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A joint study by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the “la Caixa” Foundation, and the Biosanitary Research Institute of Granada (ibs.GRANADA) has provided new evidence on the ability of phthalates to interfere with sexual development. The findings of this study, published in Environmental Research, show that prenatal exposure to certain phthalates is associated with a slightly elevated risk of children having started puberty between 7 and 10 years of age.
Phthalates are chemical compounds that are used as plasticisers and fragrance retainers in a wide range of consumer products. They are used, for example, in the manufacture of PVC and can be found in building materials, cosmetics, plastic toys and food packaging, among other products. Previous studies have found associations between these endocrine-disrupting chemicals and a number of adverse reproductive health effects such as urogenital malformations, poorer sperm quality, reduced testosterone levels, placental/umbilical dysfunction, preterm delivery, low birth weight, ovarian insufficiency and endometriosis.
In vitro and animal studies have shown that phthalates exert anti-androgenic activity, i.e. the ability to inhibit the effects of male sex hormones. On the basis of this hypothesis, the research team set out to assess the possible influence of these compounds on pubertal development in boys and girls. The researchers chose to study prenatal phthalate exposure, as it is during this stage that the adrenal and gonadal axes — which control the onset and progression of puberty — develop.
The study included 788 boys and girls from Gipuzkoa, Sabadell and Valencia who were enrolled in the INMA Project cohort study. Prenatal exposure to phthalates was quantified by means of maternal urine samples collected during pregnancy. Later, when the children were between 7 and 10 years of age, pubertal development was assessed by means of a parental questionnaire. On the basis of the responses, children were classified into five developmental stages: 1) pre-puberty, 2) early puberty, 3) mid-puberty, 4) late puberty and 5) post-puberty. The children’s body mass index was also taken into account, as obesity plays an important role in pubertal development.
Analyses showed that phthalates were present in more than 99% of the urine samples collected during pregnancy. Findings varied by compound tested, as well as by the sex and body mass index of the participants. However, it was observed that higher prenatal exposure to certain phthalates was associated with a slightly increased risk of puberty onset. These findings were more evident in boys with normal weight and in girls who were overweight or obese.
Specifically, prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a substance used to make plastics more flexible, was associated with increased risk of puberty onset in both boys and girls. Prenatal exposure to DEHP, di-ethyl phthalate (DEP) and di-n-butyl phthalate (DnBP) was associated with earlier onset of puberty in normal-weight boys. However, prenatal exposure to butyl benzyl phthalate (BBzP) and di-iso-nonyl-cyclohexane-1,2-dicarboxylate (DINCH®) was associated with later onset of puberty only in overweight or obese boys. As for girls, prenatal exposure to di-iso-butyl phthalate (DiBP), DnBP and DINCH® was associated with slightly earlier onset of puberty in girls who were overweight or obese.
Associations were observed for some of the phthalates studied individually, but not for the grouping of all phthalates.
“We cannot affirm that phthalates are associated with precocious puberty as a clinical pathology, as we did not assess when this process started in each participant,” commented ibs.GRANADA researcher Carmen Freire, first author of the study. “What is clear is that the age at puberty onset has decreased in recent decades and our findings suggest that phthalates could be one of the factors involved.”
“Our findings in boys are somewhat surprising,” commented ISGlobal researcher Maribel Casas, last author of the study. “Due to the anti-androgenic activity of phthalates, we would have expected these compounds to interfere with pubertal development in the opposite direction — that is, by delaying it. However, determining the effects of these compounds is very complex, as they tend to be multifactorial and exposure never occurs in isolation, but rather in conjunction with a whole range of substances and environmental factors.”
It is now considered normal for puberty to start from the age of 8 years in girls and 9 years in boys. Factors associated with age at puberty onset include obesity, although other factors, such as environmental exposures and stress, also play a role.

Apoptosis, a type of programmed cell death (PCD), is a biological process through which unwanted cells are eliminated in multicellular organisms. In most cells, certain proteins known as “caspases” trigger apoptosis. This process is especially important for the treatment of cancer, since inducing cell death in cancer cells can help in their elimination.
Other than apoptosis, several types of PCDs occur in cells, including paraptosis, necroptosis, and autophagy. Of these, paraptosis is the most recently identified type of PCD, which is caused by the influx of excess calcium in the cells, leading to cell death.
Cancer cells often become resistant to drugs that induce apoptosis and other types of PCDs. In such cases, inducing paraptosis, which is not dependent on caspases, could act as a promising anti-cancer treatment. Hence, the development of compounds that can induce paraptosis in cancer cells is crucial.
To this end, a team of researchers from the Tokyo University of Science, led by Prof. Shin Aoki in collaboration with Mr. Kohei Yamaguchi and Dr. Kenta Yokoi, conducted a study to develop novel complex-peptide hybrids with paraptosis-inducing potential. This study was made available online on 11 April 2022, and subsequently published in Volume 33 of the journalBioconjugate Chemistry, on 20 April 2022.
“Previously, we synthesized an iridium complex-peptide hybrid compound and observed that it induced cell death in cancer cells, which was different from apoptosis. Since this compound was unlike other paraptosis-inducing compounds, we wanted to understand its mechanism of paraptosis induction. Our goal now is to synthesize new compounds and elucidate how they induce paraptosis in cells, before we share this crucial information with the public,” explains Prof. Aoki while discussing the team’s motivation behind this study.
The newly synthesized compounds were composed of a triptycene core — an aromatic hydrocarbon — with two or three cationic peptides made of the amino acids lysine and glycine (represented as KKKGG) through a C8 alkyl linker chain, at different positions of the triptycene units. As a result, three triptycene core hybrids (TPHs) were produced, namely, 5, syn-6, and anti-6.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects all the organ systems of the body. This chronic disease includes periods of illness, called flare ups, and periods of remission, when symptoms are few. There is so far no cure for this disease; treatments involve preventing flare ups and reducing their severity and duration. One of the most severe forms of SLE is neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system — the brain and spinal cord.
A team of researchers, led by Professor Masaaki Murakami at the Institute for Genetic Medicine, Hokkaido University, have identified a stress-induced molecular mechanism that affects NPSLE, revealing a potential target for the treatment of the disease. Their findings were published in the journal Annals of the Rheumatic Diseases.
The research team focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be many causes for dNPSLE, but its pathogenesis remains poorly understood. The researchers were most interested in the effects of stress, as chronic stress is known to be involved in the development of many autoimmune diseases.
In order to identify stress-induced molecular mechanisms that might affect dNPSLE, they conducted experiments on mice models that exhibit SLE-like symptoms. After subjecting a set of these mice to sleep deprivation stress, they were able to identify that the medial prefrontal cortex (mPFC) of the brain was abnormally activated.
In the mPFC, the expression of at least 509 genes was significantly affected by sleep deprivation. The team specifically noted the upregulation of a microglial proinflammatory gene that is required for two interleukins, IL12 and IL23. Further, they showed that upregulation of these two interleukins caused activation of the microglial cells of the mPFC. Blocking IL12 and IL23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms.
Most importantly, they showed that levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE were higher than that of healthy individuals, to such an extent that it can be used as a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied. Together, these indicate that the findings from the mice models may be applicable to humans.
“In revealing the effect of the stress-induced effects on the expression of IL12 and IL23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease,” said Masaaki Murakami.
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Published33 minutes agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesFor the first time in the US, a pharmaceutical firm has asked to be allowed to sell birth control pills over the counter. The announcement comes just weeks after the Supreme Court overturned the constitutional right to abortion. The firm, Paris-based HDA Pharma, says its application to the Food and Drug Administration is unrelated. The pills, the most common form of contraception in the US, have long required a prescription. Studies have shown that over 50% of approximately 6.1 million pregnancies in the US each year are unintended. While birth control pills were first approved for use in the US more than 60 years ago, about one-third of US women who have tried to get or fill prescriptions have reported difficulties doing so. Globally, more than 100 countries provide oral contraceptives without a prescription, making the US one of the few countries to require one. Several major US medication organisations – including the American Medical Association and American Academy of Family Physicians – have called on US authorities to do the same. Frédérique Welgryn, Chief Strategic Operations and Innovation Officer at HRA Pharma, argued that the firm’s application was a “ground-breaking moment” in reproductive equity in the US. The application, the company has said, follows years of research intended to help make its case to US regulators. US retailers limit buying emergency contraceptivesThousands march to White House for abortion rights”Moving a safe and effective birth control pill to OTC [over the counter] will help even more women and people access contraception without facing unnecessary barriers.”According to the company, a decision from the FDA is expected next year. An approval would apply exclusively to the firm’s Opill drug, which was acquired from Pfizer in 2014. Patients have been able to use the pill, if prescribed, since 1973. The BBC has reached out to the FDA for comment. HDA’s application comes amid intense public debate over reproductive rights in the US, with Democratic lawmakers and pro-choice activists urging the FDA to consider similar requests. In March, for example, 50 congressmen of the House of Representatives’ Pro-Choice Caucus wrote an open letter calling on the administration to “review applications for over the counter birth control pills without delay and solely on the data”. Ms Welgryn told the New York Times that the firm’s application was unrelated and “a really sad coincidence”. “Birth control is not a solution for abortion access,” she said. Since the Supreme Court’s abortion ruling, leading US retailers have reported rationing birth control pills amid surging demand. More on this storyThousands march to White House for abortion rights1 day agoUS retailers limit buying emergency contraceptives29 JuneAbortions stopped at Mississippi’s last clinic3 days ago

The development of new types of drugs based on DNA and RNA is happening at a rapid pace. The mRNA vaccines against COVID-19 are just one of many examples of DNA/RNA-based drugs on the market. Many are on the way, but the production of the modified necessary DNA/RNA is costly. A research group at Aarhus University has now found an effective and inexpensive method for producing stable DNA sequences attached to chemical groups that e.g., ensures that the drugs are directed into the right cells.
The production of short DNA and RNA sequences, called oligonucleotides, is today essential in connection with diagnostics (COVID-19 test), DNA sequencing, gene synthesis for synthetic biology and gene therapy, such as in the CRISPR-Cas9 method.
The technology of oligonucleotide production has been advanced since it was developed in 1981, but the underlying chemistry remains largely unchanged. One is still dependent on phosphoramidites, which are chemical compounds that, unfortunately, are unstable in the production process.
However, Kurt Gothelf and his research group have previously shown a more efficient way to produce the building blocks for oligonucleotides by developing a flow-based method to make phosphoramidites immediately before they are to be used, thus avoiding this degradation. You can read more about this in a previous article here: “New method for producing synthetic DNA” (https://inano.au.dk/about/news-events/news/show/artikel/new-method-for-producing-synthetic-dna).
Expensive to acquire DNA sequences with special functionalities
There is a great need for oligonucleotides that have been modified with special functionalities. For example, oligonucleotides modified with certain sugars have been shown to be taken up by the liver. Based on this, several oligonucleotide drugs are used to regulate proteins that are, in fact, produced in the liver and thus can cure diseases. It is also important to be able to attach dyes to oligonucleotides as this is often used in diagnostics and research.
Usually, these functionalities are inserted into oligonucleotides by the building blocks, the phosphoramidites, being produced with a specific chemical handle or the desired functional group. There are commercial catalogs with several hundred varieties of these modified phosphoramidites. However, such modified phosphoramidites are, in most cases, very expensive to obtain and, as mentioned above, they are unstable in liquids at room temperature.
New easy and cheap method for synthesis of special building blocks
In a recently published scientific article published in Nucleic Acids Research, which is the leading oligonucleotide journal, Angel Santorelli and Kurt Gothelf present an easy and inexpensive method of introducing modifications to oligonucleotides without the need for special phosphoramidites.
For this purpose, they use chemical compounds called sulfonyl azides, which can provide oligonucleotides with many different functionalities during the chemical synthesis of the oligonucleotides.
The method is compatible with the previously mentioned automated and flow-based method for oligonucleotide synthesis, where degradation of the phosphoramidites is avoided. The recently published method, for the synthesis of modified phosphoramidites, can thus serve as a simple alternative to the unstable and expensive special phosphoramidites currently used in the production of modified oligonucleotides.
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A new study by Tel Aviv University and Ben Gurion University of the Negev, in collaboration with the Israeli Ministry of Health, has found that the fourth COVID-19 vaccine is effective in protecting the elderly population in long-term care facilities from the Omicron variant. The groundbreaking study included approximately 40,000 elderly Israelis living in institutions supervised by the Ministry of Health’s “Senior Shield” program, a task force launched by Israel’s government to oversee the prevention and control of COVID-19 in the country’s geriatric facilities. According to its results, elderly at-risk individuals vaccinated with the fourth dose of the Pfizer vaccine have a 34 percent reduced risk of contracting the Omicron variant, a 64 to 67 percentreduced risk of requiring hospitalization due to COVID, and a 72 percent reduced risk of death from the virus.
The study was led by Prof. Khitam Muhsen and Prof. Dani Cohen of the School of Public Health at Tel Aviv University, Prof. Ron Dagan of Ben Gurion University, Prof. Nimrod Maimon, director of the Internal Medicine Department at Soroka Medical Center and until recently head of the Ministry of Health’s Senior Shield program, as well as program staff members Ami Mizrahi, Omri Bodenheimer, and Boris Boltyansky, in collaboration with Lea Gaon and Zafrira Hillel-Diamant of the Ministry’s Department of Geriatrics. The study was published in the journal JAMA Internal Medicine.
“Our study compared 24,088 residents of Senior Shield facilities who received a fourth dose of the Pfizer vaccine — that is, the second booster shot — with 19,687 residents who were vaccinated with the first three doses four months or more prior to the follow-up, but who chose not to get the second booster,” explains Prof. Muhsen. “These are residents of geriatric institutions, nursing homes and assisted living facilities that are part of the Ministry of Health’s Senior Shield system — a total of about 1,000 institutions across the country. This population is particularly vulnerable to infection, morbidity and mortality from the coronavirus, due to the nature and living conditions of the institutions, the fact that many residents need help with daily activities, and the previous health issues that many of the residents suffer from.”
When the Omicron wave spread throughout Israel between January and March of this year, there was no registered and available vaccine for this particular variant, which underwent significant mutations in the spike protein that allows the virus to attach to and penetrate human cells. Because the existing COVID-19 vaccines target the spike protein, there has been much discussion in Israel and the rest of the world about the effectiveness of existing vaccines against the Omicron variant in general, and in particular with regards to a second booster shot. Israel was the first country to approve the second booster (the fourth dose of the vaccine) for those aged 60 and above. The present study is based on data from the Senior Shield population database, which constituted the first large group to receive the second booster.
Prof. Muhsen points out that this new study was conducted on a national scale, and that it successfully addressed the methodological problems that characterize observational epidemiological studies on the effectiveness of COVID vaccines. “We monitored the infections, hospitalizations and mortality rates in these two groups throughout the Omicron wave, and found that the members of the group that received the fourth vaccine were infected at a rate that was 34 percent less than the control group; were hospitalized for mild-to-moderate illness 64 percent less, and for severe illness 67 percent less than the control group; and had a mortality rate that was 72 percent less than the group vaccinated with only the first three doses. These are significant data, because the Senior Shield population is one of the groups who suffer the most severe morbidity from the coronavirus, at a much higher rate than the general population. We assume that the fourth dose of the vaccine boosted the level of neutralizing antibodies, which conferred cross-protection against the Omicron variant. Our study points to the significant benefit of administering the fourth dose of the vaccine, and confirms that the policy adopted by the State of Israel was the correct one. The decision to vaccinate at-risk populations with the fourth dose was a wise choice that saved a lot of human lives.”
Prof. Muhsen adds: “This is a groundbreaking and innovative study based on a database of the elderly population in care facilities. Previous studies have been conducted in the general population, and therefore also among relatively young populations with an average age of around 72, whereas the average age in our study was 80. Moreover, in general, people who go to be tested or vaccinated against COVID tend to exhibit positive health behaviors, so it is very difficult to compare their morbidity levels to those of unvaccinated people or those who have been vaccinated with three doses. We have no information as to why some of the residents chose not to receive the fourth vaccine dose, but both groups in our study underwent routine and ‘blind’ COVID tests according to uniform Senior Shield protocol, regardless of whether or not they received the vaccine. Therefore, our study was less affected by the ‘healthy vaccinee effect,’ and its results can also be applied to other populations, in Israel and around the world.”
According to Prof. Dani Cohen, “The study indicates that giving booster shots and raising the level of antibodies through a vaccine based on the original COVID-19 strain provides significant protection against the onset of serious illness even after infection with new variants, including those that are very different from the original, such as Omicron.”
Prof. Nimrod Maimon adds that “The task of protecting institutions for people living outside of the home is a very important aspect of the Ministry of Health’s Senior Shield program. The database that the project has built and accumulated about the institutions and their residents has allowed for rapid and effective vaccination campaigns, which have yielded dramatic results in curbing illness from the coronavirus amongst these populations. The impressive results of the program have received widespread international praise, with health authorities from many countries around the world seeking to learn from the Senior Shield program.”
Prof. Ron Dagan concludes that the results presented in the study demonstrate once again the critical role of vaccines and the use of structured and effective systems in curbing waves of severe morbidity and mortality in at-risk populations.
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Blood pressure levels dropped significantly among Chinese adults with high blood pressure who ate a modified heart-healthy, lower sodium traditional Chinese cuisine for four weeks, according to new research published today in the American Heart Association’s flagship journal Circulation.
A key feature of the Chinese heart-healthy diet, modeled along the lines of the Dietary Approaches to Stop Hypertension (DASH) diet, was sodium reduction. An unhealthy diet, especially one high in sodium, is a key modifiable risk factor for high blood pressure.
“Compared with the nutrient composition of a usual Chinese diet in urban China, our heart-healthy diet of traditional Chinese cuisine cut sodium in half, from 6,000 mg daily to 3,000 mg daily, reduced fat intake and doubled dietary fiber. It also increased protein, carbohydrates and potassium,” said the first author and co-chair of the study team Yanfang Wang, Ph.D., a nutritionist and professorial research fellow at Peking University Clinical Research Institute in Beijing, China.
According to the study, Chinese people account for more than one-fifth of the world’s population. Like in other parts of the world, the cardiovascular disease burden has increased rapidly in recent decades in China. Unhealthy changes in the Chinese diet have been a major factor driving the rise in cardiovascular disease.
According to a 2012 China National Nutrition Survey, consumption of healthy foods such as grains (34%), tubers and legumes (80%), and vegetables and fruits (15%) decreased significantly. In contrast, consumption of meat (162%), eggs (233%), and edible oil (132%) increased dramatically over the same time.
“Chinese people who live in the U.S. and elsewhere often maintain a traditional Chinese diet, which is very different from a Western diet,” said the chair of the study team Yangfeng Wu, M.D., Ph.D., professor of epidemiology and sciences in clinical research at Peking University Clinical Research Institute in Beijing, China. “Healthy Western diets such as DASH and Mediterranean have been developed and proven to help lower blood pressure, however, until now, there has not been a proven heart-healthy diet developed to fit into traditional Chinese cuisine.”
The study included 265 Chinese adults, average age of 56 years old, with systolic blood pressure equal to or greater than 130 mm Hg. Slightly more than half of the participants were women, and nearly half were taking at least one high blood pressure medication when the study began. Participants were recruited from Beijing, Shanghai, Guangzhou and Chengdu. These are four major cities in China, each with a corresponding regional cuisine: Shangdong, Huaiyang, Cantonese and Szechuan, respectively.

A new study from Carnegie Mellon University found that drinking alone during adolescence and young adulthood strongly increases risk for alcohol use disorder (AUD) later in life. This risk is especially high for women. The results are available in the July issue of the journal Drug and Alcohol Dependence.
“Most young people who drink do it with others in social settings, but a substantial minority of young people are drinking alone. Solitary drinking is a unique and robust risk factor for future alcohol use disorder,” said lead author Kasey Creswell, associate professor of psychology at CMU. “Even after we account for well-known risk factors, like binge drinking, frequency of alcohol use, socioeconomic status, and gender, we see a strong signal that drinking alone as a young person predicts alcohol problems in adulthood.”
Excessive alcohol use is a worldwide burden, contributing to 3 million deaths globally each year. Doctors often screen young people for risky alcohol use, but their questions have focused on the frequency and quantity of alcohol consumed. Creswell believes the social context in which young people drink is a critical but often overlooked indicator of future alcohol misuse.
Creswell joined Yvonne Terry-McElrath and Megan Patrick at the University of Michigan to analyze data from the Monitoring the Future study, an ongoing epidemiological study of drug and alcohol use among American youth followed into adulthood. Approximately 4,500 adolescents (age 18) responded to surveys asking about their patterns of alcohol use and whether they consumed alcohol while alone. These participants were then followed for 17 years, providing information about their alcohol use and drinking alone in young adulthood (ages 23/24) and reporting AUD symptoms in adulthood (age 35).
Results showed that adolescents and young adults who reported drinking alone were at increased risk for developing AUD symptoms in adulthood compared to their peers who only drank in social settings. The team controlled for a host of well-established early risk factors for alcohol problems, such as binge drinking and frequent drinking. They found the odds of having AUD symptoms at age 35 were 35% higher for adolescents who drank alone, and 60% higher for young adults who drank alone, compared to social-only drinkers. Adolescent females who drank alone appeared to be at particular risk for developing future alcohol problems in adulthood.
About 25% of adolescents and 40% of young adults reported drinking alone. These findings suggest targeted interventions may be helpful to educate and inform these groups, especially young women, of the risks of solitary drinking to prevent the development of AUD in the future.
Previous work by Creswell and others has shown that young people drink alone as a way to cope with negative emotions, which is a pattern of alcohol use that has been consistently linked to the development of alcohol problems. Creswell noted that the pandemic has increased solitary drinking among young people.
“With concurrent increases in pandemic-related depression and anxiety, we may very well see an increase in alcohol problems among the nation’s youth,” Creswell said.
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Materials provided by Carnegie Mellon University. Original written by Stacy Kish. Note: Content may be edited for style and length.

Immunotherapy has revolutionized treatment for many forms of cancer, but glioblastoma multiforme (GBM), the most common and deadly form of brain cancer, has remained untouched. GBM tumors are sometimes referred to as “cold” — that is, the immune system has a difficult time detecting and targeting them, allowing tumor cells to continue to grow unchecked, even with the advent of immunotherapy drugs. A study led by investigators at Brigham and Women’s Hospital presents a new approach for turning up the heat and setting up immunotherapy treatment for success. When researchers used biodegradable implants loaded with a drug that can activate the STING pathway — a pathway known to stimulate the immune system — in preclinical models, they saw evidence of immune activity and a robust immune effect. Their findings, published in PNAS, suggest that activating the STING pathway could help make GBM more susceptible to immunotherapy treatment.
“Glioblastoma tumors are resistant to therapies that work well in other cancers, so our goal here is to take down the shield that the tumor is using to protect itself,” said corresponding author Sean Lawler, PhD, formerly of the Harvey Cushing Neuro-Oncology Laboratories and the Department of Neurosurgery at the Brigham. Lawler is now at Brown University.
“Our promising findings point to a new approach of using drug-loaded brain implants to change the tumor microenvironment to support combination therapies, including immunotherapies,” said co-author E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at the Brigham.
The STING pathway gets its name from the stimulator of interferon genes (STING) protein, which is critical for helping cells sense pathogens and cancer cells. While STING is well known, it had not been examined in detail in the context of GBM. One of the challenges of treating GBM is that tumors are hidden behind the blood-brain barrier (BBB), which prevents drugs from crossing from circulating blood into the fluid of the central nervous system. To overcome this delivery challenge, investigators from the Brigham’s Department of Neurosurgery collaborated with experts from the Wyss Institute, who developed a biocompatible hydrogel that could be loaded with a drug that activates STING and is released over time. If successful, such a hydrogel could be implanted directly into the brain during surgery to remove a patient’s tumor.
“We show here that the activation of the STING pathway completely remodels the immune environment of the tumor and attracts cells that will get rid of it in mice and will produce long-term immunity against relapse. We were further excited to see that human GBM explants respond to STING agonists by secreting a wide array of cytokines, demonstrating the pathway is active in human tumors and can be used as a new approach to enable immunotherapy to work in GBM,” said first and co-corresponding author Gilles Berger, PharmD-PhD, now an associate professor at the University of Brussels, in Belgium.
The team tested this approach in mouse models of GBM, finding that the treatment promoted long-term survival and immune memory. In the paper, they describe a shift in the tumor immune landscape after treatment, with an influx of innate immune cells including inflammatory macrophages, neutrophils and natural killer (NK) cells. Further experiments showed that NK cells were critical — depleting these cells diminished the response.
The authors note that while their findings are promising, stimulating a strong immune response in the brain must be done with great caution. The study is an important proof of principle, but further refinement, optimization and rigorous testing of the gel delivery system are needed. The authors also want to test different drug combinations to determine what approach may be most effective.
Lawler credits the progress to date to the collaboration between neurosurgeons, cancer researchers and biomedical engineers.
“It’s a lesson in team science,” he said. “We knew this was an interesting pathway, we found the right people to develop the initial tools, and we turned to collaborators at the Dana-Farber Cancer Institute and the Wyss who were sources of great knowledge. This has been a jigsaw puzzle, and the next piece will be clinical collaboration to bring this closer to patient care.”
Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant # NIH 5 P30 CA06516. Additional funding by Expect Miracles Foundation and the Robert A. and Renée E. Belfer Family Foundation.
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The first U.S. application for sale of a nonprescription birth control pill has taken on new meaning in the wake of the Supreme Court decision ending the constitutional right to abortion.WASHINGTON — More than 60 years after the approval of oral contraceptives revolutionized women’s sexual health, the Food and Drug Administration has received its first application to supply a birth control pill over the counter — just as the Supreme Court’s decision to overturn Roe v. Wade has put access to contraception more squarely at the heart of the clash over reproductive rights.A Paris-based company, HRA Pharma, announced on Monday that it asked the F.D.A. to authorize its pill, which is available by prescription, for over-the-counter-sales in the United States. Cadence Health, another pill manufacturer that has been in close dialogue with the F.D.A. about switching its pill to over-the-counter status, said it hopes to move closer to submitting an application in the coming year.The timing of HRA Pharma’s F.D.A. submission, just weeks after the Supreme Court decision, is “a really sad coincidence,” said Frédérique Welgryn, the company’s chief strategic and innovations officer. “Birth control is not a solution for abortion access,” she said.Under ordinary circumstances, filing an application to sell a prescription drug over the counter might go unnoticed in Washington. But birth control is a delicate issue for the F.D.A. Cadence and HRA Pharma have been mired for years in the agency’s pre-application process, and HRA’s formal application comes at an especially fraught moment in the campaign for reproductive rights.The Supreme Court’s ruling in Dobbs v. Jackson Women’s Health Organization, which struck down Roe and eliminated the constitutional right to abortion, included a concurring decision by Justice Clarence Thomas suggesting that the 1965 decision that established a right to contraception should also be overturned. On Friday, President Biden denounced the Dobbs ruling as “an exercise in raw political power,” and vowed to expand access to reproductive health care.On Capitol Hill, scores of House Democrats signed a letter earlier this year to F.D.A. Commissioner Robert Califf requesting a “timely review” of any applications to take birth-control pills over the counter. More than 100 Democrats have signed on to a bill requiring insurance companies to cover the cost of over-the-counter birth control. (The Affordable Care Act already requires insurers to cover prescription contraceptives.)“As we are seeing the outfall and the chaos of the Supreme Court decision, more families are looking to, ‘Well, how can I make sure I control my own choices in life?’” said Senator Patty Murray, Democrat of Washington, chairwoman of the Senate Health Committee and the lead sponsor of the measure. “We want to make sure that women not only get access, but those who have trouble affording it get access as well.”Demonstrators gathered outside of the Supreme Court after the decision to reverse Roe v. Wade. A concurring opinion by Justice Clarence Thomas in the case suggested that the court could revisit the basis for a right to contraception.Anna Rose Layden for The New York TimesHRA Pharma officials said they expect an F.D.A. decision in about 10 months, which is typical for over-the-counter applications. The F.D.A. declined to comment.Supporters of reproductive rights are also calling on Mr. Biden to have the F.D.A. move quickly on its review of over-the-counter contraceptives in light of the Dobbs decision. Dana Singiser, a founder of the Contraceptive Access Initiative, a nonprofit advocacy group, said the experience with Covid-19 shows that the F.D.A. “can work with urgency during a public health emergency, which is what women are facing right now with the overturning of Roe v. Wade.”But Mr. Biden has taken a hands-off posture toward the F.D.A. Jen Klein, who advises the president on gender policy, told reporters on Friday that the agency “has to go through its process.” And if history is any guide, the path to approval will be bumpy.In 2011, the F.D.A. approved the over-the-counter sale of Plan B, an emergency contraceptive, to teenagers 16 and younger — only to have Kathleen Sebelius, then the health secretary in the Obama administration, take the exceedingly rare step of overruling its decision after President Barack Obama expressed reservations about giving minors access to the drug without parental consent. Ms. Sebelius was eventually overruled by a federal judge.“Years of legal wrangling finally got them to follow the science,” said Kelly Blanchard, the president of Ibis Reproductive Health, a global nonprofit group that partnered with HRA Pharma to conduct the research needed to submit the application. “We hope they follow the science and approve without an age restriction in this case.”But access for teenagers is likely to emerge as a sticking point. Leaders of the anti-abortion movement have not taken a position on over-the-counter birth control pills, but they strongly oppose giving them to minors without any adult involvement.“I agree with Obama; it’s common sense not to recklessly sell these pills,” said Kristi Hamrick, a spokeswoman for Students for Life, an anti-abortion group. “As a father of two daughters, he understood that taking adults out of the equation is a problem.”Roughly half of all pregnancies in the United States are unintended, according to the Guttmacher Institute, a research organization that supports abortion rights. Reproductive-rights activists view an over-the-counter birth control pill as an easy and effective tool for women in rural, poor and historically marginalized communities to avoid unwanted pregnancies, which in turn reduces the abortion rate.A decision by the F.D.A. in 2011 to approve over-the-counter sales of Plan B, an emergency contraceptive, set off a political and legal battle.Sarah Silbiger/ReutersThe Dobbs decision has cast a spotlight on the barriers women, especially poor ones, face in gaining access to contraception — a point that Representatives Barbara Lee of California and Diana DeGette of Colorado, the Democrats who chair the House Pro-Choice Caucus, made in a letter they sent to Dr. Califf in March.“Despite decades of proven safety and effectiveness, people still face immense barriers to getting birth control due to systemic inequities in our healthcare system,” said the letter, also signed by 57 other Democrats. “These barriers are disproportionately borne by people of color, immigrants, L.G.B.T.Q.+ people, low-income individuals, young people and people in rural communities.”In a May 18 reply, Dr. Califf wrote that the F.D.A. “acknowledges the public health benefits of increased access to oral contraceptives.” Decisions on whether to approve over-the-counter status for oral contraceptives, he said, are “guided by the best available science.”Young women, in particular, are eager for over-the-counter pills, said Angela Maske, who manages the #FreeThePill Youth Council, an advocacy group aligned with HRA Pharma.Ms. Maske, 25, said she was denied contraception while a student at Georgetown University, a Catholic institution whose student health center provides contraception if needed for medical conditions, such as acne, “but not directly for contraception,” according to its website.The policy, she said, made her feel as though she were being encouraged to lie, which “felt icky and immoral.” Over-the-counter pills — which she noted are available in more than 100 countries — would have solved the problem, she said.Medical experts say that birth control pills are among the safest and most-studied medicines on the market, but that getting the necessary prescription can be a barrier to access. Several major medical organizations, including the American Medical Association, the American College of Obstetricians and Gynecologists and the American Academy of Family Physicians say that oral contraceptives are appropriate for over-the-counter use.HRA Pharma’s pill is a so-called mini pill, meaning it contains only the hormone progestin, which plays a role in the menstrual cycle and pregnancy.The mini pill is widely used in Britain, but accounts for less than 10 percent of the U.S. market for oral contraceptives, partly because the pills can cause unscheduled bleeding and require greater vigilance on the part of patients, who must take them at the same time every day. “Combination pills,” which include both progestin and estrogen, are much more commonly used.“Oral contraceptives are safe, and they are safe medications for most people,” said Dr. Jonas Swartz, an obstetrician and gynecologist at Duke University Health System. “There’s good data that people can do screening with, either online tools or checklists, to determine if they are not candidates for using combined pills or progestin-only pills.”Both Cadence, which makes a combination pill, and HRA Pharma have been communicating with the F.D.A. for more than six years about getting approval to sell their pills over the counter. Cadence, which has not received F.D.A. approval to proceed with a clinical trial that is essential to its application, may have to wait another two years before it can do so.Samantha Miller, the co-chief executive of Cadence, said the F.D.A. has put the company’s “actual use trial” — its study to determine how women use the pill in a real-world setting — on hold. She said the company is “actively working” with the agency “to overcome this regulatory hurdle by developing a user-friendly technology interface for our over-the-counter product.”HRA Pharma, which was recently purchased by Perrigo, a multinational maker of over-the-counter pharmaceuticals based in Dublin, already sells its progestin-only pill over the counter in Britain, where the drug is marketed under the name Hana. In the United States, it is sold by prescription as Opill.Cost is almost certain to be an issue. Because the Affordable Care Act requires insurers to cover the expense of prescription contraceptives, women who have insurance and are already taking Opill may be loath to switch. Ms. Welgryn of HRA Pharma said the company is determined to make its product “very affordable for consumers.” Cadence has made a similar promise.Oral contraceptives had become entwined with the women’s rights movement even before 1960, when the first birth control pill was approved by the F.D.A. In the 1940s and 1950s, Margaret Sanger, the founder of Planned Parenthood, closely followed research on birth control and funded some of it herself, according to a Planned Parenthood history.Margaret Sanger, who founded the American Birth Control League in 1921, spoke before a Senate committee about federal birth control legislation in Washington in 1934.Associated PressThe early pills included high doses of hormones and carried the risk of side effects; it took scientists more than a decade to recognize those risks and lower the doses. Feminists were “very eager for contraception, but very wary about the first generation of pills,” said Carole Joffe, a professor of obstetrics and gynecology at the University of California, San Francisco.But the prospect of being able to separate sex from childbearing freed women to enter the workplace and to chart their own professional courses on their own timetable — a development that the Harvard economists, Claudia Goldin and Lawrence F. Katz, have called the “power of the pill.”But it was not until 1965, with the ruling in the landmark case of Griswold v. Connecticut, that the Supreme Court established a right to contraception — and then only for married people.“It was revolutionary, because in my grandmother’s age, they had no choices,” said Senator Murray of Washington.For decades, pharmaceutical companies demonstrated little interest in offering birth control pills over the counter. Oral contraceptives were hardly blockbuster moneymakers, although if either HRA or Cadence becomes the first to have its type of pill approved for over-the-counter use it will be granted a temporary monopoly on that market, intended to help the company recoup research and development costs.In the 1980s, a company flirted with the idea, but abandoned it, said Dr. Daniel Grossman, an expert in reproductive health at the University of California, San Francisco. And the political and legal battle over Plan B, he said, gave pharmaceutical manufacturers “cold feet.”“They saw how even if you had done the studies exactly the way F.D.A. had laid them out,” he said, “you could still get blocked for political reasons.”