Researchers have identified genetic signatures that may explain the ethnic differences in the severity of prostate cancer, particularly in sub-Saharan Africa.

In two studies published in Nature and Genome Medicine, researchers detailed how they used genetic sequencing of prostate cancer tumors from Australian, Brazilian, and South African donors to identify a new prostate cancer taxonomy and cancer drivers that not only distinguish patients by genetic ancestry, but also predict which cancers are likely to become life-threatening.

Our understanding of prostate cancer has been severely limited by a research focus on Western populations, said senior author Vanessa Hayes, genomicist and Petre Chair of Prostate Cancer Research at the University of Sydneys Charles Perkins Centre and Faculty of Medicine and Health in Australia. Being of African descent, or from Africa, more than doubles a mans risk for lethal prostate cancer. While genomics holds a critical key to unravelling contributing genetic and non-genetic factors, data for Africa has till now, been lacking.

In the Nature study, the researchers used whole-genome sequencing of treatment-nave prostate cancer samples from 183 ancestrally and globally distinct patients. They generated a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants.

We found Africans to be impacted by a greater number and spectrum of acquired (including cancer driver) genetic alterations, with significant implications for ancestral consideration when managing and treating prostate cancer, said Hayes.

Among the significant findings were elevated tumor mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations, and a higher total of mutational signatures. Additionally, they identified driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1.

In the Genome Medicine study, the researchers used whole genome sequencing and best practice workflows to analyze structural variations for 180 prostate tumors derived from 115 African, 61 European, and four ancestrally admixed patients.

In African-derived tumors there was a 1.6- to 2.5-fold increase in duplication events. African-derived tumors were also twofold more likely to present with a hyper-SV subtype.

Through African inclusion, we have made the first steps not only towards globalizing precision medicine but ultimately to reducing the impact of prostate cancer mortality across rural Africa, explains University of Pretorias Professor Riana Bornman, an international expert in mens health and clinical lead for the Southern African Prostate Cancer Study in South Africa.

References

Study reveals aggressive prostate cancer linked to ancestral heritage

African-specific molecular taxonomy of prostate cancer

Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers

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Studies Reveal Aggressive Prostate Cancer Linked to Ancestral Heritage - DocWire News

Manufacturing partner, Lonza, has today (September 6) announced a collaboration with Touchlight, a biotech company that works with enzymatic DNA production enabling genetic medicine.

Through this collaboration, Lonza says it will have the ability to expand it end-to-end offering for mRNA manufacturing with an additional source of DNA raw material. This material comes from Touchlights doggybone DNA (dbDNA). Touchlight says it will be able to widen the channels making it easier for customers to get to the dbDNA technology.

The company developed thesynthetic DNA vector, known as doggybone -named after its schematic structure DNA or dbDNA and enzymatic manufacturing process, which they say enables them to produce DNA at unprecedented speed, scale and purity.

Lonzas customers will be able to access the enzymatic DNA technology; a linear, covalently closed DNA vector, produced using an enzymatic manufacturing process which enables GMP production.

Access to this technology, the companies say, will expand the options for Lonzas customers beyond the traditional method of working with plasmid DNA (pDNA), while continuing to benefit from the Lonzas integrated mRNA manufacturing offering.

Andr Goerke, vice president, business unit head mRNA, Lonza, said: The strategic collaboration with Touchlight enables Lonza to further enhance its position as a global leader in mRNA manufacturing.

We can now provide our customers with a strong foundation to deliver an end-to-end offering that includes access to a novel synthetic DNA technology. Such an integrated solution can prove beneficial in speeding up time to market, which is critical in the fast-paced industry of mRNA manufacturing.

DNA serves as the starting template for the production of mRNA. Through an enzymatic in vitro transcription process, this DNA sequence is then transcribed into a single-stranded RNA molecule, which is then processed into mRNA. Current mRNA-based therapeutics in development include vaccines for infectious diseases and immuno-oncology.

Karen Fallen, CEO, Touchlight DNA services, added: We are delighted to provide Touchlight customers the benefits of an end-to-end mRNA offering through our collaboration with Lonza. Lonza is the leading CDMO in mRNA manufacturing and has an established, global mRNA manufacturing network. The alliance allows both companies to innovate and to extend their offering on a global level.

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Lonza and Touchlight collaboration will expands customer's access to DNA - Labiotech.eu

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Eight months after falling ill with covid-19, the 73-year-old woman couldnt remember what her husband had told her a few hours before. She would forget to remove laundry from the dryer at the end of the cycle. She would turn on the tap at a sink and walk away.

Before covid, the woman had been doing bookkeeping for a local business. Now, she couldnt add single-digit numbers in her head.

Was it the earliest stage of dementia, unmasked by covid? No. When a therapist assessed the womans cognition, her scores were normal.

What was going on? Like many people whove contracted covid, this woman was having difficulty sustaining attention, organizing activities, and multitasking. She complained of brain fog. She didnt feel like herself.

But this patient was lucky. Jill Jonas, an occupational therapist associated with the Washington University School of Medicine in St. Louis who described her to me, has been providing cognitive rehabilitation to the patient, and she is getting better.

Cognitive rehabilitation is therapy for people whose brains have been injured by concussions, traumatic accidents, strokes, or neurodegenerative conditions such as Parkinsons disease. Its a suite of interventions designed to help people recover from brain injuries, if possible, and adapt to ongoing cognitive impairment. Services are typically provided by speech and occupational therapists, neuropsychologists, and neurorehabilitation experts.

In a recent development, some medical centers are offering cognitive rehabilitation to patients with long covid (symptoms that persist several months or longer after an infection that cant be explained by other medical conditions). According to the Centers for Disease Control and Prevention, about 1 in 4 older adults who survive covid have at least one persistent symptom.

Experts are enthusiastic about cognitive rehabilitations potential. Anecdotally, were seeing a good number of people [with long covid] make significant gains with the right kinds of interventions, said Monique Tremaine, director of neuropsychology and cognitive rehabilitation at Hackensack Meridian Healths JFK Johnson Rehabilitation Institute in New Jersey.

Among the post-covid cognitive complaints being addressed are problems with attention, language, information processing, memory, and visual-spatial orientation. A recent review in JAMA Psychiatry found that up to 47% of patients hospitalized in intensive care with covid developed problems of this sort. Meanwhile, a new review in Nature Medicine found that brain fog was 37% more likely in nonhospitalized covid survivors than in comparable peers who had no known covid infections.

Also, theres emerging evidence that seniors are more likely to experience cognitive challenges post-covid than younger people a vulnerability attributed, in part, to older adults propensity to have other medical conditions. Cognitive challenges arise because of small blood clots, chronic inflammation, abnormal immune responses, brain injuries such as strokes and hemorrhages, viral persistence, and neurodegeneration triggered by covid.

Getting help starts with an assessment by a rehabilitation professional to pinpoint cognitive tasks that need attention and determine the severity of a persons difficulties. One person may need help finding words while speaking, for instance, while another may need help with planning and yet another may not be processing information efficiently. Several deficits may be present at the same time.

Next comes an effort to understand how patients cognitive issues affect their daily lives. Among the questions that therapists will ask, according to Jason Smith, a rehabilitation psychologist at the University of Texas Southwestern Medical Center in Dallas: Is this [deficit] showing up at work? At home? Somewhere else? Which activities are being affected? Whats most important to you and what do you want to work on?

To try to restore brain circuits that have been damaged, patients may be prescribed a series of repetitive exercises. If attention is the issue, for instance, a therapist might tap a finger on the table once or twice and ask a patient to do the same, repeating it multiple times. This type of intervention is known as restorative cognitive rehabilitation.

It isnt easy because its so monotonous and someone can easily lose attentional focus, said Joe Giacino, a professor of physical medicine and rehabilitation at Harvard Medical School. But its a kind of muscle building for the brain.

A therapist might then ask the patient to do two things at once: repeat the tapping task while answering questions about their personal background, for instance. Now the brain has to split attention a much more demanding task and youre building connections where they can be built, Giacino continued.

To address impairments that interfere with peoples daily lives, a therapist will work on practical strategies with patients. Examples include making lists, setting alarms or reminders, breaking down tasks into steps, balancing activity with rest, figuring out how to conserve energy, and learning how to slow down and assess what needs to be done before taking action.

A growing body of evidence shows that older adults can learn to use these strategies and that it does, in fact, enhance their everyday life, said Alyssa Lanzi, a research assistant professor who studies cognitive rehabilitation at the University of Delaware.

Along the way, patients and therapists discuss what worked well and what didnt, and practice useful skills, such as using calendars or notebooks as memory aids.

As patients become more aware of where difficulties occur and why, they can prepare for them and they start seeing improvement, said Lyana Kardanova Frantz, a speech therapist at Johns Hopkins University. A lot of my patients say, I had no idea this [kind of therapy] could be so helpful.

Johns Hopkins has been conducting neuropsychiatric exams on patients who come to its post-covid clinic. About 67% have mild to moderate cognitive dysfunction at least three months after being infected, said Dr. Alba Miranda Azola, co-director of Johns Hopkins Post-Acute COVID-19 Team. When cognitive rehabilitation is recommended, patients usually meet with therapists once or twice a week for two to three months.

Before this kind of therapy can be tried, other problems may need to be addressed. We want to make sure that people are sleeping enough, maintaining their nutrition and hydration, and getting physical exercise that maintains blood flow and oxygenation to the brain, Frantz said. All of those impact our cognitive function and communication.

Depression and anxiety common companions for people who are seriously ill or disabled also need attention. A lot of times when people are struggling to manage deficits, theyre focusing on what they were able to do in the past and really mourning that loss of efficiency, Tremaine said. Theres a large psychological component as well that needs to be managed.

Medicare usually covers cognitive rehabilitation (patients may need to contribute a copayment), but Medicare Advantage plans may differ in the type and length of therapy theyll approve and how much theyll reimburse providers an issue that can affect access to care.

Still, Tremaine noted, not a lot of people know about cognitive rehabilitation or understand what it does, and it remains underutilized. She and other experts dont recommend digital brain-training programs marketed to consumers as a substitute for practitioner-led cognitive rehabilitation because of the lack of individualized assessment, feedback, and coaching.

Also, experts warn, while cognitive rehabilitation can help people with mild cognitive impairment, its not appropriate for people who have advanced dementia.

If youre noticing cognitive changes of concern, ask for a referral from your primary care physician to an occupational or speech therapist, said Erin Foster, an associate professor of occupational therapy, neurology, and psychiatry at Washington University School of Medicine in St. Louis. Be sure to ask therapists if they have experience addressing memory and thinking issues in daily life, she recommended.

If theres a medical center in your area with a rehabilitation department, get in touch with them and ask for a referral to cognitive rehabilitation, said Smith, of UT Southwestern Medical Center. The professional discipline that helps the most with cognitive rehabilitation is going to be rehabilitation medicine.

Judith Graham, a contributing columnist, writes the Navigating Aging column for KHN. She has covered health care for more than 30 years. Find Judith on Twitter @judith_graham

This story was produced byKHN, which publishesCalifornia Healthline, an editorially independent service of theCalifornia Health Care Foundation.

KHN(Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs atKFF(Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. Find KHN on Twitter@KHNews

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Elderly are more affected by COVID brain fog, but 'cognitive rehab' could be an effective treatment - Genetic Literacy Project

An Inserm team at the Lille Neuroscience & Cognition laboratory (Inserm/Universit de Lille, Lille University Hospital) has joined forces with its counterparts at Lausanne University Hospital (CHUV) to test the efficacy of GnRH injection therapy in order to improve the cognitive functions of a small group of patients with Down syndrome. First the scientists revealed a dysfunction of the GnRH neurons in an animal model of Down syndrome and its impacts on the cognitive function impairment associated with the condition. Then a pilot study testing GnRH pulsatile injection therapy was conducted in seven patients. The results were promising : the therapy led to improved cognitive function and brain connectivity. This study has been published in Science.

Down syndrome, also known as trisomy 21, affects around one in 800 births and results in a variety of clinical manifestations, including decline in cognitive capacity. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer's disease. Gradual loss of the ability to smell, typical of neurodegenerative diseases, is also commonly encountered from the prepubertal period, with potential sexual maturation deficits occurring in men.

GnRH-secreting neuron dysfunction identified in Down syndrome

Recent discoveries have suggested that the neurons expressing gonadotropin-releasing hormone (GnRH) - which is known for regulating reproduction via the hypothalamus - could also act on other brain regions with a potential role in other functions, such as cognition.

With this idea in mind, the Lille Neuroscience & Cognition laboratory team led by Inserm Research Director Vincent Prvot studied the mechanism which regulates GnRH in mouse models of Down syndrome.

The laboratory demonstrated that five strands of microRNA regulating the production of this hormone - which are found on chromosome 21 are dysfunctional. This supernumerary chromosome then leads to abnormalities in the neurons that secrete GnRH. These findings were confirmed at both genetic and cellular levels. The Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies seen in the mice were closely linked to dysfunctional GnRH secretion.

Restoring GnRH production to restore cognitive function

The Inserm scientists were then able to demonstrate that restoring physiological GnRH system function restores cognitive and olfactory functions in trisomic mice.

These findings in mice were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine of the University of Lausanne and head of the Endocrinology, Diabetology, and Metabolism Department at CHUV. Her research focuses on congenital GnRH deficiency, a rare disease which manifests by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy in order to reproduce the natural pulsatile rhythm of this hormones secretion, in order to induce puberty.

The researchers therefore decided to test the efficacy of pulsatile GnRH therapy on cognitive and olfactory deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team was able to demonstrate the restoration of olfactory and cognitive functions in mice.

Pulsatile GnRH therapy improves cognitive function and neural connectivity in a small patient group

The next stage for the scientists and doctors involved a pilot clinical trial in patients to evaluate the effects of this treatment. Seven men with Down syndrome, between 20 and 50years of age, received one subcutaneous dose of GnRH every two hours for 6months via a pump placed on the arm. Cognition and olfactory tests as well as MRI exams were performed before and after the treatment.

From the clinical viewpoint, cognitive performance increased in 6 of the 7 patients with better three-dimensional representation, better understanding of instructions, improved reasoning, attention, and episodic memory. However, the treatment had no impact on the ability to smell. These measures to improve cognitive functions were confirmed by brain imaging conducted by the CHUV Department of Clinical Neurosciences, which revealed a significant increase in functional connectivity.

These data suggest that the treatment acts on the brain by strengthening the communication between certain regions of the cortex."Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions," explains Prvot. "In Down syndrome, pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects," adds Pitteloud.

These promising findings now justify the launch of a larger study with the inclusion of women to confirm the efficacy of this treatment in people with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer's disease.

Source

GnRH replacement rescues cognition in Down Syndrome

Maria Manfredi-Lozano1,2#, Valerie Leysen1,2#, Michela Adamo3,4#, Isabel Paiva5, Renaud Rovera6, Jean-Michel Pignat7, Fatima Ezzahra Timzoura1,2, Michael Candlish8,, Sabiha Eddarkaoui1, Samuel A. Malone1,2, Mauro S. B. Silva1,2, Sara Trova1,2, Monica Imbernon1,2, Laurine Decoster1,2, Ludovica Cotellessa1,2,Manuel Tena-Sempere9, Marc Claret10, Ariane Paoloni-Giacobino11, Damien Plassard12, Emmanuelle Paccou3, Nathalie Vionnet3, James Acierno3, Aleksandra Maleska Maceski13, Antoine Lutti14, Frank Pfrieger15, S. Rasika1,2, Federico Santoni4, Ulrich Boehm8, Philippe Ciofi16, Luc Bue1, Nasser Haddjeri6, Anne-Laurence Boutillier5, Jens Kuhle13, Andrea Messina3,4, Bogdan Draganski14,17, Paolo Giacobini1,2, Nelly Pitteloud3,4*, Vincent Prevot1,2 *

1 Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, UMR-S 1172, Labex DistAlz,Lille, France2 Laboratory of Development and Plasticity of the Neuroendocrine Brain, FHU 1000 days forhealth, EGID, Lille, France3 Department of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital,1011 Lausanne, Switzerland4 Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland5 Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364, Universit deStrasbourg-CNRS, Strasbourg, France6 Univ. Lyon, Universit Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research InstituteU1208, Bron 69500, France7Department of Clinical Neurosciences, Neurorehabilitation Unit, University Hospital CHUV,Lausanne, Switzerland8 Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland UniversitySchool of Medicine, 66421, Homburg, Germany9 Univ. Cordoba, IMIBC/HURS, CIBER Fisiopatologa de la Obesidad y Nutricin, Instituto deSalud Carlos III, Cordoba, Spain10 Neuronal Control of Metabolism Laboratory, Institut d'Investigacions Biomdiques August Pi iSunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigacin Biomdica en Red(CIBER) de Diabetes y Enfermedades Metablicas Asociadas (CIBERDEM), 08036 Barcelona,Spain11Department of Genetic Medicine, University Hospitals of Geneva, 4 rue Gabrielle-Perret-Gentil,1211, Genve, Switzerland12 CNRS UMR 7104, INSERM U1258, GenomEast Platform, Institut de Gntique et de BiologieMolculaire et Cellulaire (IGBMC), Universit de Strasbourg, Illkirch, France13 Neurologic Clinic and Polyclinic, MS Centre and Research Centre for Clinical Neuroimmunologyand Neuroscience Basel; University Hospital Basel, University of Basel, Basel Switzerland14 Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences,Department of Clinical Neurosciences, Lausanne University Hospital and University ofLausanne, Switzerland15 Centre National de la Recherche Scientifique, Universit de Strasbourg, Institut desNeurosciences Cellulaires et Intgratives, 67000 Strasbourg, France16 Univ. Bordeaux, Inserm, U1215, Neurocentre Magendie, Bordeaux, France17 Neurology Department, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig,Germany New address, Institute of Cell Biology and Neuroscience and Buchmann Institute for MolecularLife Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt am

Main, Germany

# these authors contributed equally

* these authors contributed equally

Science, September 1, 2022

https://doi.org/10.1126/science.abq4515

Contact details

Vincent Prvot

Inserm Research Director

"Development and Plasticity of the Neuroendocrine Brain" team leader

Unit U1172 Lille Neuroscience & Cognition Lille, France

Email:vincent.prevot@inserm.fr

Telephone number provided upon request

Nelly Pitteloud

Professor at Universit de Lausanne

Head of Department, Endocrinology, Diabetology, and Metabolism, CHUV

Email: nelly.pitteloud@chuv.ch

Press contact

presse@inserm.fr

medias@chuv.ch

GnRH replacement rescues cognition in Down Syndrome

1-Sep-2022

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A therapy found to improve cognitive function in patients with Down syndrome - EurekAlert