Severe Maternal Morbidity, Mortality Up With Infertility Treatment

Women with infertility-treated pregnancy have an increased risk for severe maternal morbidity or maternal death, with invasive infertility treatment associated with an increased likelihood of having three or more severe maternal morbidity indicators, according to a study published online Feb. 4 in the CMAJ, the journal of the Canadian Medical Association.

Natalie Dayan, M.D., from the McGill University Health Centre in Montreal, and colleagues conducted a cohort study using population-based registries from 2006 to 2012. Using propensity score matching, based on demographic, reproductive, and obstetric factors, the authors compared pregnancies achieved using infertility treatment with unassisted pregnancies. Overall, 11,546 infertility treatment pregnancies were matched with 47,553 untreated pregnancies.

The researchers found that severe maternal morbidity or maternal death occurred in 356 and 1,054 infertility-treated and untreated pregnancies, respectively (30.8 versus 22.2 per 1,000 deliveries; relative risk, 1.39). Women who received invasive infertility treatment (odds ratio, 2.28; 95 percent confidence interval, 1.56 to 3.33) but not those who received noninvasive treatment (odds ratio, 0.99; 95 percent confidence interval, 0.57 to 1.72), had an increased likelihood of having three or more severe maternal morbidity indicators.

“Studies comparing invasive with less invasive infertility treatment should extend their focus beyond rates of live births to encompass maternal health outcomes,” the authors write.

Abstract/Full Text

https://www.physiciansbriefing.com/obgyn-women-s-health-11/childbirth-health-news-126/severe-maternal-morbidity-mortality-up-with-infertility-tx-742115.html

State Prisons Need More Smoking-Cessation Programs

Many inmates in U.S. state prisons who want to quit smoking have nowhere to turn for help, a new study finds.

That increases their risk of smoking-related diseases, including cancer, heart disease and stroke.

And the risk is especially high for black men, who are six times more likely to be imprisoned than non-Hispanic white men. They also have higher rates of tobacco use both in and out of prison and are more likely to die from smoking-related illness, researchers said.

The Rutgers University study included 169 inmates in three Northeast correctional centers. Smoking rates were high, especially among blacks, who were slightly more interested than other inmates in kicking the habit, according to the study.

Many smokers who had tried to quit said it had been a year or more since their last attempt, and most who did quit relapsed within a year. Most inmates who quit did so without treatment.

“Many of these inmates want to quit. They just lack the means and understanding on how to do so,” said lead author Pamela Valera, an assistant professor of public health at Rutgers University in New Jersey.

Cigarettes were the most widely used tobacco product, with pipes, cigars and chew/snuff among others used at the three correction centers, the study found. Inmates had a high rate of menthol cigarette use.

More than half said their cellmate smokes around them.

“Our study will help health researchers and smoking cessation treatment specialists to better understand the smoking behaviors of inmates — why they begin and continue to smoke — in order to better tailor and implement important cessation programs to assist them in quitting for life,” Valera said.

Many prisons could do more to help inmates quit, but have instead imposed smoking bans, which can’t prevent smoking or a return to tobacco use after their release, according to Valera.

Less than half of people studied had a medical professional in prison talk to them about quitting, Valera said.

She called for prison-wide smoking-cessation programs and helping inmates who have quit be a positive influence on others, Valera said.

The study was recently published in the journal Health Psychology Open.

More information

The U.S. Centers for Disease Control and Prevention offers a guide for quitting smoking.

SOURCE: Rutgers University, news release, Jan. 28, 2019

https://consumer.healthday.com/cancer-information-5/smoking-cessation-news-628/state-prisons-need-more-smoking-cessation-programs-study-742099.html

Simply shining light on ‘dinosaur metal’ compound kills cancer cells

A new compound based on Iridium, a rare metal which landed in the Gulf of Mexico 66 M years ago, hooked onto albumin, a protein in blood, can attack the nucleus of cancerous cells when switched on by light, University of Warwick researchers have found.

The treatment of cancer using light, called Photodynamic therapy, is based on chemical compounds called photosensitizers, which can be switched on by light to produce oxidising species, able to kill cancer cells. Clinicians can activate these compounds selectively where the tumour is (using optical fibres) thus killing cancer cells and leaving healthy cells intact.

Thanks to the special chemical coating they used, the Warwick group was able to hook up Iridium to the blood protein Albumin, which then glowed very brightly so they could track its passage into cancer cells, where it converted the cells’ own oxygen to a lethal form which killed them.

Not only is the newly formed molecule an excellent photosensitiser, but Albumin is able to deliver it into the nucleus inside cancer cells. The dormant compound can then be switched on by light irradiation and destroy the cancer cells from their very centre.

The bright luminescence of the iridium photosensitiser allowed its accumulation in the nucleus of tumour cells and its activation leading to the cancer cell death to be followed in real time using a microscope.

Professor Peter Sadler, from the Department of Chemistry at the University of Warwick comments:

“It is amazing that this large protein can penetrate into cancer cells and deliver iridium which can kill them selectively on activation with visible light. If this technology can be translated into the clinic, it might be effective against resistant cancers and reduce the side effects of chemotherapy”

Dr Cinzia Imberti, from the University of Warwick comments:

“It is fascinating how albumin can deliver our photosensitiser so specifically to the nucleus. We are at a very early stage, but we are looking forward to see where the preclinical development of this new compound can lead.”

“Our team is not only extremely multidisciplinary, including biologists, chemists and pharmacists, but also highly international, including young researchers from China, India and Italy supported by Royal Society Newton and Sir Henry Wellcome Fellowships.”

---

Story Source:

Materials provided by University of Warwick. Note: Content may be edited for style and length.

---

Journal Reference:

1. Pingyu Zhang, Huaiyi Huang, Samya Banerjee, Guy J. Clarkson, Chen Ge, Cinzia Imberti, Peter J. Sadler. Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer Therapy. Angewandte Chemie International Edition, 2019; DOI: 10.1002/anie.201813002

https://www.sciencedaily.com/releases/2019/02/190204085956.htm

Rise in overdoses from opioids in diarrhea drug

A Rutgers study has uncovered a new threat in the opiate epidemic: Overdoses of loperamide, an over-the-counter diarrhea medication, have been steadily increasing in number and severity nationwide over five years.

Misuse of the drug is particularly alarming because non-prescription drugs like loperamide are inexpensive, readily available online and in retail stores, undetectable on routine drug tests and can be bought in large quantities at one time.

“When used appropriately, loperamide is a safe and effective treatment for diarrhea — but when misused in large doses, it is more toxic to the heart than other opioids which are classified under federal policy as controlled dangerous substances,” said senior author Diane Calello, executive and medical director of the New Jersey Poison Control Center at Rutgers University Medical School. “Overdose deaths occur not because patients stop breathing, as with other opioids, but due to irregular heartbeat and cardiac arrest.”

The study, published in the journal Clinical Toxicology, found increasing instances in which patients with opioid use disorder misused loperamide to prevent or self-treat withdrawal symptoms. To a lesser extent, some took massive doses to get a high similar to heroin, fentanyl or oxycodone.

The researchers reviewed cases of patients with loperamide exposure reported by medical toxicologists to a national registry, the Toxicology Investigators’ Consortium, from January 2010 to December 2016, reporting a growing number of cases over that time frame. The Poison Control Center database (National Poison Data System) also reported a 91 percent increase during that time period, which in 2015 included 916 exposures and two deaths.

The patients reporting misuse in the Rutgers study were predominantly young Caucasian men and women. The majority used extremely high doses of loperamide, the equivalent of 50 to 100 two-milligram pills per day.

Calello noted that New Jersey Poison Control has reported several fatalities or near-fatalities from loperamide in the past 12 months.

“Possible ways of restricting loperamide misuse include limiting the daily or monthly amount an individual could purchase, requiring retailers to keep personal information about customers, requiring photo identification for purchase and placing medication behind the counter,” she said. “Most importantly, consumers need to understand the very real danger of taking this medication in excessive doses.”

---

Story Source:

Materials provided by Rutgers University. Note: Content may be edited for style and length.

---

Journal Reference:

1. Vincent R. Lee, Ariel Vera, Andreia Alexander, Bruce Ruck, Lewis S. Nelson, Paul Wax, Sharan Campleman, Jeffrey Brent, Diane P. Calello. Loperamide misuse to avoid opioid withdrawal and to achieve a euphoric effect: high doses and high risk. Clinical Toxicology, 2018; 1 DOI: 10.1080/15563650.2018.1510128

https://www.sciencedaily.com/releases/2019/02/190204085947.htm

Excess immune pruning of synapses in neural cells from schizophrenia patients

A study led by Massachusetts General Hospital (MGH) investigators finds evidence that the process of synaptic pruning, a normal part of brain development during adolescence, is excessive in individuals with schizophrenia. While previous studies have found structural abnormalities in the brains of people with schizophrenia that suggested a role for abnormal synaptic pruning, this study — published in Nature Neuroscience — is the first to directly observe excessive synaptic pruning using cells from patients with schizophrenia.

“This approach lets us model at least one of the abnormalities of schizophrenia ‘in a dish’,” says Roy Perlis, MD, MSc, of the MGH Department of Psychiatry and the Center for Genomic Medicine, senior author of the report. “It is one of the first indications in cells from patients of what is contributing to the abnormalities in pruning that have been suspected. And we hope to use these cells to screen for new treatments that may ultimately address that abnormality.”

Studies in recent years have revealed that microglia, which are innate immune cells active within the central nervous system, play an important role in brain development by removing unneeded synapses — points of communication between brain cells — and other neural structures. This process is particularly active during adolescence and early adulthood, the time of life when symptoms of schizophrenia and other mental illnesses often first appear.

A new system developed by Perlis’s team has made it possible, for the first time, to study synaptic pruning in patient-derived human cells. In an earlier study the investigators described creating induced microglia-like (iMG) cells from monocytes derived from blood samples cultured under special conditions. They then developed a way to measure synaptic pruning by observing those cells devour synaptic structures called synaptosomes isolated from cultured neurons. In the current study they used iMG cells and synaptosomes obtained from men with schizophrenia and from healthy control participants to determine patient versus control differences in the model of synaptic pruning. In addition, they validated their findings in by growing microglia together with neurons, directly measuring the uptake by microglia of synaptic markers from the neurons.

Their experiments showed that the engulfment and elimination of synapses by iMG cells was most rapid and extensive when both microglia and synapses were derived from men with schizophrenia. Microglia from patients with schizophrenia more extensively pruned synapses from either patients or controls, while control microglial cells ingested the fewest synapses of all. The results suggest that factors from both microglia and neurons contribute to increased synaptic pruning in people with schizophrenia.

Several gene variants have been associated with an increased risk of schizophrenia, and one of those most strongly associated relates to the complement system, which contributes to the ability of immune cells to remove microbes and dying cells. The investigators found that increased expression in neurons of a specific complement protein variant was associated with increased synaptic uptake by iMG cells, although that variant is not the only contributor to increased microglial uptake.

Since preclinical research has suggested that the antibiotic drug minocycline might have benefits against neurodegenerative diseases, although the mechanism is not known, the investigators pretreated microglial cell cultures with a range of minocycline doses before applying the cells to neurons derived from patients with schizophrenia and from controls. The highest minocycline doses almost totally eliminated synaptic engulfment.

To investigate whether minocycline, which is often prescribed to treat acne, might also decrease schizophrenia risk in humans by reducing synaptic pruning during adolescence, the researchers analyzed data from up to 10 years of electronic health records from two academic medical centers. Of more than 22,000 individuals prescribed at least one of five common antibiotics between the ages of 10 and 18, 203 subsequently were diagnosed with a psychotic disorder. The more than 3,800 individuals who were treated with minocycline or the related antibiotic doxycycline for at least 90 days had a significantly reduced risk of a subsequent psychotic disorder diagnosis than did those receiving other antibiotics.

“As encouraged as we are by these initial results, they represent a first step,” says Perlis, a professor of Psychiatry at Harvard Medical School. “Although we studied cells from more patients than any previous study we’re aware of, we need even larger numbers to better understand what is different in cells from individuals with schizophrenia. There is reason to be hopeful that we are starting to understand what causes this devastating disorder as a first step towards developing strategies to prevent, not just treat it. But there is also much more work to be done.”

---

Story Source:

Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

---

Journal Reference:

1. Carl M. Sellgren, Jessica Gracias, Bradley Watmuff, Jonathan D. Biag, Jessica M. Thanos, Paul B. Whittredge, Ting Fu, Kathleen Worringer, Hannah E. Brown, Jennifer Wang, Ajamete Kaykas, Rakesh Karmacharya, Carleton P. Goold, Steven D. Sheridan, Roy H. Perlis. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nature Neuroscience, 2019; DOI: 10.1038/s41593-018-0334-7

https://www.sciencedaily.com/releases/2019/02/190204114612.htm

Years of dreams about CARs turn into reality for Atara

Atara’s emergence last year as a CAR-T contender might have taken some investors by surprise. In fact, though it was not widely known, back in 2015 the group was already mooting the possibility of licensing CAR-T assets from the Memorial Sloan Kettering Cancer Center (MSKCC) to supplement its existing cell therapy offering.

It took a few years but deals have now been done, bringing in technology developed by none other than MSKCC’s Dr Michel Sadelain, one of the biggest names in the field. And some might see the recently announced departure of Atara’s chief executive as clearing the way to bring in a CAR-T leader to take the helm.

This is a suggestion the company does not entirely accept, insisting that it also recognises the importance of tab-cel, its late-stage cell therapy, which uses unmodified T cells. “We’re looking at [our portfolio] as different pillars,” Dietmar Berger, head of R&D, tells Vantage, “where the underlying principle is … allogeneic T-cells.”

Last month Atara unexpectedly revealed the departure of its founding chief executive, Isaac Ciechanover, and the search is on for a successor.

While the group styles itself as an allogeneic player, hoping to take on the likes of Allogene and Cellectis, its leading current CAR-T assets are in fact autologous. The plan, says Mr Berger, is to develop CAR-T cells “autologous first, as proof of concept, and then put them on the allogeneic platform”.

Whether this means that the autologous CARs will never see the light of day beyond clinical trials is not clear, as the company will not reveal its commercialisation strategy.

Odd timing?

Given the problems Novartis and Gilead have had in turning CAR-T into a profitable business it seems an odd time for Atara to be jumping into the technology. But the group insists that its work represents an advance on those initial therapies.

Its lead CAR-T assets came via four recent deals. Two separate tie-ups are in place with Dr Sadelain, in addition to a deal with Dr Marco Davila, Dr Sadelain’s former MSKCC colleague who now works at the Moffitt Cancer Center, and a patent licence with the NIH.

To investors Dr Sadelain is best known as one of the scientific founders of Juno. That business now having been sold to Celgene, Dr Sadelain appears to be free to work with other companies, including Atara and Fate Therapeutics, which is working with him on an allogeneic project using an induced pluripotent stem cell line.

Most importantly, Atara’s MSKCC tie-up involves a mesothelin-targeting CAR that in the clinic yielded a 15% overall remission rate, comprising two responses; a third response emerged on retreatment with an anti-PD-1. Atara plans to take this forward as ATA2271, an asset that will use Dr Sadelain’s novel 1XX co-stimulatory domain and a PD-1 dominant negative receptor to eliminate T cells’ checkpoint signal.

Other mesothelin CARs have disappointed, but Atara reckons the MSKCC project is different thanks to a binding domain that preferentially hits high-density mesothelin-expressing cells and not normal tissue. This binder had been developed at the NIH, hence the need for Atara to sign a separate licence with that US organisation.

Meanwhile, the Moffitt has given the company two CAR-T projects: ATA2431, a triple construct activated if either CD19, CD20 or CD22 antigens are encountered, and ATA2321, a dual CAR for acute myelogenous leukaemia. Mr Berger says the primary targets for the latter have not yet been selected, but that to reduce toxicity it is “and-gated”, meaning that both antigens have to be engaged for activity to be seen.

Atara also has rights to Dr Davila’s next-generation co-stimulatory domains, which like MSKCC’s involve variations on CD28. Interestingly, Mr Berger says Atara has not licensed one of Dr Sadelain’s most revolutionary projects, an auto/trans co-stimulated “armoured CAR” that impressed with initial clinical data in December (The (unsung) best of Ash 2018, December 5, 2018).

Welcome

So far investors have welcomed Atara’s embrace of CAR-T: the stock has trodden water despite the choppy biotech market.

“At least one [CAR-T asset] will move to IND at the end of this year or beginning of next,” Mr Berger promises. In the meantime, investors’ focus will be on two phase III studies of tab-cel, in EBV-positive post-transplant lymphoproliferative disorder, due to read out by mid-year, followed by a US filing.

Tab-cel has been Atara’s lead for the past few years; it comprises banks of EBV-sensitised T cells that can be partially HLA-matched to patients using an algorithm. The cell lines are already recommended for use at MSKCC, but Atara wants to commercialise the concept using its own manufacturing.

This fits neatly with the CAR-T projects, which are to be produced at the same 90,000-square foot manufacturing plant that Atara opened at Thousand Oaks, California, last year. Not only that, but the existing EBV-positive T cell lines will form the basis of Atara’s allogeneic CAR-T work, says Mr Berger.

Given such synchrony it is clear why the company wants to keep both of these pillars in place.

http://www.evaluate.com/vantage/articles/interviews/years-dreams-about-cars-turn-reality-atara

DBV Technologies to Present Data on Epicutaneous Immunotherapy at AAAAI

DBV Technologies (Euronext: DBV – ISIN: FR0010417345 – Nasdaq Stock Market: DBVT), a clinical-stage biopharmaceutical company, today announced that abstracts highlighting clinical and pre-clinical data from its Viaskin technology platform were accepted for poster presentation at the 2019 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting; Food Allergy: Advances in Prevention and Treatment in San Francisco, CA, February 22 -25, 2019. The abstracts became available on the AAAAI meeting website on February 4(th).

“It is exciting to see the AAAAI highlight food allergies as a serious unmet medical need, and we look forward to underscoring epicutaneous immunotherapy as a potentially important clinical advancement in treating these diseases,” said Dr. Hugh Sampson, Chief Scientific Officer and Interim Chief Medical Officer of DBV Technologies and Kurt Hirschhorn Professor of Pediatrics at the Icahn School of Medicine at Mount Sinai. “Epicutaneous immunotherapy, by using the skin to activate the immune system, offers a novel way to potentially transform how we treat our food-allergic patients in a non-invasive manner.”

Selected Abstracts of Interest:

Peanut Allergy Data

“Efficacy and Safety of Epicutaneous Immunotherapy for Peanut Allergy in Subjects With and Without Atopic Dermatitis” will be presented by Dr. Carla M.
Davis, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX. * Poster Number: 735
* Session Number: 4208
* Session Title: Food Immunotherapy * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45am-10:45am

“Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in Young Children” will be presented by Dr. David Fleischer, Director, Allergy and Immunology Center and Associate Section Head, Children’s Hospital Colorado * Poster Number: 749
* Session Number: 4208
* Session Title: Food Immunotherapy * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45am-10:45am

EPIT Mechanism of Action Research

“Skin Dendritic Cells Progressively Subvert The Activation Of Pathogenic Type-2 Immunity Upon Epicutaneous Allergen Immunotherapy” will be presented by Dr. LeoLaoubi, DBV Technologies.
* Poster Number: 734
* Session Number: 4208
* Session Title: Food Immunotherapy * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45am-10:45am

“Langerhans Cells Increase Their Expression of Integrin avb8 Through Migration and are Needed for Tregs Induction by Epicutaneous Immunotherapy (EPIT)” will be presented by Dr. Vincent Dioszeghy, DBV Technologies.
* Poster Number: 622
* Session Number: 3802
* Session Title: BCI Featured Poster Session * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Sunday February 24, 2019 * Presentation Time: 4:30 – 6:00pm

Cashew Nut Allergy Data

“Development of a Cashew Nut Allergy Mouse Model to Evaluate the Efficacy of Epicutaneous Desensitization Treatment” will be presented by Dr. Pierre-Louis Hervé, DBV Technologies.
* Poster Number: 787
* Session Number: 4209
* Session Title: Food Allergy and Treatment * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45am-10:45am

DBV-Sponsored Research

“Shared Cooking Equipment in Restaurants: A Quantitative Risk Assessment for Peanut-Allergic Consumers” will be presented by Dr. Benjamin C. Remington, TNO Ziest, The Netherlands.
* Poster Number: 724
* Session Number: 4207
* Session Title: Food Allergen Structures * Poster Hall Location: Moscone Center South, Exhibition Level, Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45am-10:45am

“Double-Blind, Placebo-Controlled Randomized Trial of Epicutaneous Immunotherapy in Children with Milk-Induced Eosinophilic Esophagitis” will be presented by Dr.
Jonathan Spergel, Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.
* Poster Number: L30
* Session Number: 4216
* Session Title: Late Breaking Poster Session * Poster Hall Location: Moscone Center South Hall B * Presentation Date: Monday, February 25, 2019 * Presentation Time: 9:45-10:45am

https://www.marketscreener.com/DBV-TECHNOLOGIES-10189744/news/DBV-Technologies-to-Present-Data-on-Epicutaneous-Immunotherapy-at-AAAAI-2019-27961506/