Stable, hydrogen-burning, M dwarf stars make up about 75% of all stars in the Galaxy. They are extremely long-lived, and because they are much smaller in mass than the Sun (between 0.5 and 0.08 ...M(Sun)), their temperature and stellar luminosity are low and peaked in the red. We have re-examined what is known at present about the potential for a terrestrial planet forming within, or migrating into, the classic liquid-surface-water habitable zone close to an M dwarf star. Observations of protoplanetary disks suggest that planet-building materials are common around M dwarfs, but N-body simulations differ in their estimations of the likelihood of potentially habitable, wet planets that reside within their habitable zones, which are only about one-fifth to 1/50th of the width of that for a G star. Particularly in light of the claimed detection of the planets with masses as small as 5.5 and 7.5 M(Earth) orbiting M stars, there seems no reason to exclude the possibility of terrestrial planets. Tidally locked synchronous rotation within the narrow habitable zone does not necessarily lead to atmospheric collapse, and active stellar flaring may not be as much of an evolutionarily disadvantageous factor as has previously been supposed. We conclude that M dwarf stars may indeed be viable hosts for planets on which the origin and evolution of life can occur. A number of planetary processes such as cessation of geothermal activity or thermal and nonthermal atmospheric loss processes may limit the duration of planetary habitability to periods far shorter than the extreme lifetime of the M dwarf star. Nevertheless, it makes sense to include M dwarf stars in programs that seek to find habitable worlds and evidence of life. This paper presents the summary conclusions of an interdisciplinary workshop (http://mstars.seti.org) sponsored by the NASA Astrobiology Institute and convened at the SETI Institute.
Background
Postoperative radioactive iodine (RAI) administration is widely utilized in patients with differentiated thyroid cancer. While beneficial in select patients, it is critical to recognize ...the potential negative sequelae of this treatment. The prevention, diagnosis, and management of the salivary and lacrimal complications of RAI exposure are addressed in this consensus statement.
Methods
A multidisciplinary panel of experts was convened under the auspices of the American Head and Neck Society Endocrine Surgery and Salivary Gland Sections. Following a comprehensive literature review to assess the current best evidence, this group developed six relevant consensus recommendations.
Results
Consensus recommendations on RAI were made in the areas of patient assessment, optimal utilization, complication prevention, and complication management.
Conclusion
Salivary and lacrimal complications secondary to RAI exposure are common and need to be weighed when considering its use. The recommendations included in this statement provide direction for approaches to minimize and manage these complications.
Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable ...for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.
Incidental capture in commercial fishing gear is a threat to many populations of marine megafauna, including sea turtles. While research has largely focused on pelagic longline impacts on sea ...turtles, fixed‐gear fisheries are a significant, historically understudied source of injury and mortality.
The present study assesses the interaction of endangered leatherback sea turtles (Dermochelys coriacea) with fixed‐gear fisheries in high‐latitude seasonal foraging habitat where sub‐adult and adult turtles aggregate.
Records of leatherback‐fishery interactions (n = 205) were compiled from databases of publicly‐reported sea turtle sightings in Atlantic Canada (1998–2014) to identify the spatio‐temporal distribution of these events; to identify corresponding fisheries and gear types; and to describe the mechanics and outcomes of entanglements in fixed gear.
Most reports came from coastal Nova Scotia (n = 136) and Newfoundland (n = 40), with reporting rates peaking in the mid‐to‐late 2000s. The majority of entanglements were reported during the summer months of July and August when leatherbacks are seasonally resident and several fisheries are active in continental shelf waters.
Entanglements were most commonly reported in pot gear (e.g. snow crab, lobster, whelk) and trap nets (e.g. mackerel), reflecting extensive use of polypropylene lines distributed in the upper water column where leatherback foraging activity is concentrated.
Given reporting biases and uncertainty regarding post‐release survivorship, entanglement mortalities should be considered a gross underestimate of true mortality rates.
This study highlights both the importance of looking beyond pelagic longlines to evaluate leatherback interactions with fixed‐gear fisheries in high‐use continental shelf foraging habitat, and of involving the fishing industry in developing mitigation measures to reduce entanglement rates and associated turtle mortality.
Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, ...rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.
Tapinarof cream 1% (VTAMA
®
; Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis ...in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%;
n
= 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment.
Clinicaltrials.gov numbers
: NCT03956355, NCT03983980, NCT04053387.
Background
Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment ...of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.
Methods
Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).
Results
The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (
n
= 91), the ORR was 36.3 % (95 % confidence interval CI, 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.
Conclusion
Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
The ability to rapidly recognize words and link them to referents is central to children’s early language development. This ability, often called word recognition in the developmental literature, is ...typically studied in the looking-while-listening paradigm, which measures infants’ fixation on a target object (vs. a distractor) after hearing a target label. We present a large-scale, open database of infant and toddler eye-tracking data from looking-while-listening tasks. The goal of this effort is to address theoretical and methodological challenges in measuring vocabulary development. We first present how we created the database, its features and structure, and associated tools for processing and accessing infant eye-tracking datasets. Using these tools, we then work through two illustrative examples to show how researchers can use Peekbank to interrogate theoretical and methodological questions about children’s developing word recognition ability.
This sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac ...genetics clinics.
An audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test.
This audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease.
We provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape.
•We describe the current models of care for genetic heart diseases throughout Australia•Genetic testing identified a causative variant in 29% of cases•Data will inform the implementation and impact of whole genome sequencing in Australian healthcare
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