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We discuss a teleparallel version of Newton--Cartan gravity. This theory arises as a formal large-speed-of-light limit of the teleparallel equivalent of general relativity (TEGR). Thus, it provides a geometric formulation of the Newtonian limit of TEGR, similar to standard Newton--Cartan gravity being the Newtonian limit of general relativity. We show how by a certain gauge-fixing the standard formulation of Newtonian gravity can be recovered., Comment: 28+4+1 pages (main text, references, appendix), published in Classical and Quantum Gravity. v2: extended discussions, added references, corrected typos. v3: corrected typo

Risk-based genetic tests are often used to determine cancer risk, when to initiate screening, and frequency of screening, but rely on interest in genetic testing. We examined overall interest in genetic testing for cancer risk assessment and willingness to change behavior, and whether these are affected by demographic or socioeconomic factors. We conducted a community needs health survey in 2019 among primary care and cancer patients, family members and community members in New York City. We used univariable analysis and relative risk regression to examine interest in genetic cancer risk testing and willingness to modify lifestyle behaviors in response to an informative genetic test. Of the 1225 participants, 74.0% (n = 906) expressed interest in having a genetic test to assess cancer risk. Interest in genetic testing was high across all demographic and socioeconomic groups; reported interest in genetic testing by group ranged from 65.0 (participants aged 65 years and older) to 83.6% (participants below federal poverty level). Among the 906 participants that reported interest in genetic testing, 79.6% were willing to change eating habits, 66.5% to change exercise habits, and 49.5% to lose weight in response to an informative genetic test result. Our study reveals that interest in genetic testing for cancer risk is high among patients and community members and is high across demographic and socioeconomic groups, as is the reported willingness to change behavior. Based on these results, we recommend that population-based genetic testing may result in greater reduction cancer risk, particularly among minoritized groups. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-022-00610-2.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

A lineage of the Mountain Sucker species complex (Pantosteus jordani) exists as a genetically and morphologically distinct taxon restricted to the Missouri River basin. This species is thought to be declining throughout its range and is assumed to be extirpated from the southern portion of its distribution. We developed a quantitative PCR‐based environmental DNA assay for P. jordani to help define and monitor its current range. The assay is both specific to P. jordani and sensitive to low amounts of DNA, with a detection limit of 10 DNA copies per reaction. In vitro experiments involved testing DNA from twenty tissue samples, collected from the Missouri River basin in Montana and Wyoming. The assay efficiently detected DNA of all P. jordani samples and did not amplify DNA of any closely related nontarget species. Additionally, 29 environmental DNA samples were taken in 19 waterbodies within P. jordani range and its presence or absence was determined prior to sampling at six of 29 sites. All sites where P. jordani was known absent produced negative results, and all sites where it was known present were confirmed with environmental DNA detections. The new assay was able to detect P. jordani at ten sites which were not previously known to contain individuals, demonstrating that this tool has the potential to rapidly expand the current understanding of this taxon's distribution.

When analyzing environmental samples for DNA from multiple taxa, researchers must usually decide between iterative analyses with single‐taxon assays—which are reliable and sensitive, but also laborious to apply—and approaches such as metabarcoding that can simultaneously target multiple species, but which are less sensitive for detection across taxa. Here, we test an intermediate approach that allows efficient, parallel assessment of taxon‐specific qPCR assays via high‐throughput quantitative PCR (HT‐qPCR). Based on an assessment of over 500 environmental samples, we found that sensitivity and specificity of our HT‐qPCR approach were similar (concordance 0.900–1.000) to values achieved through single‐species qPCR in six out of seven assays tested. Thus, HT‐qPCR may provide analyses of similar quality as single‐species qPCR analyses for environmental DNA, but at a lower cost per taxon. We see this approach as being a valuable addition to the eDNA sampling toolbox, particularly for situations where reliable inferences are needed for a defined suite of rare invasive or imperiled taxa.

The retinoblastoma protein regulates mutagenic potential via control of UV-induced DNA lesion acquisition, thus revealing novel mechanisms that contribute to its tumor suppressor capabilities., Carcinogenic insult, such as UV light exposure, creates DNA lesions that evolve into mutations if left unrepaired. These resulting mutations can contribute to carcinogenesis and drive malignant phenotypes. Susceptibility to carcinogens (i.e., the propensity to form a carcinogen-induced DNA lesion) is regulated by both genetic and epigenetic factors. Importantly, carcinogen susceptibility is a critical contributor to cancer mutagenesis. It is known that mutations can be prevented by tumor suppressor regulation of DNA damage response pathways; however, their roles carcinogen susceptibility have not yet been reported. In this study, we reveal that the retinoblastoma (RB1) tumor suppressor regulates UV susceptibility across broad regions of the genome. In particular, centromere and telomere-proximal regions exhibit significant increases in UV lesion susceptibility when RB1 is deleted. Several cancer-related genes are located within genomic regions of increased susceptibility, including telomerase reverse transcriptase, TERT, thereby accelerating mutagenic potential in cancers with RB1 pathway alterations. These findings reveal novel genome stability mechanisms of a tumor suppressor and uncover new pathways to accumulate mutations during cancer evolution.

Effects of historical fire suppression in forested ecosystems, combined with increasingly frequent and prolonged periods of drought due to a changing climate, are predicted to drive increases in the extent and intensity of wildfires in western North America and elsewhere. Understanding the effects of wildfires on forest‐dependent species and interactions among species is important for conservation and management decisions. We used data collected from a long‐term carnivore monitoring program in northern California and southern Oregon, USA to investigate the effects of three mixed‐severity wildfires and salvage logging on a population of fishers (Pekania pennanti), forest‐dependent carnivoran of conservation concern, and a co‐occurring population of gray foxes (Urocyon cinereoargenteus), a competitor of similar body size. We developed a spatial capture‐recapture population model to estimate the short‐term effects of the wildfires and salvage logging on fisher and gray fox abundances, distributions, apparent survival and recruitment, and species interactions using non‐invasive genetic data collected three years prior to and three years following wildfires. Fisher abundance decreased significantly in areas of low‐, medium‐, and high‐severity wildfire. Gray fox abundance decreased in the years before the wildfires, but rebounded in subsequent years. Medium‐severity wildfire had a negative effect on gray fox density, but high‐severity wildfire and fisher density had positive effects on gray fox density. Salvage logging had negative effects on both fisher and gray fox density. Our results suggest that increased severity, extent, and frequency of wildfires in the western USA will affect fisher populations negatively and alter the composition of mesocarnivoran communities.

Molecular tools are commonly directed at refining taxonomies and the species that constitute their fundamental units. This has been especially insightful for groups for which species hypotheses are ambiguous and have largely been based on morphological differences between certain life stages or sexes, and has added importance when taxa are a focus of conservation efforts. Here, we examine the taxonomic status of Arsapnia arapahoe, a winter stonefly in the family Capniidae that is a species of conservation concern because of its limited abundance and restricted range in northern Colorado, USA. Phylogenetic analyses of sequences of mitochondrial and nuclear genes of this and other capniid stoneflies from this region and elsewhere in western North America indicated extensive haplotype sharing, limited genetic differences, and a lack of reciprocal monophyly between A. arapahoe and the sympatric A. decepta, despite distinctive and consistent morphological differences in the sexual apparatus of males of both species. Analyses of autosomal and sex‐linked single nucleotide polymorphisms detected using genotyping by sequencing indicated that all individuals of A. arapahoe consisted of F1 hybrids between female A. decepta and males of another sympatric stonefly, Capnia gracilaria. Rather than constitute a self‐sustaining evolutionary lineage, A. arapahoe appears to represent the product of nonintrogressive hybridization in the limited area of syntopy between two widely distributed taxa. This offers a cautionary tale for taxonomists and conservation biologists working on the less‐studied components of the global fauna.

The last decade has witnessed the development of sophisticated biobehavioral and genetic, ambulatory, and other measures that promise unprecedented insight into psychiatric disorders. As yet, clinical sciences have struggled with implementing these objective measures and they have yet to move beyond “proof of concept.” In part, this struggle reflects a traditional, and conceptually flawed, application of traditional psychometrics (i.e., reliability and validity) for evaluating them. This paper focuses on “resolution,” concerning the degree to which changes in a signal can be detected and quantified, which is central to measurement evaluation in informatics, engineering, computational and biomedical sciences. We define and discuss resolution in terms of traditional reliability and validity evaluation for psychiatric measures, then highlight its importance in a study using acoustic features to predict self-injurious thoughts/behaviors (SITB). This study involved tracking natural language and self-reported symptoms in 124 psychiatric patients: (a) over 5–14 recording sessions, collected using a smart phone application, and (b) during a clinical interview. Importantly, the scope of these measures varied as a function of time (minutes, weeks) and spatial setting (i.e., smart phone vs. interview). Regarding reliability, acoustic features were temporally unstable until we specified the level of temporal/spatial resolution. Regarding validity, accuracy based on machine learning of acoustic features predicting SITB varied as a function of resolution. High accuracy was achieved (i.e., ~87%), but only when the acoustic and SITB measures were “temporally-matched” in resolution was the model generalizable to new data. Unlocking the potential of biobehavioral technologies for clinical psychiatry will require careful consideration of resolution.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Detectors based upon the noble elements, especially liquid xenon as well as liquid argon, as both single- and dual-phase types, require reconstruction of the energies of interacting particles, both in the field of direct detection of dark matter (Weakly Interacting Massive Particles or WIMPs, axions, etc.) and in neutrino physics. Experimentalists, as well as theorists who reanalyze/reinterpret experimental data, have used a few different techniques over the past few decades. In this paper, we review techniques based on solely the primary scintillation channel, the ionization or secondary channel available at non-zero drift electric fields, and combined techniques that include a simple linear combination and weighted averages, with a brief discussion of the applications of profile likelihood, maximum likelihood, and machine learning. Comparing results for electron recoils (beta and gamma interactions) and nuclear recoils (primarily from neutrons) from the Noble Element Simulation Technique (NEST) simulation to available data, we confirm that combining all available information generates higher-precision means, lower widths (energy resolution), and more symmetric shapes (approximately Gaussian) especially at keV-scale energies, with the symmetry even greater when thresholding is addressed. Near thresholds, bias from upward fluctuations matters. For MeV-GeV scales, if only one channel is utilized, an ionization-only-based energy scale outperforms scintillation; channel combination remains beneficial. We discuss here what major collaborations use., 42 Pages, 2 Tables, 11 Figures, 13 Equations

Background MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. Methods Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. Results Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. Conclusions Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.

ObjectivesWe report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC).Materials and methodsIn a 3+3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100mg/m2, days 1, 8, 15) and veliparib (days 1-7) every 21days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle.ResultsTwenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63years. Primary disease sites included hypopharynx (n=5), larynx (n=5), oral cavity (n=4), oropharynx (n=3), and nasal cavity (n=1). Through all of IC, the most common grade 3+adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350mg BID. With 40.9month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached.ConclusionAddition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.

Background/purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a highly contagious and lethal virus, devastating healthcare systems throughout the world. Following a period of stability, the coronavirus disease 2019 (COVID-19) pandemic appears to be re-intensifying globally. As the virus continues to evolve, so does our understanding of its implications on ST-segment elevation myocardial infarction (STEMI). We sought to describe a single center STEMI experience at one of the epicenters during the COVID-19 pandemic. Methods/materials We conducted a retrospective, observational study comparing STEMI patients during the pandemic period (March 1, 2020 to August 31, 2020) to those with STEMI during the pre-pandemic period (March 1, 2019 to August 31, 2019) at NYU Langone Hospital – Long Island, a tertiary care center in Nassau County, New York. Additionally, we describe our subset of COVID-19 patients with STEMI during the pandemic. Results The acute myocardial infarction (AMI) team was activated for a total of 183 patients during both periods. There were a similar number of AMI team activations during the pandemic period (n = 93) compared to the pre-pandemic period (n = 90). Baseline characteristics did not differ during both periods however, infection control measures and additional investigation were required to clarify the diagnosis during the pandemic, resulting in a signal towards longer door-to-balloon times (95.9 min vs. 74.4 min, p = 0.0587). We observed similar inpatient length of stay (LOS) (3.6 days vs. 5.0 days, p = 0.0901) and mortality (13.2% vs. 9.2%, p = 0.5876). There was a total of 6 COVID-19 positive patients who presented with STEMI, of which 4 were emergently taken to the cardiac catheterization laboratory with successful percutaneous coronary intervention (PCI) performed in 3 patients. The 2 patients who were not offered primary PCI expired, as both were treated medically, one with thrombolytics. Conclusions Our single center study, in New York, at one of the epicenters of the pandemic, demonstrated a similar number of AMI team activations, mimicking the seasonal variability seen in 2019, but with a signal towards longer door-to-balloon time. Despite this, inpatient LOS and mortality remained similar., Highlights • The ongoing COVID-19 pandemic continues to evolve, as does our understanding of its implications on STEMI. • Our study demonstrated similar AMI activations but longer door-to-balloon times during the pandemic compared to the pre-pandemic period. • As we continue to manage these pandemic patients, despite longer door-to-balloon times, primary PCI remains the standard of care for STEMI.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

Introduction: SARS-CoV-2 (S-2) infection duration and its impact on patients with cancer and mild to moderate COVID-19 undergoing cancer-directed therapy (CDT), especially in the underserved population, is not well described. We conducted a retrospective study to analyze S-2 positive (+) patients on CDT to describe the S-2 duration and its impact on CDT. Methods:Two hundred ninety-nine patients with cancer were tested with nasopharyngeal (NP) S-2 PCR assay at Columbia University Medical Irving Center (CUIMC), a Minority-NCI Community Oncology site, of which 77 (26%) tested positive. We retrospectively analyzed 26 S-2 (+) patients with mild-to-moderate COVID-19 receiving CDT who consented to the study. NP PCR was repeated every 1 to 2 weeks until 2 successive negative (−) PCRs were obtained prior to restarting CDT. Time to 2 (−) PCR and serology results were recorded. Cycling thresholds (Ct) were obtained for S-2 specific targets and represented an indirect measure of viral load. Results: Demographics of N = 26 patients are: Hispanic (N = 17, 65%), Black (N = 1, 4%), White (N = 7, 27%), and undeclared (N = 1, 4%). Among the tumor histologies represented, gastrointestinal (N = 9, 35%), breast (N = 5, 19%), and sarcoma (N = 3, 12%) were most common. Median time to 2 (−) PCR was 32 days. Twenty patients required greater than 14 days to achieve 2 sequential (−) swabs. CDT was delayed in 21 patients (81%) of whom three experienced disease progression, likely attributed to an interruption in CDT, which was delayed by a mean of 53 days. Interestingly, nine (41%) patients had Ct values greater than 34 for the pan SARS target and seven (32%) patients had Ct values greater than 34 for the SARS-COV-2 target. Sixteen of 16 patients on CDT, tested positive for IgG antibodies at the time of consent, despite protracted viral detectability by NP PCR. Conclusion: Patients receiving CDT appear to have prolonged detectable S-2 by PCR, which can lead to interruption of CDT and POD in patients. We believe and recommend that patients with asymptomatic to mild COVID-19 and aggressive malignancies are at greatest risk for cancer related morbidity and mortality due to CDT cessation and should be considered for continued CDT without interruption. Ct values and serology testing are tools that can help identify those patients on CDT who may be at greatest risk of worsening COVID-19 or of spreading S-2.

Canine distemper virus (CDV) is a multi-host pathogen with variable clinical outcomes of infection across and within species. We used whole-genome sequencing (WGS) to search for viral markers correlated with clinical distemper in African lions. To identify candidate markers, we first documented single-nucleotide polymorphisms (SNPs) differentiating CDV strains associated with different clinical outcomes in lions in East Africa. We then conducted evolutionary analyses on WGS from all global CDV lineages to identify loci subject to selection. SNPs that both differentiated East African strains and were under selection were mapped to a phylogenetic tree representing global CDV diversity to assess if candidate markers correlated with documented outbreaks of clinical distemper in lions (n = 3). Of 54 SNPs differentiating East African strains, ten were under positive or episodic diversifying selection and 20 occurred in the clinical strain despite strong purifying selection at those loci. Candidate markers were in functional domains of the RNP complex (n = 19), the matrix protein (n = 4), on CDV glycoproteins (n = 5), and on the V protein (n = 1). We found mutations at two loci in common between sequences from three CDV outbreaks of clinical distemper in African lions, one in the signaling lymphocytic activation molecule receptor (SLAM)-binding region of the hemagglutinin protein and another in the catalytic center of phosphodiester bond formation on the large polymerase protein. These results suggest convergent evolution at these sites may have a functional role in clinical distemper outbreaks in African lions and uncover potential novel barriers to pathogenicity in this species.

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle dose-limiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.

Background: Various spatiotemporal models have been proposed for predicting ambient particulate exposure for inclusion in epidemiological analyses. We investigated the effect of measurement error in the prediction of particulate matter with diameter

Alternative lengthening of telomeres (ALT) in human cells is a conserved process that is often activated in telomerase-deficient human cancers. This process exploits components of the recombination machinery to extend telomere ends, thus allowing for increased proliferative potential. Human MUS81 (Mus81 in Saccharomyces cerevisiae) is the catalytic subunit of structure-selective endonucleases involved in recombination and has been implicated in the ALT mechanism. However, it is unclear whether MUS81 activity at the telomere is specific to ALT cells or if it is required for more general aspects of telomere stability. In this study, we use S. cerevisiae to evaluate the contribution of the conserved Mus81-Mms4 endonuclease in telomerase-deficient yeast cells that maintain their telomeres by mechanisms akin to human ALT. Similar to human cells, we find that yeast Mus81 readily localizes to telomeres and its activity is important for viability after initial loss of telomerase. Interestingly, our analysis reveals that yeast Mus81 is not required for the survival of cells undergoing recombination-mediated telomere lengthening, i.e. for ALT itself. Rather we infer from genetic analysis that Mus81-Mms4 facilitates telomere replication during times of telomere instability. Furthermore, combining mus81 mutants with mutants of a yeast telomere replication factor, Rrm3, reveals that the two proteins function in parallel to promote normal growth during times of telomere stress. Combined with previous reports, our data can be interpreted in a consistent model in which both yeast and human MUS81-dependent nucleases participate in the recovery of stalled replication forks within telomeric DNA. Furthermore, this process becomes crucial under conditions of additional replication stress, such as telomere replication in telomerase-deficient cells., Author summary Cancer cell divisions require active chromosome lengthening through extension of their highly repetitive ends, called telomeres. This process is accomplished through two main mechanisms: the activity of an RNA-protein complex, telomerase, or through a telomerase-independent process termed alternative lengthening of telomeres (ALT). Human MUS81, the catalytic subunit of a set of structure-selective endonucleases, was found to be essential in human cells undergoing ALT and proposed to be directly involved in telomere lengthening. Using telomerase-deficient Saccharomyces cerevisiae cells as a model for ALT, we tested the hypothesis that Mus81-Mms4, the budding yeast homolog of human MUS81-dependent nucleases, is essential for telomere lengthening as proposed for human cells. Using genetic and molecular assays we confirm that Mus81-Mms4 is involved in telomere metabolism in yeast. However, to our surprise, we find that Mus81-Mms4 is not directly involved in recombination-based mechanisms of telomere lengthening. Rather it appears that Mus81-Mms4 is involved in resolving replication stress at telomeres, which is augmented in cells undergoing telomere instability. This model is consistent with observations in mammalian cells and suggest that cells undergoing telomere shortening experience replication stress at telomeres.

Clinical trials are critically important for the development of new cancer treatments. According to recent estimates, however, clinical trial enrollment is only about 8%. Lack of patient understanding or awareness of clinical trials is one reason for the low rate of participation. The purpose of this observational study was to evaluate the readability of cancer clinical trial websites designed to educate the general public and patients about clinical trials. Nearly 90% of Americans use Google to search for health-related information. We conducted a Google Chrome Incognito search in 2018 using the keywords “cancer clinical trial” and “cancer clinical trials.” Content of the 100 cancer clinical trial websites was analyzed using an online readability panel consisting of Flesch-Kincaid Grade Level, Flesch Reading Ease, Gunning-Fog Index, Coleman-Liau Index, and Simple Measure of Gobbledygook scales. Reading level difficulty was assessed and compared between commercial versus non-commercial URL extensions. Content readability was found to be “difficult” (10.7 grade level). No significant difference in readability, overall, and between commercial and non-commercial URL extensions was found using 4/5 measures of readability; 90.9% of commercial versus 49.4% of non-commercial websites were written at a >10th grade ( P = .013) using Gunning-Fog Index. Written cancer clinical trials content on the Internet is written at a reading level beyond the literacy capabilities of the average American reader. Improving readability to accommodate readers with basic literacy skills will provide an opportunity for greater comprehension that could potentially result in higher rates of clinical trial enrollment.

Estimating air pollution exposure has long been a challenge for environmental health researchers. Technological advances and novel machine learning methods have allowed us to increase the geographic range and accuracy of exposure models, making them a valuable tool in conducting health studies and identifying hotspots of pollution. Here, we have created a prediction model for daily PM2.5 levels in the Greater London area from 1st January 2005 to 31st December 2013 using an ensemble machine learning approach incorporating satellite aerosol optical depth (AOD), land use, and meteorological data. The predictions were made on a 1 km x 1 km scale over 3960 grid cells. The ensemble included predictions from three different machine learners: a random forest (RF), a gradient boosting machine (GBM), and a k-nearest neighbor (KNN) approach. Our ensemble model performed very well, with a ten-fold cross-validated R2 of 0.828. Of the three machine learners, the random forest outperformed the GBM and KNN. Our model was particularly adept at predicting day-to-day changes in PM2.5 levels with an out-of-sample temporal R2 of 0.882. However, its ability to predict spatial variability was weaker, with a R2 of 0.396. We believe this to be due to the smaller spatial variation in pollutant levels in this area. © 2020 by the authors.

Background Neuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB. Consequently, investigating LY2090314, a clinically relevant GSK-3 inhibitor, on NB cellular proliferation and may be beneficial for NB treatment. Methods The effect of LY2090314 was compared with a previously studied GSK-3 inhibitor, Tideglusib. Colorimetric, clonogenic, and live-cell image confluency assays were used to study the proliferative effect of LY2090314 on NB cell lines (NGP, SK-N-AS, and SH-SY-5Y). Western blotting and caspase glo assay were performed to determine the mechanistic function of LY2090314 in NB cell lines. Results LY2090314 treatment exhibited significant growth reduction starting at a 20 nM concentration in NGP, SK-N-AS, and SH-SY-5Y cells. Western blot analysis indicated that growth suppression was due to apoptosis as evidenced by an increase in pro-apoptotic markers cleaved PARP and cleaved caspase-3 and a reduction in the anti-apoptotic protein, survivin. Further, treatment significantly reduced the level of cyclin D1, a key regulatory protein of the cell cycle and apoptosis. Functionally, this was confirmed by an increase in caspase activity. LY2090314 treatment reduced the expression levels of phosphorylated GSK-3 proteins and increased the stability of β-catenin in these cells. Conclusions LY2090314 effectively reduces growth of both human MYCN amplified and non-amplified NB cell lines in vitro. To our knowledge, this is the first study to look at the effect of LY2090314 in NB cell lines. These results indicate that GSK-3 may be a therapeutic target for NB and provide rationale for further preclinical analysis using LY2090314.

BACKGROUND Continuous peripheral nerve blocks can be administered as continuous infusion, patient-controlled boluses, automated boluses, or a combination of these modalities. MATERIAL AND METHODS Ten patients undergoing either ankle (5) or distal radius (5) open reduction and internal fixation received single-injection ropivacaine sciatic nerve block or infraclavicular brachial plexus block and catheter. Infusion pumps were set to begin administering additional ropivacaine 6 h following the initial block as automated boluses supplemented with patient-controlled boluses. RESULTS Patients had similar pain scores when compared to previously published controls; however, local anesthetic consumption was lower in the patients, resulting in increased infusion and analgesia duration by 1 or more days in each group. CONCLUSIONS For infraclavicular and popliteal sciatic catheters, automated boluses may provide a longer duration of analgesia than continuous infusions following painful hand and ankle surgeries, respectively.

We extend the systematic calculation of an approximately relativistic Hamiltonian for centre of mass and internal dynamics of an electromagnetically bound two-particle system by Sonnleitner and Barnett [1] to the case including a weak post-Newtonian gravitational background field, described by the Eddington--Robertson parametrised post-Newtonian metric. Starting from a proper relativistic description of the situation, this approach allows to systematically derive the coupling of the model system to gravity, instead of `guessing' it by means of classical notions of relativistic effects. We embed this technical result into a critical discussion concerning the problem of implementing and interpreting general couplings to the gravitational field and the connected problem of how to properly address the question concerning the validity of the Equivalence Principle in Quantum Mechanics., 27+4+3 pages (main text, appendix, and references), to be published in Physical Review A. Differences to v1: added references, extended conclusions, corrected typos

In this Letter, we report that surface-bound nanobubbles reduce protein denaturation on methylated glass by irreversible protein shell formation. Single-molecule total internal reflection fluorescence (SM-TIRF) microscopy was combined with intramolecular Forster resonance energy transfer (FRET) to study the conformational dynamics of nitroreductase (NfsB) on nanobubble-laden methylated glass surfaces, using reflection brightfield microscopy to register nanobubble locations with NfsB adsorption. First, NfsB adsorbed irreversibly to nanobubbles with no apparent desorption after 5 h. Moreover, virtually all (96%) of the NfsB molecules that interacted with nanobubbles remained folded, whereas less than 50% of NfsB molecules remained folded in the absence of nanobubbles on unmodified silica or methylated glass surfaces. This trend was confirmed by ensemble-average fluorometer TIRF experiments. We hypothesize that nanobubbles reduce protein damage by passivating strongly denaturing topographical surface defects. Thus, nanobubble stabilization on surfaces may have important implications for antifouling surfaces and improving therapeutic protein storage.