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Wednesday, July 4, 2018

Cancer Linked to Infertility in Men and Women


Men treated for infertility with intracytoplasmic sperm injection (ICSI) had a significantly increased risk of early-onset prostate cancer, according to data from several large registries.
Use of ICSI to facilitate conception was associated with a 47% higher risk of prostate cancer as compared with men who conceived naturally. Analysis of cancer cases by age at diagnosis showed that men who underwent ICSI had almost a three-fold greater risk of developing prostate cancer before age 50 but not at older ages.
Despite the association with ICSI, the results did not implicate ICSI as the causative factor in early-onset prostate cancer, reported Yahia Al-Jebari, of Lund University in Sweden, and colleagues at the European Society of Human Reproduction and Embryology (ESHRE) meeting in Barcelona. Instead, the study added to existing evidence of an association between impaired sperm production and an increased risk of prostate cancer.
“The increased risk of prostate cancer is definitely not because of the ICSI treatment per se, which we know has no biological impact on the male,” Al-Jebari said in a statement. “In Sweden, ICSI is reserved for men who cannot conceive through in vitro fertilization (IVF), and we would expect most fertile men having fertility treatments to be in the IVF group. So in this study, the ICSI fathers are highly selected and generally have very poor semen quality.”
A separate ESHRE study suggested that infertility in women increases the risk of ovarian cancer, but that ovarian stimulation associated with IVF is not to blame, reported Anja Pinborg, MD, of Copenhagen University Hospital in Denmark.
ICSI and Prostate Ca
Previous studies yielded inconsistent data regarding the association between male infertility and prostate cancer. Registry-based studies showed a lower risk of prostate cancer among childless men as compared with men who were biological fathers, Al-Jebari’s group noted. Other studies suggested that men with impaired fertility have an increased risk of prostate cancer as compared with fertile men.
To continue investigation of male infertility and prostate cancer, researchers analyzed data from birth, assisted reproduction, and cancer registries in Sweden. They identified all men who fathered children from 1994-2014 and compared those who conceived with the aid of ICSI or IVF versus men who conceived naturally. Follow-up continued to 2016.
The analysis included 1.2 million men, 52 million person-years of follow-up, and 3,211 prostate cancer diagnoses. The data showed that men who had undergone ICSI had a 47% increase in the hazard for prostate cancer versus the control group (95% CI 1.15 to 1.89, P=0.002). Conception via IVF did not increase the risk of prostate cancer versus natural conception (HR 1.14, 95% CI 0.91 to 1.43, P=0.25).
Stratification of the cancers by age at diagnosis showed that conception with the aid of ICSI increased the hazard for prostate cancer diagnosis before age 50 to 2.94 versus the control group (95% CI 1.84 to 4.71, P<0.001). ICSI was not associated with an increased risk of later-onset prostate cancer. After excluding men whose prostate cancer diagnosis occurred before conception, the hazard for prostate cancer remained elevated, overall (HR 1.32, 95% CI 1.01 to 1.72, P=0.045) and for early-onset disease (HR 2.54, 95% CI 1.52 to 4.24, P<0.001).
Al-Jebari acknowledged that relatively few men in the ICSI group developed prostate cancer (n=63) and that the trial did not include comparisons with men who had never fathered children.
IVF and Ovarian Ca
The study of IVF and ovarian cancer had its origin in a hypothesized association of the risk-increasing effect of IVF. Previous studies led to conflicting findings, Pinborg’s group noted. Further confounding the issue, several studies showed that nulliparous women have an increased risk of ovarian cancer.
In an attempt to clarify the relationship between IVF and ovarian cancer, investigators analyzed data from the Danish National ART-Couple II (DANAC II) cohort, which includes all women receiving assisted reproductive technology (ART) in Denmark from 1994-2015. Each DANAC II woman was matched by age with 10 women with no history of ART. Follow-up in both groups continued until a first cancer diagnosis, death, loss to follow-up or Dec. 31, 2015.
Data analysis included 58,472 women who received ART and 549,210 who did not. Both groups had a low incidence of ovarian cancer, which was nonetheless higher in the women who had received ART (0.11% vs 0.06%, HR 1.20, 95% CI 1.10 to 1.31).
Subgroup analysis showed that female-origin infertility was associated with an ovarian cancer incidence in nulliparous women (HR 2.38, 95% CI 2.17 to 2.60) similar to that of nulliparous women in the non-ART control group (HR 2.03, 95% CI 1.89 to 2.19). ART for male-factor infertility or unexplained causes was associated with a reduced risk of ovarian cancer (HR 0.87, 95% CI 0.76 to 1.00).
ART’s association with excess ovarian cancer risk reached a peak in the first 2 years after initiation of treatment and disappeared altogether after 12 years, suggesting possible detection bias during ART treatment.
Calling the data reassuring, Pinborg said in a statement, “I would advise infertile women contemplating ART treatment to go ahead. Ovarian stimulation itself is not introducing any excess risk of ovarian cancer.”
Al-Jebari, Vassard, and co-authors disclosed no relevant relationships with industry.
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Patients Often Mistake Migraine ‘Triggers’


Chocolate and other foods commonly thought to trigger migraine were found to have little relationship to headache onset when patients kept systematic track, according to several studies presented here.
Study participants used a web interface or smartphone app to record their food consumption and timing of headaches, allowing researchers to analyze patterns of association. One analysis looked at headache occurrence on weekdays versus weekends.
These findings were presented at the American Headache Society (AHS) annual meeting. The conference also featured an expert debate about whether people prone to migraine should always avoid potential triggers.
A wide range of factors are thought to trigger migraine headache. Some, such as stress, lack of sleep, and hormonal fluctuations, are supported by considerable evidence. Others, such as specific food items, are more anecdotal and research has yielded mixed results. Digital tools that make it easier for patients to record their experience can help shed light on suspected associations.
“We know that migraine and its triggers differ for every person,” said AHS scientific program committee chair Peter Goadsby, MD, PhD, of King’s College London. “These data will hopefully help healthcare providers when evaluating the lifestyle and experiential factors of an individual patient’s life.”
Chocolate and Other Triggers
Stephen Donoghue, PhD, of N1-Headache, formerly known as Curelator Headache, and colleagues presented a series of posters describing studies looking at the links between suspected triggers and migraine occurrence.
Patients with migraine used the Curelator Headache digital platform, available through a web interface or an iPhone app, to answer questions about more than 70 migraine-related factors. A total of 774 people tracked these factors and the occurrence of headaches daily for at least 90 days. More than 80% were women and the mean age was 43 years.
Just over half of the participants (53.7%) said that chocolate was a suspected trigger, with 27.0% saying it had a mild effect (1-3 on a 10-point scale), 14.6% rating it had a moderate effect (4-6), and 12.0% saying it was a strong factor (7-10); 46.3% said they did not suspect chocolate as a trigger.
Among the 606 participants who entered enough data for analysis, chocolate was found to be associated with an increased risk of headache attacks for 10 people (1.7%) and a decreased risk for 16 people (2.6%), with no association noted for the remaining 580 people (95.7%).
About one in five participants did not enter enough data, reported too little or insufficient variability in their chocolate consumption, or had too few or too many migraine attacks to allow for reliable analysis.
“Chocolate is certainly not a common trigger,” the investigators concluded. “It is probable that the low levels of association for both increased and decreased attack risk are simply stochastic. Nevertheless, we cannot rule out that chocolate may be a trigger for some people and a protector for others — but they would be the exception rather than the rule.”
Results were generally similar for nitrates, used as a preservative for foods such as processed meats, and the food additive monosodium glutamate (MSG).
A total of 347 participants (47.5%) suspected nitrate as a migraine trigger, while 384 (52.5%) did not. Among the 370 people who entered enough data for analysis, nitrates were shown to be associated with increased headache risk for 10 people (2.7%), decreased risk for five people (1.4%), and no association was seen for 355 people (95.9%).
Likewise, 385 (52.6%) suspected MSG as a triggering factor, while 347 (47.4%) did not. Among the 227 people with analyzable data, MSG was found to be associated with increased risk for seven people (3.1%), decreased risk for two people (0.9%), and no association for 218 people (96.0%).
For both nitrates and MSG, more than half of study participants did not enter enough data or were not analyzable for various reasons.
For all three triggers, the researchers noted that there was no clear link between the degree of suspicion and the likelihood of identifying an association. Many people reported no consumption of chocolate, nitrates, or MSG, which the researchers suggested might indicate avoidance of a suspected trigger.
“Contrary to the widespread expectations of our users, the data reveals that foods containing chocolate, MSG, and nitrates are rarely associated with migraine attacks and surprisingly, for a minority of individuals, they may be associated with a lower risk of attack,” N1-Headache founder and CEO Alec Mian, PhD, said in a company press release.
The investigators also looked at the association between type of day — weekday or weekend — and migraine occurrence. Among the 707 participants eligible for this analysis, 26 (3.7%) had an increased risk of headache attacks on non-work days, 10 (1.4%) had a decreased risk, and 623 (88.1%) had no identifiable association.
“The concept of ‘weekend headache’ is widely accepted among clinicians and patients, yet clinical trials to date have yielded conflicting results which neither confirm nor deny the presence of this headache pattern,” the researchers concluded. “For almost all subjects in this study, the risk of migraine did not differ on work days compared to days off and holidays.”
Triggers: To Avoid or Not to Avoid
During the debate on migraine triggers, Richard Lipton, MD, of Albert Einstein College of Medicine in New York City, took the “should avoid all triggers” position, noting that these can be highly variable across individuals.
His opponent, Paul Martin of Australian National University in Canberra, countered that there are so many purported migraine triggers, and they are so ubiquitous, that is futile to try to avoid them all at all times — and trying to do so can actually increase anxiety. Instead, people with migraines should receive help to cope with triggers.
During a media briefing in advance of the meeting, Goadsby suggested a new way of thinking about migraine triggers.
“What we’re learning by studying the premonitory phase that occurs in the days or hours before the attack, when the patient will feel tired or get a bit moody or crave sweet or savory things, is that the brain has actually started to have the attack,” he told reporters. “Chocolate is an excellent example. When the brain drives you to take some chocolate and a day and a half later you get migraine, the association is absolutely correct, but the causality is different — the mechanism has already started.”
“What we’re learning from the diary work is that while you can recommend general regularity, an individual needs to ask themselves whether what they’re calling a trigger is actually the beginning of their attack. That releases them from the punishment of worrying about the trigger and gives them information about what is about to happen,” Goadsby continued. “Obviously, if you feel you’re in the premonitory phase that is not a night to go out, to stay up late, to find your favorite alcohol. It’s a night to be careful, to look after yourself, to prepare for the next day. This understanding is going to empower patients to get better control.”
Donoghue and Mian are employees of N1-Headache. Goadsby and Lipton reported relationships with numerous companies active in migraine drug development. Martin reported no relevant disclosures.
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Hong Kong exchange picks up steam with two biotech IPOs from Innovent, MicuRx


Amid the IPO frenzy taking place on the Nasdaq, the stock exchange in Hong Kong has quietly caught up with two applications at the end of last week — the third and fourth companies to try the route since the city opened up to pre-revenue biotechs wanting to list.

The first candidate is Innovent Biologics, a 7-year-old biotech unicorn long rumored to be angling for a public listing and handed $150 million in a Series E crossover round weeks ago. They were joined by fellow Shanghai-based drugmaker MicuRx Pharma, which is looking for some help powering through various studies for its drugs treating multiple drug resistant infections.
In an unusual chairman’s letter that starts off the application document, Innovent founder and CEO Michael Yu reflected on the founding philosophy of the company:
The reality is that there is a huge gap between China’s biopharmaceutical industry and international standards. China’s biopharmaceutical production capacity is less than one-fiftieth of that of the United States, and not even one-tenth of that of South Korea. Among the top ten best-selling drugs in the world, eight are biologics and five are monoclonal antibody drugs, while China’s bestselling drugs are still mostly chemical drugs and traditional Chinese medicines. Imported drugs dominate China’s antibody drug market, and for most Chinese patients, these life-saving drugs are often unaffordable and out of reach.
His answer to that need has now grown to a 510-strong company with a pipeline of 17 drugs, with seven in clinical development and four in Phase III trials.
Sintilimab, a PD-1 inhibitor currently under priority review in China, is the star here; Innovent is also looking to start early-stage trials of the drug in the US while using it as a base for two other assets they are co-developing with Eli Lilly.
As is standard in these applications, Innovent redacted anything that could remotely give the IPO away, so we don’t know whether it is indeed seeking $300 million to $500 million, as Reuters previously reported. What we do know is that sintilimab, together with three biosimilars — going after blockbusters like Avastin, Rituxan and Humira — will claim most of the raise, from trials and registration filings to commercialization.
Great Biono Fortune, a coalition of Innovent employees, owns the largest chunk of stock at 10.22%, followed by Lilly Asia Ventures and F-Prime Capital, which have 8.86% each.

MicuRx, meanwhile, has kept its ambitions tightly under wraps. CEO Zhengyu Yuan founded the company after an R&D stint at Vicuron (merged with Pfizer) with the help of then-colleague Mike Gordeev, now CSO.
The company, which has teams in both San Francisco and Shanghai, closed a $15 million financing last year to complete a Phase III for its lead oral antibiotic, contezolid (MRX-1). The bulk of the raise will go toward MRX-4, a prodrug formulation of MRX-1 dubbed contezolid acefosamil. While the drug is only beginning human studies in China, it’s ready to roll with a Phase II in the US later in the year. MicuRx will also invest some cash into a preclinical polymicin antibiotic backed by CARB-X.
A BVCF subsidiary and Morningside are the largest shareholders, controlling 29.12% and 26.50% respectively.
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New clues to sepsis may speed diagnosis


Sepsis is an infection that kills as many Americans each year as stroke and Alzheimer’s combined-about 250,000-but very little has changed in the treatment of this age-old scourge.
Now researchers at Columbia University Irving Medical Center have found a clue in understanding how an  can spiral into  by blunting the body’s immune response. This research may also help doctors identify the patients who may need immediate intensive treatment to save their lives.
From Infection to Organ Failure
Sepsis can start with a simple infected cut. When the immune system fails to fight off the infection, sepsis occurs when inflammation spreads throughout the body, leaving patients vulnerable to organ damage, severe secondary infections, and death. While time is of the essence, doctors lack quick, efficient ways to diagnose this deadly condition.
“The best treatment for sepsis starts with rapid detection. Our results suggest that specific molecules called microRNAs may be potential biomarkers of poor prognosis, indicating the need for more aggressive treatment options,” explains the study’s senior leader Sankar Ghosh, Ph.D., the Silverstein and Hutt Family Professor of Microbiology & Immunology and chair of the Department of Microbiology & Immunology at Columbia University Vagelos College of Physicians and Surgeons (VP&S).
The immune system initially launches a vigorous attack against sepsis, but then the innate immune response shuts down. In a search to understand the underlying mechanism, Ghosh’s team identified two microRNAs (miR-221 and miR-222) that are produced in immune cells during prolonged inflammation. These microRNAs silence inflammatory gene expression and in a mouse model of sepsis suppress the immune system at a time when the body desperately needs a full immune response.
Identifying Patients in Danger of Sepsis
Patients with suspected sepsis had a similar reaction. Among 30 hospitalized patients, those with evidence of exhibit higher levels of miR-221 and miR-222 in their blood samples. In septic patients, those with elevated miR-221 and miR-222 also exhibited evidence of immunosuppression.
The two microRNAs could be the basis of a test to help physicians classify patients into those with organ failure who are at high risk of sepsis and death and those patients with milder infections. With faster diagnosis, doctors could start antibiotics and fluids to control the infection more quickly before patients succumb to organ failure and secondary infections.
“When doctors face sepsis in the hospital, it is usually a mystery as to what is causing the infection, but they must act quickly. They can choose to use the broadest spectrum of antibiotics for an aggressive approach to cover every bacterial cause of infection, but this may later cause antibiotic resistance, a growing problem,” says study co-author Daniel Freedberg, MD, assistant professor of medicine at CUIMC. “Any test that can identify the cause of sepsis to guide treatment options is invaluable.”
Clinical trials will be needed to validate the usefulness of testing  for these microRNAs as a quick guide to prognosis and treatment. The research comes at a time when the number of sepsis cases per year has been on the rise in the United States, according to the National Institutes of Health. Creating better diagnostics may be able to help reverse this trend and save lives.
 Explore further: Putting the brakes on sepsis
More information: John J. Seeley et al. Induction of innate immune memory via microRNA targeting of chromatin remodelling factors, Nature (2018). DOI: 10.1038/s41586-018-0253-5
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New tools for brain mapping should boost research into depression, dementia


Researchers at Florida Institute of Technology have developed the fastest method to date for creating a key molecule used by neuroscientists at Columbia University in mapping brain activity. They also discovered ways to create two new versions of that molecule – a neurotransmitter called glutamate – that can further advance this critical field of study.
This work, funded by the National Institutes of Health, was published in the American Chemical Society journal, ACS Chemical Neuroscience 2018.
“Our  to the  are as valuable as cameras are to Google Maps,” said Nasri Nesnas, a professor of chemistry at Florida Tech who is the principal investigator and corresponding author of the paper. “We now have the fastest method to make the best cameras.”
Glutamate, or Glu, plays a critical role in  activities related to emotion, cognition and memory. Therefore, neuroscientists are working to decode the brain to understand neurological disorders including depression and dementia, in part by studying “glutamatergic receptors,” where Glu is the molecule of interest.
The human brain is the most complex organ in the human body and is composed of over 85 billion neurons. Each of these neurons can be linked through up to 10,000 connections, known as synapses. Synaptic connections act like brain “switches” and release small molecules called neurotransmitters that pass along electrical signals.
New Tools Developed for Brain Mapping; Should Boost Research into Depression, Dementia
The UV lamps in this photo reactor will activate the neurotransmitter glutamate, thus enabling it to serve as a powerful tool to map the brain. Credit: Florida Institute of Technology
Glu is the most common neurotransmitter. To aid neuroscientists in mapping the enormously complex brain circuitry, researchers have used light to activate inactive, or “caged,” neurotransmitters in live brain tissue, including glutamate.
The work reported on in ACS Chemical Neuroscience will make the process of making caged Glu more effective, Nesnas said, by cutting the number of steps in half and overall time by 80 percent, while doubling the yields of previous methods.
“There were challenges that many scientists had with making these photo-responsive Glu tools. We have made this process more facile and efficient, and we also made two other variations of these tools that have the potential to perform better since they may not pose the same interference problems that the previous one had with other receptors on neurons,” Nesnas said.
Graduate student Charitha Guruge, the lead author of the paper and one of four Florida Tech Ph.D. students involved in the research – Yannick Ouedraogo, Richard Comitz and Jingxuan Ma are the other collaborators – said he is excited about developing tools that should lead to better understanding of – and thus possible cures for – some of the most perplexing and damaging ailments of our time.
“I find working in this area to be truly rewarding, since there are too many neurological disorders, especially those relating to depression, dementia and bipolar, far from being understood,” he said. “I would like to be able to use chemistry to develop these tools to help the neuroscience community reach answers quickly.”
 Explore further: Remake, refill, reuse: recycling at the synapse revealed
More information: Charitha Guruge et al. Improved Synthesis of Caged Glutamate and Caging Each Functional Group, ACS Chemical Neuroscience (2018). DOI: 10.1021/acschemneuro.8b00152
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Staying safe in the sun — a dermatologist helps separate facts from hype


Skin cancer is the number-one cancer diagnosis in the United States – it’s more common than breast, prostate, and lung cancers combined. Skin cancers can be divided into two types – nonmelanoma (basal and squamous cell carcinomas) and melanoma, with melanoma being the least common but most life-threatening. Each year, some 90,000 people are diagnosed with melanoma. Sarah Arron, MD, Ph.D., shares her thoughts on skin cancer prevention and helps separate the facts from the hype.
Which SPF?
The  (SPF) number indicates the time it will take for UVB rays to redden your skin. I tell my patients to choose SPF 30 or higher because most people do not apply  as directed.
SPF moisturizer?
These are a great idea! It’s important that you like wearing the sunscreen enough to make it a part of your daily routine.
Eyes and lips?
Wear lip balm with SPF 15 and sunglasses with UV blockers in the lenses.
If being in the sun makes me happy, why should I protect myself from it?
Sun exposure can boost mood, and that makes sunshine addictive for some people. We like to rationalize that addiction by saying it must be healthy if it makes us feel or look good. But it’s not.
There is no such thing as a healthy tan, even though the tanning bed industry promotes its products that way. Until we dismiss the idea of a “healthy” tan, we’ll continue to see an epidemic of skin cancer in this country.
Are there other ways to prevent skin cancers?
Seek the shade and avoid outdoor activities during the peak sun hours of 10 a.m. to 2 p.m. Sports enthusiasts can go out in the early morning, take a break, and go out again later in the afternoon.
Staying safe in the sun – a dermatologist helps separate facts from hype
Carina Woodruff, MD, examines a patient during a free skin cancer screening at UCSF. Credit: Barbara Ries
You can also buy UV protective clothing, including hats (in many styles), swim tights, swim shirts, sleeves for tennis players, and more.
What about my vitamin D levels?
It’s true that one of the ways our skin makes vitamin D is through UV radiation. But there are many other ways to get vitamin D, such as leafy greens, fortified milk, and supplements. Moreover, it’s rare that individuals are so scrupulous about avoiding  that it causes vitamin D deficiency.
What does broad-spectrum mean?
It means the sunscreen provides protection from both types of damaging ultraviolet (UV) radiation – UVA and UVB. Both contribute to skin aging and skin cancers. UVB is the dominant sunburn and suntanning ray, whether the ultraviolet rays come from the sun or a tanning salon, while UVA penetrates deeper into the skin, causing premature aging and wrinkling. The SPF number measures only UVB protection, so you need to make sure your sunscreen specifies UVA protection as well.
Chemical vs. mineral?
Each has its pros and cons. Mineral sunscreens contain titanium and zinc oxide. People with sensitive skin may have less reaction to a mineral sunscreen. Some of my patients prefer minerals due to concern about chemical safety and a preference for a natural approach. The downside is that these may feel thicker and heavier and can leave a ghost-like sheen on the face. Chemical sunscreens include avobenzone and oxybenzone in their ingredients and are usually formulated to feel lighter and appear more elegant. Neither is more protective than the other.
Do people with dark skin need to wear sunscreen?
Yes. When the sun affects our skin, there are two levels of damage. One is immediate, which we recognize as sunburn and which mostly affects lighter-skinned individuals. Patients with darker skin who don’t get sunburned may think their skin is protected, but there’s a second kind of damage that leads to loss of elasticity and premature aging of skin, as well as DNA mutations in the cells that may ultimately cause skin cancer.
What are the warning signs of cancer?
In general, with skin  we’ll see a persistent lesion that is growing and changing in shape and appearance and that bleeds without ever healing. It’s very important that people get to know their own  and their own spots, so that when new things appear they can point them out to their primary care doctor or dermatologist. I recommend a head-to-toe screening with a dermatologist to establish a baseline for the future.
Which skin-protection websites are trustworthy?
For our organ transplant recipients (who have a 60- to 100-fold higher risk of ), we produced a downloadable booklet – and the information in it is relevant to all patients: skincancer.ucsf.edu.
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How to start exercising when you’re out of shape


Though you may face challenges if you’re carrying excess weight or haven’t been active in a long time, you can still get fit and gain all the benefits that exercise has to offer.
The easiest way to get started is with walking because it’s low-impact and low-risk, and all you need is a pair of supportive walking or running shoes. Begin by scheduling one dedicated walk each day, and then find opportunities to take additional steps, like going window-shopping at lunch or walking in place instead of sitting while watching TV. You might like the impetus of a home treadmill, which you can set at a slow speed to start.
Another simple way to exercise at home is to get more dynamic with . For example, pick up the pace as you do household chores, and work in sessions that are at least 10 minutes long.
You can also dive into  by working out in , whether you swim or take a water fitness class. Water makes you feel lighter and more agile, so many people find it easier to move in a pool than on dry land.
Riding a  is also less strenuous on your body than weight-bearing exercises, even walking. Try a recumbent bike; its seat is lower to the ground and your legs will be extended, which may feel more comfortable to you.
Just don’t let enthusiasm put you at risk of burnout by doing too much too soon. Increase the length and the intensity of your workouts at a slow, steady pace as you progress.
 Explore further: A 3×10 exercise plan that’ll work for you
More information: The U.S. National Institute of Diabetes and Digestive and Kidney Diseases has tips on how to stay active at any weight, as well as why fitness is so important.
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