How Fluctuations in Sex Hormones Impact AMD

MDMag — The pathogenesis of conditions of the eye such as age-related macular degeneration (AMD) could be impacted by gender-based differences in hormone fluctuations.

Newly published data from a team of investigators from Temple University’s Sbarro Institute has found that variations in sex steroid homeostasis have an effect on the physiology of human male retinal-pigment epithelial cells (RPEs), which are impacted by the inflammation caused by AMD.

According to the authors, the data from this study show high clinical significance as it considers these steroid fluctuations as the prompters of locale changes in the retina. These changes then are able to impact the pathological situation that occur along with aging in the non-reproductive systems—like the eye.

“The main goal of our investigation was to define whether male gender can be considered a risk factor in developing age-related retinal disease including AMD,” Antonio Giordano, MD, PhD, the director of the Sbarro Institute at Temple University, and lead author, told MD Magazine. “Estrogens have historically been associated with women’s physiology, however, over the last 2 decades, several studies have shown that these hormones play a fundamental role in men.”

The pathogenesis of AMD is still not understood despite intense clinical research, although there has been a link, while controversial, found between AMD and gender—more specifically, the effects on RPEs when exposed habitually to estradiol, a reproductive hormone which aids in treating the symptoms caused by menopause, and progesterone, often used to aid in the treatment of uterine changes for post-menopausal women.

“To mimic sex steroid hormone fluctuations occurring with aging, we exposed retinal pigment epithelial cells, ARPE-19, to acute, prolonged or chronic estradiol and progesterone challenges,” Carlo Astarita, PhD, from the University of Siena and a researcher at Temple, as well as coauthor of the study, said in a statement.

Astarita noted that the researchers found that chronic estradiol treatment resulted in RPE cell death via necrosis, occurring due to mechanisms involving the subcellular localization of the retinoblastoma-related protein pRb2/p130 and the extracellular plasminogen activator inhibitor type-2 (PAI-2).

Conversely, the study revealed that chronic exposure to progesterone caused the nuclear subcellular rearrangement and co-immunolocalization of pRb2/p130 with PAI-2. Additionally, it induced the accumulation of cells in the G2/M phase, and a subsequent reduction in necrosis and a surge in apoptosis.

“Today, the mechanisms governing the action of sex steroid hormones in maintaining the health of the eye are still largely unknown and our investigation offers the unique opportunity to unravel the effects of sex hormones,” Mina Massaro-Giordano, MD, a co-author of the study and professor of Ophthalmology at the Hospital of the University of Pennsylvania, said. “Not only in determining gender differences, but also in affecting the physiology of non-reproductive systems, such as the eye.”

“The biology underlying gender-related circumstances should be considered by the clinicians involved in the treatment of eye conditions such as AMD,” Giordano added.

The study’s findings had implication for the transgender community as well, a community that Giordano referred to as “underserved.”

“Exogenous administration of physiologically significant amounts of sex hormones for long periods of time is a common clinical practice for transgender patients seeking sex reassignment,” he said.

The study received funding in part from a grant from the Ken and Ann Douglas Charitable Foundation and the Sbarro Health Research Organization (SHRO).

The study, “Effect of sex steroid hormone fluctuations in the pathophysiology of male- retinal pigment epithelial cells,” was published in the Journal of Cellular Physiology.

Copied from MDMag post          PubMed Abstract      Article at Journal of Cellular Physiology

Cancer DNA Sequencing Has Potential, but Not a Magic Bullet, Says Expert

recent report by NPR science writer Richard Harris explores the efficacy of DNA sequencing in the treatment of cancer. Antonio Giordano, MD, PhD, President of the Sbarro Health Research Organization (SHRO) at Temple University comments on the potential, and the shortfalls, of this strategy in both the clinical and research setting.

“Only a few of the genetic mutations that occur in cancer actually act as ‘drivers’ to tumor malignancy,” Giordano says. “Most act simply as ‘passengers’ in the tumor.”

“This makes finding a genetic target for treatment like finding a needle in a haystack,” says Giordano.

With research focused on cell cycle mechanisms for over 30 years, Giordano’s work has often concentrated on the impact that genetic mutation has on natural cellular processes and the subsequent effect on the growth and spread of cancer.

“We have identified proteins which act as the engine of the cells, such as the cyclin-dependent kinases, as well as a key member of the retinoblastoma family of tumor suppressors which act as the ‘brakes’ on tumor growth,” says Giordano. “Based on this fundamental knowledge, with my collaborator Dr Francesca Pentimalli, we are currently developing strategies that can specifically target these mechanisms in cancer cells.”

“Many therapies are aimed at inhibiting active oncogenes, often identified through DNA sequencing,” Giordano says. “Alternatively, we are testing drugs designed to restore the body’s natural ability of the retinoblastoma protein RBL2/p130 to suppress cancer.”

“We predict this will be successful in treating cancer types in which the RBL2/p130 ability to inhibit tumor growth is suppressed by other oncogenic pathways, rather than mutated itself,” says Giordano.

The major difficulty in using DNA sequencing to identify a treatment target, Dr. Giordano says, lies in the heterogeneic nature of tumors.

“No tumor is identical to another from the molecular point of view, and, even a tumor from a single individual changes over time. Subpopulations and mutations occur as the tumor develops, through progression, and after it is challenged therapeutically,” Giordano says.

“This often renders DNA sequencing insufficient on its own to capture the complexity of tumour cells’ genetic machinery. Eventually the tumour microenvironment affects the stability and function of the protein coded by DNA and can ‘muddy the water’ when it comes to identifying a single genetic treatment target,” says Giordano.

“Fortunately, many alterations in cancer affect a limited number of cancer signalling pathways, and we already have therapeutic tools for many of these targeted genes in our anticancer drug arsenal,” Giordano says.

Lastly, Giordano believes more emphasis should be placed on effective communication of scientific breakthroughs to doctors and patients.

“Cancer DNA sequencing, and even other types of profiling, can be very informative,” says Giordano, “but the main hurdle is the cost-effectiveness of these approaches which cannot be routinely used in the clinical practice.”

“For example, late mutation can occur during the natural progress of tumor growth, and these sometimes act as a marker of resistance to treatment,” says Giordano. ”Similar to the story on NPR about Ben Stern, a patient in which a previously treated tumor had grown back, doctors and patients should consider the timing and signs of when DNA sequencing may offer a solution.”

“But sensational announcements should be avoided,” cautions Giordano, “and clinicians should avoid looking to DNA sequencing as a ‘magic bullet.’”

“The winning recipe must be to build on step-by-step achievements of research aimed at the same target: to improve the survival of patients with cancer,” Giordano concludes.

Original Newswise Release

Detecting Pompe Disease with More Accuracy Key to Urgent Intervention

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Credit: Sbarro Health Research Organization (SHRO)
“Vacuolated PAS positive lymphocytes in the peripheral blood of Pompe patients”

Researchers identified a new, more sensitive screening test to recognize Pompe disease, a metabolic disorder affecting cellular processing of glycogen in numerous tissues of the body. The test detects the presence of more than four lymphocytes containing glycogen in blood films of subjects with suspicious neuromuscular disease, and has demonstrated 100% sensitivity and 94% specificity identifying patients with Pompe disease. Moreover, positivity of vacuolated lymphocytes to the Periodic-Acid Schiff staining (PAS) seems to be an hallmark of autophagic myopathies. This new method of detection will allow clinicians to differentiate Pompe disease and autophagic myopathies from other neuromuscular disorders more accurately.

The study was published online in December 2017, in the Journal of Cellular Physiology.

Pompe disease, also known as Glycogen storage disease type II, is a metabolic disorder caused by an accumulation of glycogen in the lysosomes due to a deficiency of alpha-glucosidase, a lysosomal enzyme acid. The build-up of glycogen affects various body tissues, particularly heart, skeletal and respiratory muscles, as well as lymphocytes in peripheral blood. The classic infantile form of Pompe disease, presenting with marked generalized muscle weakness and severe hypertrophic cardiomyopathy, rapidly progresses to a fatal outcome. The late-onset form is characterized by slowly progressive myopathy involving proximal, limb-girdle, paraspinal, and respiratory muscles without cardiac involvement. Vacuolar myopathy typical of Pompe disease is the most frequent myopathy due to an impairment of autophagy, the main natural mechanism necessary to degrade and recycle cellular components.

Enzyme replacement therapy for Pompe disease became available in 2006 and resulted in dramatic reduction of mortality and morbidity for Pompe patients. The discovery and commercialization of this therapy figure prominently in the plot of the 2010 film “Extraordinary Measures,” starring Harrison Ford and Brendan Fraser. Since an early start of therapy is associated with better clinical outcomes, early diagnosis is essential in order to achieve the maximum benefit.

The research was conducted by a team of scientists lead by Dr. Simone Sampaolo and Mariarosa AB Melone, Department of  Medicine, Surgery, Neurology, Metabolic and Aging Science, Reference Center for Neurological and Neuromuscular Rare Disease, University of Campania “Luigi Vanvitelli”, Naples, in collaboration with Dr. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Department of Biology at Temple University, Philadelphia.

Pompe disease is an underdiagnosed disorder, and considering that therapy is now available, early diagnosis is crucial to obtain the best prognosis. This research proposes a reliable, cheap, simple, first-level screening method to support the diagnosis of autophagic vacuolar myopathy as Pompe disease. The test is minimally invasive and could be used as a screening test in high-risk populations, such as pregnant women and people with a family history of neuromuscular disorders.

Newswise Original Release         PubMed Abstract     Journal of Cellular Physiology

Celebrating Our Women’s Research Team!

At S.H.R.O. we are so proud of the remarkable advances our researchers are contributing to the field of medical research.

Members of our Women’s Research Team are currently studying mechanisms contributing to breast, lung, ovarian, and colon cancer.

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GoFundMe to Benefit our Women-Led Research Initiatives and Professional Advances

This month to celebrate our women scientists we are launching a GoFundMe campaign where all proceeds will go towards women-led research projects and further medical education aimed at curing and diagnosing cancer.

DONATE TO SUPPORT OUR WOMEN SCIENTISTS TODAY!   

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Scientist of the Month

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Congratulations Mia Robb, Future Dr. Robb and Scientist of the Month!

We are very happy to announce that our scientist Mia Robb was just accepted into PCOM’s medical class of 2018! Mia has worked at S.H.R.O. for the last 9 years and we are so proud of her continued commitment to the field.

As part of our GoFundMe campaign this month we will be donating 25% of all proceeds raised to begin a scholarship fund for Mia’s medical school.

 

From Medical Discovery to Food and Fine Arts, Italian-American Contributions Celebrated at Annual Foundation Conference

 

Newswise — At this year’s 42nd annual NIAF Gala Weekend at the Washington Marriott Wardman Park Hotel in D.C., all aspects of Italian heritage were celebrated, including food, the fine arts, and scientific discovery. The weekend’s events included the medical conference, “Mediterranean Diet, Human Health and Longevity,” sharing the latest in research into a vital part of Italian culture –– diet and food. Conference presentations explored how the recipes of Italian grandmothers are among the healthiest in the world and can even help fight disease, such as cancer.

Organized in collaboration with the Sbarro Health Research Organization (SHRO) at Temple University, the November 4, 2017 conference included opening remarks by SHRO President Antonio Giordano, and the presentation of the Giovan Giacomo Giordano NIAF Lifetime Achievement Award for Ethics and Creativity in Medical Research. The award was established in memory of Antonio Giordano’s father, Giovan Giacomo Giordano, a renowned pathologist and former professor  of the Department of Anatomic Pathology at the University of Naples and chairman of the Pathology Department of the National Cancer Institute of Naples “Pascale,” who dedicated much of his life to cancer research.

“Italians have been at the forefront of scientific discovery since the time of the Romans, and this is just an extension of that history,” said Gabriel Battista, Co-Chairman of the NIAF Board of Directors. “For many Italians, this researcher has confirmed what they already knew.”

Battista’s parents were born in Italy and he grew up eating the Mediterranean Diet. Today, his favorite dish consists of his homemade marinara sauce, which is made with tomatoes he finds at a farm, paired with a good bucatini.

“This isn’t a surgical procedure or a pill, it’s really good food,” said Immaculata De Vivo,  professor of medicine at Harvard Medical School, whose research has been dedicated to the mechanisms of cancer. “There really is no downside to promoting this diet.”

De Vivo explained that the Mediterranean Diet consists of little red meat, fish as the main source of protein, olive oil as a source of fat, and lots of grains, fruits and vegetables. She added that this was originally a diet for poor farmers who grew all of their own food and ate in small portions.

In an effort to understand the Mediterranean Diet as it relates to the mechanisms of cancer, De Vivo has conducted research on telomeres, which are found at the ends of human chromosomes.

Over time, a person’s telomeres become shorter as a natural part of aging. However, De Vivo found that an unhealthy diet can contribute to the shortening of telomeres at an unnaturally quick rate, which can make a person more susceptible to disease. When participating in diets such as the Mediterranean Diet, telomeres become stronger and shorten at a normal rate.

“We all knew that the Mediterranean Diet consisted of healthy foods, but this allowed us to look under the hood –– to understand why,” De Vivo said. “We found that it is the synergy of all of these ingredients, and maybe one glass of wine with a meal, that makes the diet healthy.”

As the king of the Mediterranean Diet and the second most-consumed food in the world, the tomato was also studied by the Sbarro Health Research Organization, alongside researchers at the University of Siena in Italy.

Their research found that the genetic characteristics of San Marzano and Corbarino tomatoes help block molecules involved in cell division, slowing or sometimes stopping the spread of cancer cells, such as gastric cancer.

“The term, ‘We are what we eat,’ is true, but we don’t actually understand the meaning of the cliché,” said Antonio Giordano, the founder and director of Sbarro. “We go to a supermarket without truly knowing what is really healthy or what happens to us when we eat certain foods. By conducting this research, we are unveiling exactly what about certain tomatoes makes them healthy.”

The intersection of food and good health in the Italian community was on full display in the NIAF exhibit hall, as a crowd gathered around Romana Sciddurlo, grandmother of Rosella Rago, the host of the Italian cooking show “Cooking with Nonna.” Nonna Sciddurlo kneaded the pile of dough the way her own grandmother had taught her, adding a little water in intervals to ensure a perfect texture. She smiled as she recreated the generations-old pasta recipe from scratch. They cooked and served different recipes of Sciddurlo’s homemade sauce using the same garden-grown ingredients and unique techniques that Italian grandmothers have used for generations.

To them, preserving the recipes of Italian grandmothers means to celebrate the heritage of Italian culture –– a heritage that also includes sophistication, style, community, and scientific discovery.

In addition to the achievements on display at the medical conference, the NIAF Gala Weekend demonstrated how Italian heritage extends beyond good food and scientific discovery to include many aspects of the arts and the business world. Musical performances during the gala included Sicilian-born classical guitarist Tom Sinatra, and acclaimed vocalists Alfio Bonanno, James Valenti, and Vittorio Grigolo. Honoree Jon DeLuca, son of Fred DeLuca, founder of the Subway restaurant chain, addressed the gala pledging a large gift to the foundation’s scholarship program. Emmy-winning actor Michael Badalucco gave the evening’s welcoming remarks, including a recitation of a poem by Sicilian poet Nino Provensano. Fox Business Channel anchor Maria Bartiromo shared co-host duties with NIAF President John Viola, and honored guests in attendance included Supreme Court Justice Samuel Alito.

“[NIAF] does a lot of good by offering scholarships and raising money. But that’s not all this organization is all about,” said Viola. “We are about community and family. We are about remembering where we came from and celebrating our heritage as Italians.”

Original Newswise Post

New Cancer Therapies Earn Sbarro Health Research Organization President Antonio Giordano 2017 CORE Prize for Oncology

The CORE Prize for Oncology 2017 was awarded to Professor Antonio Giordano for his groundbreaking discoveries in the field of the cell cycle, which have established an understanding of the fundamental mechanisms at the basis of cancer and the development of a new class of anticancer therapeutics.

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Prof. Carmine Pinto, President of The Italian Society of Clinical Oncologists and Chairman of Oncology at the National Cancer Institute ‘Santa Maria Nuova’ of Reggio Emilia, presents the award to Prof. Giordao

 

Newswise — Reggio Emilia Italy, 22nd November, 2017 — The 2nd International Congress on “Clinical Needs and Translational Research in Oncology,” was held November 22-23, 2017 at the Centro Oncoematologico Regio Emilia (CORE), of the USL-IRCCS of Reggio Emilia, bringing together prominent oncologists from Europe and the United States.

The CORE Prize for Oncology 2017 was awarded to two prestigious researchers, Professor Luca Gianni, Director of the Department of Oncology of the IRCCS Hospital, S. Raffaele of Milan, and Professor Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University of Philadelphia (USA), and Professor of Anatomy and Pathology of the University of Siena. Prof. Giordano was honored for his groundbreaking discoveries in the field of the cell cycle which have allowed for an understanding of the fundamental mechanisms at the basis of cancer and the development of a new class of anticancer therapeutics.

“It is a privilege for us,” says Dr. Carmine Pinto, Director of Medical Oncology, President of the Conference and former President of the Italian Association of Medical Oncology, “to be able to award the CORE Prize for Oncology 2017 to these two outstanding scientists. The discovery of the tumor suppressor RBL2/p130 by Professor Giordano has paved the way for the identification of key mechanisms underlying cell cycle regulation and new therapeutic possibilities, from molecular drug therapies to the prospects of gene therapy. Two further outcomes of these studies, impacting on care strategies, were then the identification of two additional cyclin dependent kinases, CDK9 and CDK10, and of the NSPs (Novel Structure Proteins) a new protein structure related to cell division.”

Gianni was cited for his international clinical trials for neo-adjuvant breast cancer, which advanced the treatment of breast cancer patients through the creation of a sensitivity/resistance rating for drug therapies used in both HER2 positive and negative patients, changing the paradigm of treatment for these women.

The meeting addressed issues related to the identification of new molecular targets for tumor diagnosis and treatment, and their tissue and blood determinations, combining research, innovative technology, and therapies. One focus was also devoted to immunotherapy, one of the newer areas of promise in cancer care. Participants discussed how to identify the pathologies and the patients who can benefit most from immunotherapy both in terms of healing and prolonged survival. The topic of multidisciplinary integrated treatments, involving both oncologists, radiotherapists and surgeons, for treating rectum tumors, liver metastases from colon cancer, and tumors of the head-neck area will be analyzed also for as concerns the criticalities for resources and organizational aspects. Finally, discussions addressed issues concerning drug access and public health, in order to optimize resources in terms of value, cost and effectiveness, with representatives of the Italian Medicines Agency (AIFA), Oncologic Networks and Regions working together with oncologists, patients and other stakeholders.

This second international meeting is an accomplishment for the department of oncology at Reggio Emilia, which is at the forefront of both cancer research and care. Owing to a well-integrated multidisciplinary approach, including primary prevention, screening, therapy, rehabilitation and palliative care, Reggio Emilia earned the highest rates of survival for certain cancers among other Italian cities and regions. The commitment to clinical research, which introduces new care strategies and makes innovative medicines available to patients, coupled with the results of translational research and the Tumor Registry, make Reggio Emilia an important reference point for Oncology in Italy and internationally.

During the Congress, in conjunction with the scientific work, attendees were also privileged to visit an exhibition of works by the painter Augusto Daolio, made possible by the Association Augusto per la Vita.

Original Newswise release

 

Italian-American Researchers Present Mediterranean Diet, Health, and Longevity at Annual Medical Conference

Sbarro Health Research Organization President Antonio Giordano introduces program at National Italian American Foundation 42nd Anniversary Gala Weekend In Washington D.C.

The Sbarro Health Research Organization, Inc., in collaboration with the National Italian American Foundation, Temple University’s College of Science and Technology and the Giovan Giacomo Giordano Foundation, also thanks to the kind unconditioned sponsorship of Pastificio di Martino, will organize a medical conference discussing diet and nutrition. “Mediterranean Diet, Human Health and Longevity” will be held in the Roosevelt Room 2 of the Washington Marriott Wardman Park Hotel in Washington, D.C. on November 4 from 9 to 11 a.m. as part of the  NIAF 42nd ANNIVERSARY GALA WEEKEND. (www. niaf.org)

The president of SHRO, Antonio Giordano, MD, PhD, will begin by introducing SHRO’s recent research of the Mediterranean diet as it relates to cancer prevention, followed by the words of guest speakers. Dr Giordano is also the director of the Sbarro Institute for Cancer Research and Center at Temple University in Philadelphia, PA.

The guest speakers for the conference will include Dr Michele Masucci, Vice President for Research Administration at Temple, Dr Immaculata DeVivo,  Professor in Medicine at Harvard Medical School, who’s research has been dedicated to cancer causation, and Dr. Daniela Barone, who will be prized by the scientific committee of the NIAF for her contribution to the elucidation of the biochemical effects of “corbarino” tomato extracts on cancer cells. Mr. Carmine Mariano Esq, chief of the administration of the National Cancer Institute of Naples “Pascale”, in Italy, will attend the ceremony, in recognition of the important collaboration among his Institution and the SHRO in the “Corbarino” “San Marzano” project.

In a side event, the Giovan Giacomo Giordano Foundation will also present Dr Enrico Bucci, Director of the System Biology program at SHRO and well-known research integrity expert, the Giovan Giacomo Giordano NIAF Lifetime Achievement Award for Ethics and Creativity in Medical Research. 

The award was established in memory of Antonio Giordano’s father, Giovan Giacomo Giordano ­­–– the late professor, renowned pathologist and former professor  of the Department of Anatomic Pathology at the University of Naples and chairman of the Pathology Department of the National Cancer Institute of Naples “Pascale”, in Italy, who dedicated much of his life to cancer research.

Original Newswise Post

Muse for cancer-fighting tomatoes study? Italian food

Antonio Giordano, who led the study that showed whole tomato extracts can slow the growth of stomach cancer, says Italian cuisine inspired him to investigate the dietary staple’s cancer-fighting ability.

For his latest research discovery—which showed that certain tomato extracts can slow the growth of gastric cancer—Antonio Giordano’s muse was simple: the food back home.
“What inspired me was my country, Italy,” said Giordano, a world-renowned researcher specializing in cancer and genetics and director of the Sbarro Health Research Organization housed at Temple’s College of Science and Technology. “The Mediterranean diet is considered one of the main reasons why that population has more longevity and lower rates of certain types of cancer.”
Giordano, along with a team of scientists from Temple, the University of Siena in Italy and the National Cancer Institute of Naples in Italy, conducted blind tests on seeds from various species of tomato. The tests showed that two varieties, San Marzano and Corbarino, slowed the growth of gastric cancer cells by blocking the molecules involved in cell division. Though components of tomatoes, such as the antioxidant lycopene, have been studied in the past, Giordano’s research was unique in that it used whole tomato extracts.
“We chose gastric cancer because it is one of the most aggressive types of tumors of which there is little knowledge,” Giordano said. “There are not many therapies.”
His challenge now that he’s demonstrated the ability of the tomato extracts is to explore whether the same varieties of tomato grown outside of specific regions in Italy will maintain those cancer-fighting properties. His team is now growing the tomatoes in Philadelphia and other areas of the country to test seeds germinated in U.S. soil.
“The environment can change the properties,” Giordano explained. “The soil where they grow [in Italy] has a particular richness of minerals, is very watery and is close to Mount Vesuvius, so there is a volcanic type of presence there. That can be a major change in the impact.”
Giordano said he also plans to study the effects of food preparation and cooking on the tomatoes’ ability to fight cancer and, eventually, to explore their effects on other types of cancer, including colon, breast and prostate, as well as on neurological diseases, such as Alzheimer’s. The study’s implications have the potential to be far-reaching—for development of both supplements to current cancer treatments and lifestyle changes aimed at cancer prevention.
“The research suggests that this kind of nutrient in general has the ability to protect our cells in our body,” Giordano said. “That is actually the major discovery.”

Research Reveals Gene Differences in Mouse Model Versus Humans

Retinoblastoma family, Rb2 gene, tumor suppressor gene, senescence, mesenchymal stem cells

The mouse is the most widely used model organism to understand human genetics, biology, and diseases in the research setting. Aspects of gene function in humans can be predicted by studies of the corresponding gene in mice, but new research findings have revealed important divergences between the species which scientists will need to understand better through further investigation.

The research group that made this discovery was lead by Professor Umberto Galderisi at the Department of Experimental Medicine, Campania University “Luigi Vanvitelli” in Naples, Italy, and Antonio Giordano at the Sbarro Institute for Molecular Medicine  department of Biology at Temple University in Philadelphia. Their paper, “Misidentified Human Gene Functions with Mouse Models: The Case of the Retinoblastoma Gene Family in Senescence” by Nicola Alessio et al., has been published in the journal Neoplasia.

These differences can have a significant impact on the efficacy of research findings to infer gene function in humans by means of the so-called knock-out, or in situexperiments carried out in mouse models. In their paper, the authors describe how the retinoblastoma gene family may represent an illustrative example of this possible gene divergence between humans and mice. This gene family comprises three members (RB1, RB2/P130, and P107), which regulate several aspects of cell life, such as cell cycle, apoptosis, senescence, and differentiation.

Researchers analyzed differences in functions between mice and humans in this gene family that cannot be overlooked, if scientists are to be able to interpret mouse model experiments for purposes of diagnosis and treatment of human diseases.

“We decided to investigate the role of retinoblastoma gene family members in the regulation of the senescence process,”  says Galderisi. “Senescence, or cellular aging, is the deterioration of activities that can occur in the cells. This process may have either anti- or pro-cancer functions, depending on context. For this reason, studying molecular mechanisms governing senescence is of great importance for human diseases,” Gladerisi says.

“Our interest resides on the fact that, in human mesenchymal stromal cells (MSCs), the acute silencing of RB1 did not induce unrestricted proliferation as had been described mouse model studies,” says Giordano, “but, rather, resulted in cell cycle arrest and cellular senescence.” In other words, the effect of silencing the RB1 gene had the opposite effect in the mouse model versus human, indicating that the well-known RB1-P16 axis involved in senescence may not have a general role.

The authors believe their study demonstrates that the function of a protein has many aspects that are context-dependent, such as species and cell type.

These findings could be useful as a general paradigm for caution when inferring the role of a gene in humans, based on animal studies. Furthermore, human MSCs are being studied in several ongoing clinical trials, and the drivers of senescence described in this study should be thoroughly understood in order to maintain strict control for their safe and effective use in research.

Original newswise release                      Neoplasia article

Targeting Cell Cycle Reactivation Caused by Inflammation May Provide the Way to Prevent Neuron Death in Alzheimer’s Disease

Newswise — Neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), and Huntington’s Disease are typically characterized by progressive apoptotic death of neurons. Apoptosis, or programmed cell death, in these neurodegenerative disorders is believed to be triggered by a process of cell cycle reactivation, however, the mechanisms involved in this phenomenon remain largely unsolved. Researchers studying the role of inflammation as well as the expression of Rb family proteins (RB1/p105, RBL1/p107 and Rb2/p130) in neuronal death, have discovered a clue to the mechanism for neuronal degeneration and possible target for a therapeutic approach to these disorders.

The research was conducted by a team of scientists lead by Dr. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Department of Biology at Temple University, Philadelphia in collaboration with University of Siena Italy. Their study was published online on August 2017, in the international journal Cell Cycle. The study was funded in part by a grant from the Ken and Ann Douglas Charitable Foundation.

These findings are significant because mature neuronal cells are in a permanent state of cell cycle arrest, and they do not undergo the same process of cell death and replacement as other tissues throughout the body. Shedding light on the cause for the neurodegeneration occurring in diseases like Alzheimer’s and Parkinson’s, the study authors found that inflammation induced cell cycle re-entry, causing neurons to resume the cell cycle and undergo apoptotic cell death.

The study was performed in an in vitro model of brain inflammation, which revealed an aberrant  expression of p107 and p105 following the inflammatory insult, leading researchers to conclude a possible implication of these factors in the reactivation of the cell cycle in neurons.

The pRB family is comprised of factors well known for their ability to regulate the cell cycle, and has been largely explored in cancers for their role as tumor suppressors.

Dr. Giordano’s team provides novel information on the pleiotropic activity of pRB proteins extending the investigation to fields outside of oncology. The concept emerging from their study could help in formulating innovative therapeutic approaches to halt  neurodegenerative processes like  Alzheimer’s Disease.

“Alzheimer’s Disease, similar to other neurodegenerative diseases, is an incurables disorder affecting populations worldwide,” Dr. Giordano says.  “However, in recent years, scientists have made great advances in uncovering   the cause of these pathologies. As we discover novel elements correlated to the pathways involved in these diseases, we are confident that we will be able to treat and prevent them.  Albeit it is still at an early stage, our study brings to light an important aspect of this mechanism that will speed our progress toward this common goal,” Dr. Giordano concludes.

 

Original Newswise Release         Cell Cycle Article        PubMed Abstract