Source:https://www.joslin.org/ Reviewed by Alina Shrourou, B.Sc. (Editor)Oct 22 2018Recent studies have linked development of type 2 diabetes and impaired metabolic health individuals to their parents’ poor diet, and there is increasing evidence that fathers play an important role in obesity and metabolic programming of their offspring.In a new study published today in the journal Diabetes, researchers at Joslin Diabetes Center have shown that paternal exercise has a significant impact on the metabolic health of their offspring well into adulthood.The study was led by Laurie Goodyear, PhD, senior investigator and head of the Section on Integrative Physiology and Metabolism at Joslin and professor of medicine at Harvard Medical School. The study was co-led by Kristin Stanford, PhD, a physiology and cell biology researcher who is now with The Ohio State University College of Medicine at the Wexner Medical Center.Related StoriesSupervised fun, exercise both improve psychosocial health of children with obesityRegular physical activity can be effective in reducing pain from arthritisResearchers identify molecular pathway underpinning exercise and improved motor learningGoodyear and Stanford investigated how a father’s exercise regimen would affect his offspring’s metabolic health. Using a mouse model, they fed male mice either a normal diet or a high-fat diet for three weeks. Some mice from each diet group were sedentary and some exercised freely. After three weeks, the mice bred and their offspring ate a normal diet under sedentary conditions for a year.The researchers report that adult offspring from sires who exercised had improved glucose metabolism, decreased body weight and a decreased fat mass.”It really shows how important it is for men to exercise prior to conceiving because it will have lifelong effects on the health of their offspring. When we put the males on a high-fat diet, it had a terrible effect on the offspring; but what was surprising was that situation was completely reversed when the male added in exercise. So translated to humans, even if dad isn’t eating really well, he can still affect his offspring positively by exercising,” said Goodyear. “This also will dramatically decrease the risk of developing type 2 diabetes for the offspring,” added Goodyear.The team also found that exercise caused changes in the genetic expression of the father’s sperm that suppress poor dietary effects and transfer to the offspring.”We saw a strong change in their small-RNA profile. Now we want to see exactly which small-RNAs are responsible for these metabolic improvements, where it’s happening in the offspring and why,” Stanford said.The researchers believe the results support the hypothesis that small RNAs in sperm could help transmit paternal environmental information to the next generation.
Reviewed by James Ives, M.Psych. (Editor)Apr 19 2019Researchers at The University of Texas MD Anderson Cancer Center have discovered that triple negative breast cancer (TNBC) cells can develop resistance to frontline, or neoadjuvant, chemotherapy not by acquiring permanent adaptations, but rather transiently turning on molecular pathways that protect the cells.The study, published today in Science Translational Medicine, also identifies a vulnerability that may provide a new treatment option for resistant TNBC. Among those pathways activated is a metabolic process, known as oxidative phosphorylation, which can be targeted by a small-molecule drug developed by MD Anderson’s Therapeutics Discovery division.”Modern chemotherapy is highly effective for nearly half of patients with triple negative breast cancers,” said corresponding author Helen Piwnica-Worms, Ph.D., professor of Experimental Radiation Oncology. “However, the remaining half of women will not fully respond to neoadjuvant chemotherapy, and there currently are no approved treatments to improve outcomes for them. Understanding how tumor cells become resistant will allow us to identify new targets to better treat resistant disease.”According to the American Cancer Society, an estimated 268,000 women will be diagnosed with breast cancer this year, of which 15 to 20 percent will have TNBC. Standard treatment for patients with TNBC is neoadjuvant chemotherapy followed by surgery to remove the tumor. For women with tumors that don’t fully respond to chemotherapy, there is a much higher risk of recurrence and death from the disease, said Piwnica-Worms.In order to study how TNBC cells become resistant to treatment, the researchers created mouse models, known as patient-derived xenografts (PDXs), of TNBC using tumor samples from patients enrolled in the ARTEMIS clinical trial, led by MD Anderson’s Breast Cancer Moon Shot™.Patients enrolling in ARTEMIS have tumor biopsies taken before and after neoadjuvant chemotherapy treatment, which enable researchers to study why some tumors are resistant and discover more effective strategies to bring cures to more patients. The work is part of MD Anderson’s Moon Shots Program™, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.Related StoriesAI-enabled device detects if targeted chemotherapy is workingRutgers researchers create new device to see if targeted cancer therapy is workingScientists discover how resistance to the chemotherapy drug 5-fluorouracil arisesPiwnica-Worms’ team identified several PDX models that responded to chemotherapy at first, but eventually developed resistance and resumed tumor growth. If treatment was paused, however, the residual tumors once again became sensitive to chemotherapy, indicating the resistance was temporary.Under the microscope, tumors showed distinct changes during treatment, but regrown tumors appeared similar to those before treatment. Further, an analysis of individual tumor cells showed that the heterogeneity of cells in a given tumor was maintained after treatment, suggesting that chemotherapy did not select for a small subset of resistant cells.Characterization of gene expression changes revealed a set of pathways activated as part of the resistant state, which were turned off when chemotherapy was discontinued. The researchers confirmed many of these molecular changes were mirrored in biopsies taken from ARTEMIS patients.Hoping to find new treatment targets for resistant TNBC, the researchers discovered that these cells had become dependent on oxidative phosphorylation for energy production. This pathway is the target of IACS-10759, the first-small molecular discovered and developed by MD Anderson’s Therapeutics Discovery division.When treating the PDX mice with IACS-10759 following chemotherapy treatment, the researchers observed a synergistic effect, suggesting sequential treatment of chemotherapy and IACS-10759 could prolong the duration of treatment response. IACS-10579 is now in clinical trials for a variety of hematological and solid cancer types.”Our study provides a compelling rationale for defining additional properties that enable triple negative breast cancers to survive chemotherapy treatment, so that combination therapies can be developed to eradicate this disease,” says Piwnica-Worms. “A long-term goal is to avoid the use of chemotherapy in patients with resistant disease and instead employ targeted therapies to avoid unnecessary treatments and harsh side effects.”Source: https://www.mdanderson.org/
The good news about the newly discovered protein is that it can be inhibited, thus inactivating cell processes within ovarian cancer cells to switch them from a constitutively proliferative cell cycle to one which results in senescence, or going to sleep. The key role of the protein was identified on cell culture experiments by researchers at Penn State College of Medicine.The current study focused on teasing out the differences in the metabolism of ovarian cancer cells by comparing them with cells from a normal fallopian tube.The route used to achieve this was quantitative spectrometry, which helped analyze the metabolites produced by various cellular pathways in the two type of tissue. Among the differences, it was revealed that cancer cells utilized glucose, a form of sugar, via the key energy cycle called the citric acid cycle, far more often, as against the more common use of an oxygen-requiring pathway called aerobic glycolysis. This accounts for the presence of a high level of citric acid activity in all high-grade serous ovarian cancer cells. Related StoriesLiving with advanced breast cancerUsing machine learning algorithm to accurately diagnose breast cancerMother calls for protein shake regulation after daughter diesThis means that many therapies which inhibit the breakdown of glucose (glycolysis) to destroy cancer cells may be quite ineffective. Dahl commented that this could often result, in fact, in the production of toxins that harm normal healthy tissue.Instead, the team in the current study looked at the effects of inhibiting the wildtype or normal form of an enzyme, isocitrate dehydrogenase 1 (IDH 1), which plays a vital part in the citric acid cycle. They selected this protein because it was the only one in this pathway that is expressed at higher levels in both adherent and spheroid tumor cells. Increased activity of this enzyme severely impacts progression-free survival, which is an important outcome measured in assessing the effectiveness of any cancer therapy.Mutants of this protein are common in other tumors, but the wildtype form is typically present in cells within HGSC. The researchers hypothesize that the presence of this enzyme is an important advantage to these cells, and its inhibition is a key step to inducing senescence.The researchers found that suppressing the work of this protein stopped cell division completely by suppressing the activity of multiple other genes, inhibiting vital metabolic pathways. Both adherent cells of the primary tumor, and spheroid cells of secondary HGSC, become senescent when the wildtype IDH 1 enzyme is inhibited. Thus, this could be an excellent way to treat HGSC at all stages. This is an important consideration, as ovarian cancers are rarely diagnosed at early stages.While there are already FDA (US Food and Drug Administration)-approved drugs against one of the mutant forms of this enzyme, the team wondered whether they would work against the wildtype form as well. They found that one did, and this is now a part of their continued research agenda.Aird says, “One of our long-term goals is to try and repurpose this already-approved drug as a treatment for this form of ovarian cancer.” Besides adapting existing drugs against the enzyme to fight this type of cancer, the researchers want to examine the differences in the metabolic functioning of normal and HGSC cells more closely. Another goal is to examine the effectiveness of combining IDH 1 inhibitors with other treatments. Journal reference:Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer, Erika S. Dahl, Raquel Buj, Kelly E. Leon, Jordan M. Newell, Yuka Imamura, Benjamin G. Bitler, Nathaniel W. Snyder and Katherine M. Aird, Mol Cancer Res June 17 2019 DOI: 10.1158/1541-7786.MCR-18-1233, http://mcr.aacrjournals.org/content/early/2019/06/17/1541-7786.MCR-18-1233 By Dr. Liji Thomas, MDJul 14 2019A new study shows that targeting a specific protein found within quickly spreading high-grade serous carcinomas (HGSC) of the ovary could help contain these cancers. HGSC is the most common and deadly form of epithelial ovarian cancer, which is itself the deadliest cancer of the female reproductive tract. When HGSC spreads outside the ovaries, within the peritoneal cavity, it forms detached balls called spheroids, which may look and act differently from the adherent cells of the primary tumor.The study is published in the current issue of the journal Molecular Cancer Research. However, as researcher Erika Dahl explains, “A hallmark of cancer cells is that their metabolic processes are often different from normal, healthy cells.” This is called metabolic reprogramming. As one of the outcomes, study author Katherine Aird says, “Cancer cells can grow forever without stimulus.” 70% of HGSC relapse despite treatment, becoming resistant to chemotherapy, which makes the new discovery a true potential breakthrough in the treatment of this tumor.All life at cellular and organism level depends upon thousands of life processes that provide and degrade a range of chemicals required for proper function of the cells and tissues. These intricately interdependent processes together they make up the body’s metabolism. Cancer cell Illustration. Image Credit: Jovan Vitanovski / Shutterstock
The new team in Renault’s driving seat face some politically sensitve decisions, with the company ingrained in the French psyche Gaetan Toulemonde, a French auto analyst at Deutsche Bank, told AFP that French interference is a problem and urged Renault to reduce its stake in Nissan.”Don’t forget Volvo more than 20 years ago. The marriage broke up because of the French state,” said the expert, referring to a failed merger between Renault and the Swedish manufacturer.’National property’Despite ongoing strains, analysts generally agree the two firms are now so closely interconnected that a split would be catastrophic.They need each other to develop the technology for electric vehicles, automated driving and connected cars—as well as to compete with the likes of Toyota and Volkswagen, said Lewis.”Given their platform development for the next decade is already intertwined, divorcing now would be difficult” she added.Nakanishi agreed, saying it would now be “impossible” now to end the alliance. “It took 20 years to get to this level. It would take 20 years to unwind,” he said.But Renault is also deeply ingrained in the economy and psyche of France, making any reduced presence politically sensitive.”I want the French people to know: not a day goes by where we are not following as closely as possible the situation of Renault and the alliance,” said Economy Minister Bruno Le Maire.And the bond between France and Renault was summed up in an editorial in the regional French press after the appointments were made public.”Which family has not one day driven in a Renault… it embodies the car of the people.”Referring to French rock star Johnny Hallyday, the editorial concludes: “Renault is to the car what Johnny was to French music. National property.” Explore further Citation: Nissan-Renault on smoother road but speed bumps loom: analysts (2019, January 25) retrieved 17 July 2019 from https://phys.org/news/2019-01-nissan-renault-smoother-road-loom-analysts.html “They need to reduce their stake. That is the only solution to regain trust and make the alliance workable,” added Nakanishi, as reports in the Japanese media said Paris was pushing for a full-on merger. Renault’s appointment of a new leadership duo to replace the detained Carlos Ghosn should ease tensions with Japanese partner Nissan, analysts say, although the French state’s close involvement remains a brake on ties. Carlos Ghosn took Nissan from the verge of bankruptcy and built it into the key partner of a fractious alliance France pushes Japan to accept Renault-Nissan merger: reports Ghosn was the linchpin of the three-way alliance that also includes Mitsubishi Motors, credited with driving together a sometimes fractious threesome with headquarters 10,000 kilometres apart to become the world’s top-selling auto group.But his shock arrest in Tokyo on charges of financial misconduct immediately drove a wedge between Nissan and Renault, with dark mutterings in Paris of a “coup” orchestrated by CEO Hiroto Saikawa to depose his former mentor and seize more power within the group.Saikawa himself confessed Thursday that communications had been “a bit difficult” since the arrest, noting that while Nissan had immediately jettisoned Ghosn as chairman, Renault kept him on as they awaited evidence against him.However, the appointment of old Asia hand Thierry Bollore as permanent CEO and Jean-Dominique Senard from tyre manufacturer Michelin as chairman, should open a “new chapter” in ties, Saikawa told reporters in Tokyo.Janet Lewis, head of transportation research at Macquarie Capital Securities, told AFP the alliance was “in many respects an unprecedented success story” and said it was “positive that Renault is moving forward” with Thursday’s appointments.But she added: “I believe it is less helpful that the French government seems to be so involved in the alliance.”‘Passion to be independent’ Much of the tension between the partners stems from a complex ownership structure that gives Renault 43 percent of Nissan and the French state just over 15 percent in Renault—making Paris the pivotal player.Nissan now outsells its French counterpart and its broad global footprint means it deserves to be seen as more than a junior partner, said Lewis.”Renault should be prepared to alter the working relationship to reflect what Nissan brings to the table—among other things a very strong position in both North America and China, markets where Renault has limited to no presence,” the analyst told AFP.Seen from Nissan’s perspective, the “strong interference” of the French state is “not fair”, according to Takaki Nakanishi, an auto analyst based in Tokyo.Ghosn rescued Nissan from the verge of bankruptcy by tying it to the alliance but now the Japanese firm “has a passion to be independent. They do not want to be part of the French state”, said Nakanishi. © 2019 AFP This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.