymphoblastic leukaemia (ALL), a cancer of the white blood cells has a particularly high survival rate. Thanks to major advances in treatment, more than nine in 10 children in the UK with ALL now survive for at least five years, compared with around seven in 10 in the 1980s.

Professor Vaska Saha, based at the University of Manchester, was researching ways to improve treatment options for children like Katie Currie who were facing leukaemia for a second time and led research on mitoxantrone.

The drug works by jamming a molecule in cancer cells responsible for untwisting DNA. Blocking this process literally ties the cells DNA up in knots so it cant grow and multiply. It also works on cancer cells that have resisted previous treatment- even if theyre hidden among healthy cells.

Professor Saha was part of an international team working on the clinical trial, known as ALLR3, comparing the drug idarubicin, a chemotherapy treatment normally used for young people whose leukaemia had relapsed to mitoxantrone, which had proved successful in early trials in the lab.

A total of 216 children and young people including Katie took part in the trial. They were split in to two groups. One group was given the drug idarubicin and the other group mitoxantrone.

The study evaluated the number of children whose leukaemia hadnt got worse over the three years since treatment.

Results showed that just over six out of 10 children (64.6 per cent) who had mitoxantrone, compared to less than four out of 10 children (35.9 per cent) who had idarubicin, had cancers that hadnt grown at all in the timeframe.

The study also found that the number of children alive three years after treatment, regardless of whether their cancer had grown or not, was far higher in the group on mitoxantrone compared to idarubicin. This is known as overall survival.

The trial had been planned to continue for several years. But it was halted early and all the children who had originally been given idarubicin were transferred to mitoxantrone.

Professor Saha said: A difference in outcomes like that had never been reported before. It took all of us by surprise.

Now Katie is packing her bags this September to head off to her second year at university studying nursing. Her parents are hugely proud of everything shes achieved but they recall vividly the early years when life seemed less positive.

Dad Neil said: When Katie was first diagnosed and started treatment in Glasgow, we put our trust in the doctors at the hospital.

We took it day by day, especially after she relapsed. When the cancer came back, you fear everything, but we spoke to the team about the trial and put complete faith in them.

Mum Siobhan said: We believed that, with the clinical trial Katie had the best chance of recovery. Without these trials, amazing new treatments may never be found. Mitoxantrone probably saved Katies life.

Katie, who has some side-effects from her experience including endocrine issues and the loss of vision in one eye after she developed CMV retinitis, has annual check-ups now.

Katie said: I have just had the first set of these check-ups in the adult services department, as they had been in the childrens unit before.

I felt anxious going but the doctor that treated me was still there for the checks, so that definitely helped. It is still scary though, as you dont know what they are going to say and it was a huge relief that everything was ok.

She said she always knew she wanted to be involved in healthcare, adding: "I knew I wanted to do something in medicine after what had happened to me, and I was interested in being a paramedic too but it changed over the years. By doing this, I really want to say thank you for the help I had and I am passionate about nursing.

I started uni in Sept 2021 and I still had to be shielded a bit, but I really enjoyed the course and I am just starting the second year now. I have been on two placements already and I think that my own experience has really helped me with my understanding with patients.

The course is three years long and then I can choose where I focus on. I am just so pleased to be able to do this after my experience and to give back for the help I had.

Dad Neil said the whole family including Katies sister Libby, 17, are proud of Katie.

He said: Katie has been through so much but she is resilient and so upbeat in all that she does. She just gets on with things and is so kind too.

At an early age, she talked about being involved in medicine and we did ask if she was sure she wanted to go into that after all she had experienced, but she was adamant.

Thinking back to those days of Katies treatment and relapse when she was so young, it is just amazing to be here now and for her to be off to Edinburgh following her dreams.

"Back then, we put our faith in the research and everything that goes on behind the scenes. That has been incredible for us and for Katie, but we know there is more that still needs to be done to make treatments more effective and kinder too, so that there are less side-effects.

"We know how important this work is for children in the future and thats why we support Cancer Research UK and all the research that needs to be funded.

Cancer Research UK celebrates its 20th anniversary in 2022. However, its history dates back to the founding of the Imperial Cancer Research Fund in 1902.

Thanks in part to the charitys work, childrens cancer survival in the UK has more than doubled since the 1970s when just over a third of children diagnosed survived beyond ten years. Today, its around 8 in 10 but theres still much further to go.

Cancer Research UK spokeswoman in Scotland, Lisa Adams, said: Were grateful to Katie and her family for their support.

Cancer in children and young people is different to cancer in adults- from the types of cancer to the impact of treatments and the long-term side effects survivors often experience.

Supporters can help by wearing a gold ribbon badge the awareness symbol of Childhood Cancer Awareness Month available from Cancer Research UK shops and selected TK Maxx stores during September.

Find out more here.

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Courageous Lanarkshire teen who survived leukaemia thanks to a clinical trial pursues nursing dream - Daily Record

Immune cells called group 3 innate lymphoid cells (ILC3s) play an essential role in establishing tolerance to symbiotic microbes that dwell in the human gastrointestinal tract, according to a study led by researchers at Weill Cornell Medicine.

The discovery, reported Sept. 7 in Nature, illuminates an important aspect of gut health and mucosal immunityone that may hold the key to better treatments for inflammatory bowel disease (IBD), colon cancer and other chronic disorders.

As part of this study, we define a novel pathway that drives immune tolerance to microbiota in the gastrointestinal tract, said senior author Dr. Gregory F. Sonnenberg, associate professor of microbiology and immunology in medicine and head of basic research in the Division of Gastroenterology & Hepatology, and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. This is a fundamental advance in our understanding of mucosal immunity and may hold the key to understanding what goes wrong when the immune system begins to inappropriately attack microbiota in diseases such as IBD.

Drs.Mengze Lyu and Gregory Sonnenberg

Scientists have long known that trillions of bacteria, fungi, and other microbes dwell symbiotically in the intestines of mammals. The mechanism by which the immune system normally tolerates these beneficial gut microbes, instead of attacking them, has not been well understood. But there is evidence that this tolerance breaks down in IBD, leading to harmful flareups of gut inflammation. Thus, a detailed understanding of gut immune tolerance could enable the development of powerful new treatments for IBDa class of diseases that include Crohns disease and ulcerative colitis, which affect several million individuals in the United States alone.

In the study, Dr. Sonnenberg and colleagues, including lead author Dr. Mengze Lyu, a postdoctoral researcher in the Sonnenberg lab, used single-cell sequencing and fluorescent imaging techniques to delineate immune cells in the mesenteric lymph nodes that drain the intestines of healthy mice. They focused on cells expressing a transcription factor, RORt, which are known to drive either inflammation or tolerance in response to microbes that colonize the intestine. The dominant immune cell types in these tissues, they found, were T cells and ILC3s. The latter are a family of immune cells that represent an innate counterpart of T cells, and work as a first line of defense in mucosal tissues such as the intestines and lungs.

In close collaboration with researchers at the University of Birmingham, UK, the scientists observed that in lymph node regions called interfollicular zones, ILC3s are in close association with a specific type of T cell, called RORt+ regulatory T cells (Tregs), which are adapted to dial down inflammation and immune activity to promote tolerance in the gut.

We previously defined key roles for ILC3s in regulating adaptive immunity, but these findings are exciting as they provoke a concept that ILC3s directly interact with Tregs to control immune tolerance in the gut, said Dr. David R. Withers, professor of immune regulation at the Institute of Immunology and Immunotherapy and the University of Birmingham. Dr. Withers and his laboratory are key contributors to this study and long-term collaborators of Dr. Sonnenberg.

The researchers next found evidence that ILC3s play an essential role in promoting the RORt+Treg population in the gut. Much like how immune responses are generated to disease-causing microbes, the ILC3s present pieces of gut-dwelling microbes; but this elicited RORt+ Tregs that specifically recognize these microbes rather than an inflammatory immune response. These RORt+ Tregs then suppress other T cell responses and enforce tolerance to the microbiota.

The scientists found that when they deleted the surface molecule, MHC class II, that ILC3s use to present microbial antigens, thus impeding ILC3s interactions with RORt+ Tregs, the observed RORt+ Tregs were substantially lower than in normal mice, and the affected mice developed spontaneous gut inflammation. At the same time, inflammatory RORt+ T cells, called T helper (Th)17 cells, were dramatically increased in these micein part because many Tregs, bereft of the usual signals from their ILC3 helpers, turned into Th17 cells.

Our extensive research reveals that ILC3s are necessary and sufficient enforcers of immune tolerance to gut microbes, Dr. Lyu said. In addition, we now have a sophisticated understanding of the signals that ILC3s use to communicate with T cells and drive the generation of microbiota-specific Tregs.

To confirm the potential relevance to humans, the researchers analyzed samples of inflamed gut tissue from pediatric IBD patients or healthy individuals in close collaboration with Dr. Robbyn E. Sockolow, professor of clinical pediatrics and chief of the division of Pediatric Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Weill Cornell Medicine and a pediatric gastroenterologist at NewYork-Presbyterian Komansky Children's Hospital and Center for Advanced Digestive Care. With Dr. Socklolow and the Roberts Institute Live Cell Bank, they found evidence that communication between ILC3s and RORt+Tregs is disrupted in IBD patients.

Our exciting results provide a potential explanation for why immune tolerance is impaired in IBD patients, which could provoke new therapies with the goal of re-educating the immune system to limit chronic inflammation directed against the microbiota, Dr. Sockolow said.

Dr. Sonnenberg and colleagues now are trying to determine how the ILC3-T cell tolerance mechanism distinguishes between symbiotic, helpful microbes and disease-causing ones. But the results so far suggest, that future cell therapies to restore ILC3 functionality might have powerful effects in suppressing inflammation in IBD. Further, it remains possible that this pathway could be harnessed to limit other inflammatory and autoimmune disorders, as recently demonstrated by the Sonnenberg Lab in mouse models of multiple sclerosis.

The fact that the ILC3s are essential to orchestrate tolerance by promoting antigen-specific Tregs is particularly important, Dr. Sonnenberg notes, for it suggests the possibility of highly targeted treatments that can precisely suppress a source of inappropriate immune activity without compromising immunity as a whole.

Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534); an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund; the Meyer Cancer Center Collaborative Research Initiative; The Dalton Family Foundation; the Crohns and Colitis Foundation; and Linda and Glenn Greenberg. Dr. Sonnenberg is a CRI Lloyd J. Old STAR. The JRI IBD Live Cell Bank is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family and Weill Cornell Medicine Division of Pediatric Gastroenterology, Hepatology, and Nutrition.

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Discovery Reveals How the Immune System Tolerates Friendly Gut Bacteria - Weill Cornell Medicine Newsroom

A high proportion of myeloid cells may contribute to recurrence in those with long progression-free survival by promoting cancer growth and/or suppressing antitumor immunity.

Treatment with B-cell maturation antigen (BCMA)-targeted T-cell therapy increased the likelihood of longer progression-free survival (PFS) for individuals with myeloma whose tumor immune microenvironment had a more diverse baseline T-cell repertoire, distinct changes to immune cell populations, and fewer markers of immune cell exhaustion, according to the results of a study published in Blood Cancer Discovery.

Two CAR T-cell therapies targeting the [BCMA] are now approved for the treatment of myeloma, but the challenge is that many of the responses to this therapy are not durable, and patients remain at risk for recurrence, Madhav Dhodapkar, MBBS, a professor at the Emory University School of Medicine said in a statement. A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly.

In the study, investigators from Emory University and the University of Pennsylvania analyzed 28 pre- and post-treatment bone marrow samples from 11 individuals who had clinical responses to BCMA-targeted CAR T-cell therapy in a previously reported phase 1 clinical trial.

They analyzed samples by single-cell approaches, including CITE-Seq, transcriptomics, mass cytometry, and T-cell receptor sequencing. They compared the change in bone marrow between individuals with long and short PFS, which were defined as greater than 6 months or less than 6 months, respectively.

Investigators found that in individuals with long PFS, the proportion of T cells in bone marrow increased after treatment, while myeloid cell proportions decreased.

They noted that these changes were not observed among individuals with short PFS.

A high proportion of myeloid cells may have contributed to recurrence in the individuals with long PSF by promoting cancer growth and/or suppressing antitumor immunity, the investigators said.

Additionally, post-treatment CAR and non-CAR T cells from individuals with long PFS had a distinct genomic signature with a lower expression of immune checkpoint genes and other genes associated with T-cell exhaustion compared with those with short PFS, according to investigators.

Also, T cells from individuals with long PFS had higher expression of genes associated with bone marrow retention.

Investigators also found that baseline features, such as greater T-cell receptor diversity, higher tumor expression of interferon response genes and mature plasma genes, and lower tumor expression of genes associated with epithelial-to-mesenchymal transition, were associated with PFS.

The major finding of this study is that the durability of response may be dependent on characteristics of non-CAR T cells and other immune cells in the tumor microenvironment, Dhodapka said. This finding has broad implications for the CAR T-cell therapy field, as it emphasizes the importance of the patients preexisting immune microenvironment as a determinant of durable responses.

Investigators think that understanding the baseline factors that affect durable responses could help physicians identify individuals who would benefit from BCMA-targeted CAR T-cell therapy.

Furthermore, the results could introduce opportunities to study combination therapies that target cell types or specific markers associated with relapse.

Reference

Specific components of the tumor immune microenvironment may affect the durability of responses to BCMA CAR T-cell therapy. News release. American Association for Cancer Research. August 29, 2022. Accessed August 30, 2022. https://www.aacr.org/about-the-aacr/newsroom/news-releases/specific-components-of-the-tumor-immune-microenvironment-may-affect-the-durability-of-responses-to-bcma-car-t-cell-therapy/

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Study: New Factors Are Associated With Increased PFS from BCMA-Targeted T-Cell Therapy - Pharmacy Times