Insect and mammal ovulation more alike than not?

We have a general idea of the timing of and the hormones involved in ovulation in humans. What we don’t understand are the precise mechanics regulating how the egg escapes from the follicle of cells encasing it in the ovary. Does the egg shove its way out? Does the follicle bloom like a flower? What genes govern the process, and what do they do?

Researchers have tried to study the genetic mechanics of ovulation in designer ‘knock-out’ mice, which have one gene taken out of commission (or ‘knocked-out’). But mice often have multiple, related genes in their genome and these genes can compensate for each other, so the process often still works even if a single gene is removed.

Fruit flies have a less-redundant genome and a faster life cycle than mice, making them much easier to work with. But researchers had assumed that insects are so far apart from us evolutionarily that their ovulatory process would be totally different.

Not so, according to Jianjun Sun and colleagues in UConn’s department of physiology and neurobiology and their collaborator Allan Spradling at the Carnegie Institution for Science. In the February 19 issue of PLOS Genetics they report two critical parts of ovulation that seem to be the same in both flies and mice. The first is cellular, and has to do with the fate of the follicle cells after the egg escapes. Sun’s team found that just as in mammals, in flies the follicle cells blocking the path of the egg out of the ovary degrade and slough off at ovulation. And just as in mammals, the follicle cells left behind inside the ovary after the egg escapes turn yellowish and produce steroid hormones essential for fertility.

The second has to do with Matrix metalloproteinase (Mmp), an enzyme that researchers suspect mammals need to break down the cellular matrix of the follicle in order for the egg to escape. Mice have 24 genes that code for Mmp: fruit flies have just two, mmp1 and mmp2. Sun and his colleagues found that knocking out just mmp2 all by itself reduced the mmps enzyme levels in a fly’s ovaries, and dramatically reduced the number of eggs laid. This work provide the first genetic evidence that Mmp is required for ovulation and its role is likely conserved between flies and mice.

These similarities suggest that the basics of ovulation are very similar in animals generally.

“The evolutionary distance between flies and mice is so huge, compared to the distance between mouse and human. Everything that is conserved between fly and mouse is likely be conserved in humans,” Sun says. The findings provide a foundation for other researchers to find out exactly which genes are required for ovulation in flies, and so for mice, and so for humans.

The research could prove immediately applicable to fertility disorders in humans such as polycystic ovary syndrome (PCOS), in which women don’t ovulate. Sun’s group is utilizing its fly system to look at PCOS now. But their findings could also prove useful to understanding the way cancer spreads through the body. When cancers metastasize, individual cells escape from the tumor mass and spread into the bloodstream. How exactly cancer cells escape from their original cell matrix may have something to do with the Mmp enzyme, Sun says, and that means this research could eventually inform treatments that block a cancer’s spread.

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New target for prostate cancer treatment discovered

Prostate cancer is the second most common cancer in American men, after skin cancer, according to the American Cancer Society (ACS). The ACS projects more than 27,000 deaths from prostate cancer in 2015 and is the second leading cause of cancer death in American men, behind lung cancer. One man in seven will be diagnosed with prostate cancer during his lifetime.

“When a prostate cancer tumor is in its early stages, it depends on hormones called androgens to grow,” said Nitin Patel, Ph.D., research scientist at the Institute for Genetic Medicine at the Keck School of Medicine of USC, and corresponding author on the research. “Eventually it progresses to a more lethal form, called castration-resistant prostate cancer (CRPC), and is resistant to drugs that block androgen receptors. We found that GPR158, unlike other members of the GPCR family, is stimulated by androgens, which in turn stimulates androgen receptor expression, leading to tumor growth.”

The team also discovered that GPR158 is associated with neuroendocrine transdifferentiation (NED) of epithelial prostate tumor cells, which plays a critical role in development of resistance to contemporary androgen receptor-target therapies. The scientists found that prostate cancer patients with elevated GPR158 expression experienced recurrence of prostate cancer. The GPR158 protein is a likely target for new prostate cancer drugs.

The researchers used a conditional Pten knockout mouse model of prostate cancer in collaboration with Keck School of Medicine of USC researchers Mitchell Gross, Chun-Peng Liao and Pradip Roy-Burman.

The team is now exploring the molecular pathways involved in the functional role of GPR158 in NED in the development of CRPC and exploring GPR158-targeted antibody therapeutics.

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Mammography screening: Patient pamphlets do not affect willingness to participate

In Germany, the invitation to undergo mammography screening that is sent to all women between the ages of 50 and 69 is accompanied by an information leaflet explaining the advantages and disadvantages of screening. In this issue of Deutsches �rzteblatt International, Elisabeth Gummersbach and colleagues report on a study in which they determined how well the prospective subjects understood the information presented and whether this information influenced their willingness to undergo screening. It was found that the leaflet itself made little or no difference to the women’s willingness to participate. Rather, the most important factor in the decision whether to be screened was usually a doctor’s personal recommendation.

From 2010 onward, mammography for the early detection of breast cancer has been recommended for all women in Germany aged 50 to 69. Screening nonetheless remains controversial. While it is true that women who undergo screening are less likely to die of breast cancer, they may also receive erroneous diagnoses and unnecessary treatments. Out of 1000 women who undergo mammography screening regularly for 10 years, 1 to 3 will survive who would otherwise have died of breast cancer, but 100 to 300 will have a false positive mammography finding that can cause considerable emotional distress. As many as 5 of these women may actually undergo unnecessary treatment for cancer. As the authors point out, the leaflets apparently had little or no effect on the women’s decisions to undergo screening or not: only 3.6% said it played a role in their decision, while nearly 50% said their doctor’s recommendation was a major factor. These findings imply that a leaflet alone does not enable women to make a well-informed decision about mammography screening, as required by current German law. The authors recommend that women who are candidates for mammography should have a personal discussion with an appropriate professional about this subject, in addition to being given suitable written information.

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Women back idea of more breast screens for those at high risk of cancer

Fewer women (60 per cent) would be happy to be screened less often if they were found to be at lower risk.

More than 940 women from across the UK were asked for their views on the possibility of tailoring breast screening to people’s genetic risk in a study funded by Cancer Research UK and The Eve Appeal. Two-thirds (66 per cent) supported the idea of adjusting the frequency of screening on the basis of risk.

The NHS breast screening programme offers routine mammograms based on age, rather than genetic risk. All women between 50 and 70 are invited for screening every three years, and women over 70 can request screening if they wish, because older women are at increased risk of the disease. Women with a strong family history of breast cancer may be offered a different pattern of screening.

Breast screening can help detect cancers early, when treatment is more likely to be effective, and is estimated to save around 1,300 lives from breast cancer in the UK each year.

But as well as picking up cancers that need treating, screening can also detect very slow-growing cancers that would not have been picked up without screening. This means some women are treated unnecessarily for a cancer that would not have caused any problem during their lifetimes.

Dr Susanne Meisel, research psychologist at UCL (University College London), said: “Looking at whether genetic risk could be used to tailor and improve the breast screening programme is still at an early stage, but it’s useful to find out now what the public might think about this idea. Our study showed that, overall, women seem to support it.

“It’s interesting there was less support for the idea of less frequent screening for people at lower risk of cancer. This could be because many women tend to see screening as beneficial or feel they have a right to screening, or some women might take a ‘better safe than sorry’ approach to cancer screening which may make them more accepting of potential harm from it.”

Women who took part in the study were asked five questions to assess what they believed their risk of developing breast cancer was, and their attitude to genetic testing and using genetic risk to vary screening frequency. Limited information was provided on how a modified screening programme might work, and no information was given on the current screening programme.

Athena Lamnisos, CEO of The Eve Appeal, said: “Women at increased risk of cancer deserve more than the one-size fits all approach. This study shows that women were positive about the idea of adjusting the frequency of mammography screening in line with personal genetic risk. It also shows how critical it is to develop effective communication materials — both for women at high risk and those at lower genetic risk.”

Jessica Kirby, senior health information manager at Cancer Research UK, said: “Breast screening saves lives, but it also has risks. One suggestion to try to maximise the benefit and reduce the risk is to tailor screening more effectively to people’s risk of breast cancer, but more research is needed to show whether this approach will be effective or possible.

“This interesting study suggests that women are generally positive about the idea of tailoring screening, but in the meantime, it’s critical that women are offered proper information about the benefits and risks of screening, and supported to make an informed decision.”

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Gene that pushes normal pancreas cells to change shape identified

Their findings, reported in Nature Communications, suggest that inhibiting the gene, protein kinase D1 (PKD1), and its protein could halt progression and spread of this form of pancreatic cancer, and possibly even reverse the transformation.

“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Peter Storz, Ph.D., a cancer researcher at Mayo Clinic.

“We need a new strategy to treat, and possibly prevent, pancreatic cancer. While these are early days, understanding one of the key drivers in this aggressive cancer is a major step in the right direction,” he says.

In the U.S., pancreatic cancer is the fourth most common cause of deaths due to cancer, according to the American Cancer Society. A quarter of patients do not live longer than a year after diagnosis.

Pancreatic cancer can occur when acinar cells — pancreatic cells that secrete digestive enzymes — morph into duct-like structures. This usually occurs after injury or inflammation of the pancreas and is a reversible process. However, the presence of oncogenic signaling (Kras mutations, EGF-R) can push these duct cells to develop lesions that are at risk for tumor development.

To test PKD1’s effect, the researchers used a 3-D model of pancreatic cells derived from a mouse. They manipulated PKD1 expression by either blocking the gene or inducing its activity. About a week after stimulating PKD1 expression, the researchers could see that acinar cells transformed to duct-like cells. Blocking PKD1 led to decreased formation of duct-like cells and lesions.

“This is a great model for examining what happens in a signaling pathway — we can see the changes by simply using a microscope. This model tells us that PKD1 is essential for the initial transformation from acinar to duct-like cells, which then can become cancerous,” Dr. Storz says. “If we can stop that transformation from happening — or perhaps reverse the process once it occurs — we may be able to block or treat cancer development and its spread.”

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Key indicator for successful treatment of infertile couples

“As a woman approaches menopause, her level of follicle stimulating hormone (FSH) rises,” explained Goldman. “A higher FSH level is a key indicator that the woman may not be as fertile as necessary to conceive using certain common methods of infertility treatment.”

The study determined if FSH and estrogen at the upper limits of normal, as measured on day three of the menstrual cycle, could predict treatment success as measured in live birth rates. The essential question was: should women with higher levels of FSH and estrogen be “fast-tracked” to in vitro fertilization (IVF), bypassing the conventional treatment trajectory?

Goldman and collaborators recorded no live births in the group with FSH and estrogen at the upper limits of normal, yet when the couples later pursued IVF, 33% were able to have babies.

“Some women express a preference to begin treatment for infertility with controlled ovarian hyper-stimulation (COH), whether by pill or injection, along with intrauterine insemination (IUI),” said Goldman. “When counseling women with day-three testing for FSH or estrogen at the upper limits of normal, it may be helpful for them to know that COH-IUI has not been successful in others with similar levels. Fortunately, IVF is a successful treatment for many women and if we can ‘fast-track’ them to IVF, bypassing COH-IUI, treatments will be quicker and may be less expensive.”

Insurance companies may use FSH levels to determine if they will continue payments for future treatment cycles in women with high levels.

The next steps for Goldman include probing what makes IVF so successful and how to keep the success rate while reducing costs.

Marlene Goldman, MS, ScD, is Professor of Obstetrics & Gynecology, and of Community & Family Medicine at Dartmouth’s Geisel School of Medicine. Her work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center in Lebanon, NH. She is the Vice-chair for Research in the Department of Obstetrics & Gynecology at Dartmouth-Hitchcock Medical Center. This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institutes of Health grants RO1 HD38561 and RO1 HD44547. Her collaborators included Richard Reindollar, MD PI; Daniel J. Kaser, MD, first author; June L. Fung, PhD, all from Dartmouth; and Michael M. Alper, MD from Boston IVF.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at

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Palbociclib shows promise in patients with hormone-resistant breast cancer

“The FDA approval has expanded treatments options for many metastatic breast cancer patients, but these new results are showing how effective the drug can also be for breast cancer patients who have already tried endocrine therapies and may be running out of options,” said lead investigator Angela DeMichele, MD, MSCE, associate professor in the division of Hematology/Oncology and Epidemiology and co-leader of the Breast Cancer Research Program at the Abramson Cancer Center. “Combined with the promising results from other trials looking at the effectiveness of this drug, our results indicate that palbociclib can extend the duration of disease control and produce tumor shrinkage in patients with estrogen-receptor positive (ER+) breast cancer, without the debilitating side effects of chemotherapy.”

The newly-published phase II trial primarily sought to evaluate disease response and control, while monitoring for the presence of side effects such as neutropenia, an abnormally low white blood cell count. Patients enrolled in the trial had previously undergone several prior chemotherapy and hormonal regimens for metastatic disease. Palboclib was administered once daily for 21 days each month.

Overall, researchers noted a median PFS, the time before a tumor worsens or the patient dies, of 3.7 months for patients taking the drug. However, patients with hormone receptor-positive (HR+) breast cancer — where the breast cancer cells depend on the hormones estrogen and progesterone to grow — had significantly longer PFS (5.1 months) compared to that of the HR-negative group (84 percent and 11 percent of the enrolled population, respectively). And those who had previously progressed through at least two rounds of hormonal therapy saw significantly greater benefits, suggesting substantial activity in the setting of acquired endocrine resistance.

Though some patients experienced low white blood cell counts or other side effects, symptoms were managed with dose reductions, and improvements in tumor shrinkage and disease control were still noted.

“The drug was extremely well-tolerated in this trial, and the absence of symptoms commonly associated with cancer treatment, such as nausea, diarrhea, or pain was remarkable,” said senior author Peter O’Dwyer, MD, a professor in the division of Hematology/Oncology. “Further, since dose reduction effectively restored normal neutrophil counts, safe administration of effective doses was easily accomplished.”

Only a small number of patients enrolled in the trial had triple negative breast cancer, all of whom rapidly progressed on treatment and had to discontinue participation. However, ongoing studies by DeMichele and her colleague, Amy Clark, MD, a clinical instructor in the division of Hematology/Oncology, are demonstrating potential benefits to palbociclib in ER-negative breast cancer when it is given in combination with paclitaxel.

“This approach takes advantage of the ability of palbociclib to synchronize cells within the cell cycle, potentially increasing the percentage of cells sensitive to the cytotoxic effects of traditional chemotherapy,” Clark explains. “Moreover, palbociclib may be effective in other types of cancer that operate by a similar mechanism. These trials are currently ongoing.”

Other Penn authors on the study include Kay See Tan, Daniel Heitjan, PhD, Kristi Gramlich, Maryann Gallagher, Priti Lal, MD, Michael Feldman, MD, Paul Zhang, MD, Christopher Colameco, David Lewis, Melissa Langer, Noah Goodman, Susan Domchek, MD, Keerthi Gogineni, MD, Mark Rosen, MD, and Kevin Fox, MD.

This study was funded through the Penn-Pfizer Alliance; Pfizer provided funding for the study and palbociclib, but did not participate in data collection, analysis, or writing of the manuscript. The authors report no financial conflicts of interest.

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Researchers sheds new light on biological pathways of vestibular schwannomas

Their paper, “Interplay Between VEGF-A and cMET Signaling in Human Vestibular Schwannomas and Schwann Cells,” by Sonam Dilwali, B.S., Daniel Roberts, M.D., Ph.D., and Konstantina M. Stankovic, M.D., Ph.D., FACS, is online in the Feb. 20 issue of Cancer Biology and Therapy.

Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Patients with this tumor typically present with hearing loss and tinnitus. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth.

The authors investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS. VEGF-A is important because it is inhibited by bevacizumab, the drug currently used to treat some VSs. However, bevacizumab is effective in only 55% of patients, motivating the ongoing work to discover additional drug targets in VSs.

Using freshly harvested human specimens from indicated surgeries, the authors affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, they found that VEGF-A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET, and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures.

“Our data suggest cross-talk between these two prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS,” said senior author Dr. Stankovic, , an assistant professor of otology and laryngology at Harvard Medical School.

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Certain factors influence whether cancer patients involve family members in treatment decisions

For the study, Gabriella Hobbs, MD, and Nancy Keating, MD, MPH, of Harvard Medical School, and their colleagues surveyed 5284 patients with a new diagnosis of lung or colon cancer, and asked participants how they involved their families in decisions about their care. Only 1.5 percent of patients reported family-controlled decisions. Among the remaining patients, 49.4 percent reported equally sharing decisions with family, 22.1 percent reported some family input, and 28.5 percent reported little or no input from their families. Non-English speaking Asian patients and Spanish-speaking Hispanic patients were more likely to report equally shared decisions with their families than other patients. Also, patients who were married, female, older, and insured more often equally shared decision-making with their families than their counterparts. Patients who were veterans were the least likely to share decision-making with their families.

“Understanding how patients vary in their inclusion of family members in decisions–by ethnicity, language spoken, marital status, sex, age, insurance status, and veteran status–may help physicians to better assess their patients’ preferences for engaging family members in decisions,” said Dr. Hobbs. “As we move to more patient-centered models of care, such assessments may help doctors personalize the care they offer their patients.”

Dr. Hobbs noted that as therapies for cancer patients improve, they are also becoming increasingly complex, making it challenging for patients and providers to determine the optimal therapy for each patient. With this in mind, knowing how patients make decisions and understanding the role that families play in decision-making is crucial for optimizing patient participation in treatment decisions. “Our study suggests that not all patients wish to include family in the same way. By raising awareness of these preferences, we hope that physicians will be aware of these variations and elicit their patient’s preference on how they wish to include, or not to include, families in decision-making.”

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Human neural stem cells restore cognitive functions impaired by chemotherapy

In preclinical studies using rodents, they found that stem cells transplanted one week after the completion of a series of chemotherapy sessions restored a range of cognitive functions, as measured one month later using a comprehensive platform of behavioral testing. In contrast, rats not treated with stem cells showed significant learning and memory impairment.

The frequent use of chemotherapy to combat multiple cancers can produce severe cognitive dysfunction, often referred to as “chemobrain,” which can persist and manifest in many ways long after the end of treatments in as many as 75 percent of survivors — a problem of particular concern with pediatric patients.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said Charles Limoli, a UCI professor of radiation oncology.

Study results appear in the Feb. 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Many chemotherapeutic agents used to treat disparate cancer types trigger inflammation in the hippocampus, a cerebral region responsible for many cognitive abilities, such as learning and memory. This inflammation can destroy neurons and other cell types in the brain.

Additionally, these toxic compounds damage the connective structure of neurons, called dendrites and axons, and alter the integrity of synapses — the vital links that permit neurons to pass electrical and chemical signals throughout the brain. Limoli compares the process to a tree being pruned of its branches and leaves.

Consequently, the affected neurons are less able to transmit important neural messages that underpin learning and memory.

“In many instances, people experience severe cognitive impairment that’s progressive and debilitating,” Limoli said. “For pediatric cancer patients, the results can be particularly devastating, leading to reduced IQ, asocial behavior and diminished quality of life.”

For the UCI study, adult neural stem cells were transplanted into the brains of rats after chemotherapy. They migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

Importantly, Limoli and his colleagues found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

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