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Background: Falls and sarcopenia are significant public health issues in Vietnam. Despite muscle strength being a critical predictor for these conditions, reference data on muscle strength within the Vietnamese population are lacking., Purpose: To establish the reference ranges for muscle strength among Vietnamese individuals., Methods: The study involved 4096 individuals, including 1419 men and 2677 women aged 18 years and above, from the Vietnam Osteoporosis Study. Muscle strength was assessed using a Baseline hand dynamometer for handgrip strength and a Back-Leg-Chest dynamometer for leg strength. We calculated mean values, standard deviations, interquartile ranges, and peak muscle strength (pMS) for both handgrip and leg strength across various ages. Reference curves were created with the Generalised Additive Model for Location Scale and Shape, and polynomial regression models were employed to analyse the relationship between muscle strength and age., Results: Advancing age was significantly associated with lower muscle strength. Peak muscle strength typically occurred between ages 30 and 40, with earlier peaks in women, especially in leg strength. Men consistently showed higher muscle strength than women, with variations depending on the measurement site. Specifically, average handgrip strength was 36.4 kg ± 8.4 (mean ± SD) for men and 23.2 kg ± 6.0 for women (p < 0.001). Leg strength averaged 63.9 kg ± 27.2 for men and 29.5 kg ± 13.9 for women (p < 0.001). Additionally, we produced a percentile chart illustrating muscle weakness ranges based on the 25th percentile of muscle strength and the appendicular skeletal muscle mass index (ASMI) for the Vietnamese population., Conclusion: These data provide reference ranges for evaluating muscle strength in the Vietnamese population, offering crucial insights for identifying individuals at risk of falls or sarcopenia in clinical settings., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Building social bonds is a critical task of adolescence that affords opportunities for learning, identity formation, and social support. Failing to develop close relationships in adolescence hinders adult interpersonal functioning and contributes to problems such as loneliness and depression. During adolescence, increased reward sensitivity and greater social flexibility both contribute to healthy social development, yet we lack a clear theory of how these processes interact to support social functioning. Here, we propose synthesizing these two literatures using a computational reinforcement learning framework that recasts how adolescents pursue and learn from social rewards as a social explore-exploit problem. To become socially skilled, adolescents must balance both their efforts to form individual bonds within specific groups and manage memberships across multiple groups to maximize access to social resources. We draw on insights from sociological studies on social capital in collective networks and neurocognitive research on foraging and cooperation to describe the social explore-exploit dilemma faced by adolescents navigating a modern world with increasing access to diverse resources and group memberships. Our account provides important new directions for examining the dynamics of adolescent behavior in social groups and understanding how social value computations can support positive relationships into adulthood., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This preregistered, longitudinal study examined how much adolescents value and integrate their parents' and peers' attitudes into their own attitudes from early to middle adolescence. Across three waves, participants ( N = 172, 91 female, 11-16 years across three waves; 439 data points) decided whether to pay money to learn their parents' or peers' attitudes about externalizing behaviors. Multivariate growth models revealed that adolescents were consistently willing to pay money over time to learn their parents' and peers' attitudes. The value of learning peers'-but not parents'-attitudes predicted changes in personal attitudes during adolescence, and this did not change across age. Moreover, the effect of others' attitude value on social influence weakened from early to middle adolescence, such that early adolescents who highly valued learning the attitudes of others (i.e., paid more) tended to shift their own attitudes more toward those endorsing positive influence, regardless of the source. In contrast, early adolescents who valued learning others' attitudes less were less susceptible to positive social influence. Importantly, this effect went away in middle adolescence. Although adolescents are highly motivated to learn their parents' and peers' attitudes about externalizing behaviors, how much those attitudes inform their personal attitudes depends on the source of input and the age of adolescents.learning the attitudes of others (i.e., paid more) tended to shift their own attitudes more toward those endorsing positive influence, regardless of the source. In contrast, early adolescents who valued learning others' attitudes less were less susceptible to positive social influence. Importantly, this effectwent away inmiddle adolescence.Although adolescents are highly motivated to learn their parents' and peers' attitudes about externalizing behaviors, how much those attitudes inform their personal attitudes depends on the source of input and the age of adolescents (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescents' perceptions of parent and peer norms about externalizing behaviors influence the extent to which they adopt similar attitudes, yet little is known about how the trajectories of perceived parent and peer norms are related to trajectories of personal attitudes across adolescence. Neural development of midline regions implicated in self-other processing may underlie developmental changes in parent and peer influence. Here, we examined whether neural processing of perceived parent and peer norms in midline regions during self-evaluations would be associated with trajectories of personal attitudes about externalizing behaviors. Trajectories of adolescents' perceived parent and peer norms were examined longitudinally with functional neuroimaging (n = 165; ages 11-16 years across three waves; 86 girls, 79 boys; 29.7% White, 21.8% Black, 35.8% Latinx, 12.7% other/multiracial). Behavioral results showed perceived parent norms were less permissive than adolescents' own attitudes about externalizing behaviors, whereas perceived peer norms were more permissive than adolescents' own attitudes, effects that increased from early to middle adolescence. Although younger adolescents reported less permissive attitudes when they spontaneously tracked perceived parent norms in the ventromedial and medial pFCs during self-evaluations, this effect weakened as they aged. No brain-behavior effects were found when tracking perceived peer norms. These findings elucidate how perceived parent and peer norms change in parallel with personal attitudes about externalizing behaviors from early to middle adolescence and underscore the importance of spontaneous neural tracking of perceived parent norms during self-evaluations for buffering permissive personal attitudes, particularly in early adolescence., (© 2024 Massachusetts Institute of Technology.)

Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi., Patients and Methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed., Results: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit., Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population., (©2024 The Authors; Published by the American Association for Cancer Research.)

This study investigated the impact of activated carbon, palm activated carbon, and zeolite on horse oil (HO) extracted from horse neck fat using supercritical fluid extraction with deodorant-untreated HO (CON) as a comparison. The yield and lipid oxidation of deodorant untreated HO (CON) were not significantly affected by the three deodorants. However, deodorant-treated HOs exhibited significantly elevated levels of α-linolenic acid (C18:3n3) and eicosenoic acid (C20:1n9) compared to CON (p<0.05), while other fatty acids remained consistent. Zeolite-purified HO demonstrated significantly lower levels of volatile organic compounds (VOCs) than other treatments (p<0.05). Remarkably, zeolite decreased the concentration of pentane, 2,3-dimethyl (gasoline odor), by over 90%, from 177.17 A.U. ×10 6 in CON to 15.91 A.U. ×10 6 . Zeolite also effectively eliminates sec-butylamine (ammonia and fishy odor) as compared to other deodorant-treated HOs (p<0.05). Additionally, zeolite reduced VOCs associated with the fruity citrus flavor, such as nonanal, octanal, and D-limonene in HO (p<0.05). This study suggests that integrating zeolite in supercritical fluid extraction enhances HO purification by effectively eliminating undesirable VOCs, presenting a valuable approach for producing high-quality HO production in the cosmetic and functional food industries., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

We investigated the genetic basis of teat number in sows, which is an important factor in their reproductive performance. We collected genotyping data from 20 353 pigs of three breeds (Duroc, Landrace and Yorkshire) using the Porcine SNP60K Bead Chip, and analyzed phenotypic data from 240 603 pigs. The heritability values of total teat number were 0.33 ± 0.02, 0.51 ± 0.01 and 0.50 ± 0.01 in Duroc, Landrace and Yorkshire pigs, respectively. A genome-wide association study was used to identify significant chromosomal regions associated with teat number in SSC7 and SSC9 in Duroc pig, SSC3, SSC7 and SSC18 in Landrace pig, and SSC7, SSC8 and SSC10 in Yorkshire pig. Among the markers, MARC0038565, located between the vertnin (VRTN) and synapse differentiation-inducing 1-like (SYNDIG1L) genes, showed the strongest association in the Duroc pig and was significant in all breeds. In Landrace and Yorkshire pigs, the most significant markers were located within the apoptosis resistant E3 ubiquitin protein ligase 1 (AREL1) and latent transforming growth factor beta-binding protein 2 (LTBP2) genes in SSC7, respectively. VRTN is a candidate gene regulating the teat number. Most markers were located in SSC7, indicating their significance in determining teat number and their potential as valuable genomic selection targets for improving this trait. Extensive linkage disequilibrium blocks were identified in SSC7, supporting their use in genomic selection strategies. Our study provides valuable insights into the genetic architecture of teat numbers in pigs, and helps identify candidate genes and genomic regions that may contribute to this economically important trait., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Volunteering and charitable donations are two common forms of prosocial behavior, yet it is unclear whether these other-benefitting behaviors are supported by the same or different neurobiological mechanisms. During an fMRI task, 40 participants (20 female-identifying; age: mean = 18.92 years, range = 18.32-19.92 years) contributed their time (in minutes) and money (in dollars) to a variety of local charities. With the maximum amount of time and money that participants could spend on these charities, they did not differentially donate their time and money. At the neural level, donating time and money both showed activations in brain regions involved in cognitive control (e.g., dorsolateral PFC) and affective processing (e.g., dorsal anterior cingulate cortex), but donating time recruited regions involved in reward valuation (e.g., ventral striatum) and mentalizing (e.g., temporal pole) to a greater extent than donating money. Further, the precuneus, which is also a region involved in mentalizing, more strongly tracked the varying amount of money than time donated, suggesting that the precuneus may be more sensitive to the increasing magnitude of a nonsocial exchange (e.g., donating money is a financial exchange) than a social exchange (e.g., donating time is an interpersonal exchange). Our findings elucidate shared as well as distinct neurobiological properties of two prosocial behaviors, which have implications for how humans share different resources to positively impact their community. SIGNIFICANCE STATEMENT Prosocial behaviors broadly characterize how humans act to benefit others. Various prosocial behaviors, such as volunteering and charitable donations, share the goal of positively contributing to community. Our study identifies brain regions that may serve as ubiquitous neurobiological markers of community-based prosocial behaviors. Despite this shared goal, our study also shows that the human brain responds to donating time and money in diverging ways, such that brain regions associated with processing emotional reward and thinking about others are more strongly recruited for donating time than for money. Therefore, our study sheds light on how different personal resources, such as one's time and money, within a prosocial context are represented in the brain., (Copyright © 2023 the authors.)

Many prosocial behaviors involve social risks such as speaking out against a popular opinion, bias, group norm, or authority. However, little is known about whether adolescents' prosocial tendencies develop over time with their perceptions of social risks. This accelerated longitudinal study used within-subject growth-curve analyses to test the link between prosocial tendencies and social risk perceptions, in a sample of adolescents who completed self-reports annually for three years (N = 893; M age = 12.30 years, 10 - 14 years at Wave 1, and 10 - 17 years across the full study period; 50% Girls, 33% White non-Latinx, 27% Latinx, 20% African American, 20% Mixed/Other Race). The association between social risk tolerance and prosocial tendencies changed significantly across adolescence, such that at for younger adolescents, more prosocial tendencies were associated with less social risk tolerance, whereas for relatively older adolescents, more prosocial tendencies were associated marginally with more social risk tolerance. Additional individual differences by empathy (but not sensation seeking) emerged. These findings suggest that prosocial development across adolescence may be associated with an underlying ability to tolerate social risks., Competing Interests: The authors have no conflict of interest to declare.

Not all adolescents are equally susceptible to peer influence, and for some, peer influence exerts positive rather than negative effects. Using resting-state functional magnetic resonance imaging, the current study examined how intrinsic functional connectivity networks associated with processing social cognitive and affective stimuli predict adolescents' (n = 87, ages 11-14 years) prosocial tendencies and risky behaviors in the context of positive and negative peer norms. We tested the moderating role of four candidate intrinsic brain networks-associated with mentalizing, cognitive control, motivational relevance, and affective salience-in peer influence susceptibility. Only intrinsic connectivity within the affective salience network significantly moderated the association between peer norms and adolescent behavior above and beyond the other networks. Adolescents with high intrinsic connectivity within the affective salience network reported greater prosocial tendencies in contexts with more positive peer norms but greater risk-taking behavior in contexts with more negative peer norms. In contrast, peer norms were not associated with adolescent behavior for individuals with low affective salience within-network intrinsic connectivity. The mentalizing network, cognitive control network, and motivational relevance network were not associated with individual differences in peer influence susceptibility. This study identifies key neural mechanisms underlying differential susceptibility to positive and negative peer influence in early adolescence, with a particular emphasis on the role of affective salience over traditional mentalizing, regulatory, and motivational processes., (© 2022. The Author(s).)

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner's capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner's primary goals are to facilitate PM trial options for all patients and accelerate trial enrollment onto PM trials. MatchMiner can help clinicians find trial options for an individual patient or provide trial teams with candidate patients matching their trial's eligibility criteria. From March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner's impact on trial consent, we measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process., (© 2022. The Author(s).)

This study examines associations between adolescents' positive risk taking and neural activation during risky decision-making. Participants included 144 adolescents ages 13-16 years (M age = 14.23; SD age = 0.7) from diverse racial and ethnic groups. Participants self-reported their engagement in positive and negative risk taking. Additionally, participants played the Cups task during fMRI, where they chose between a safe choice (guaranteed earning of 15 cents) and a risky choice (varying probabilities of earning more than 15 cents). Using a risk-return framework, we examined adolescents' sensitivity to both risks (safe versus risky) and returns (expected value, or potential reward as a function of its probability of occurring) at the behavioral and neural levels. All participants took more risks when the expected value of the choice was high. However, high positive risk taking was uniquely associated with dampened dmPFC tracking of expected value. Together, results show that adolescents' positive risk taking is associated with neural activity during risky decision-making. Findings are among the first to identify brain-behavior correlations associated with positive risk taking during adolescence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acute hepatopancreatic necrosis disease (AHPND) is a contagious disease for the shrimp cultivation, thus early detection of disease is an unmet need. This present study documented for the first time a simple lateral flow immunoassay (LFIA) strip using polyclonal antibodies was created for the rapid detection both of PirA vp  and PirB vp  protein simultaneously. LFIA method based on the principle of sandwich format. The label is the colloidal gold. The polyclonal antibody was conjugated with the colloidal gold acting as biorecognition element and coated onto the conjugate pad. The rabbit anti-Pir vp , anti-PirB vp  antibodies, and goat anti-rabbit IgG antibody were separately sprayed onto a nitrocellulose membrane to form two test lines and one control line, respectively. The appearance of red bands at the control line and the test line indicated a positive result. A single coloured band at control area indicated a negative result. The limit of detection of LFIA was found to be 125 ng, which could be visually detected by naked eye within 15 min. There was no cross-reactivity observed with VP non-AHPND . Furthermore, the sensitivity and specificity of LFIA were 94.0% and 98.0%, respectively. The developed test strip could be a game changer for early and in situ diagnosis of AHPND., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest in the publication., (© King Abdulaziz City for Science and Technology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population., Patients and Methods: We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints., Results: Six (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome., Conclusions: Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS., (©2021 The Authors; Published by the American Association for Cancer Research.)

Recent mechanistic models of cognitive control define the normative level of control deployment as a function of the effort cost of exerting control balanced against the reward that can be attained by exerting control. Despite these models explaining empirical findings in adults, prior literature has suggested that adolescents may not adaptively integrate value into estimates of how much cognitive control they should deploy. Moreover, much work in adolescent neurodevelopment casts social valuation processes as competing with, and in many cases overwhelming, cognitive control in adolescence. Here, we test whether social incentives can adaptively increase cognitive control. Adolescents (M age  = 14.64, 44 male, N = 87) completed an incentivized cognitive control task in which they could exert cognitive control to receive rewards on behalf of real peers who were rated by all peers in their school grade as being of either high- or low-status. Using Bayesian modeling, we find robust evidence that adolescents exert more cognitive control for high- relative to low-status peers. Moreover, we demonstrate that social incentives, irrespective of their high- or low-status, boost adolescent cognitive control above baseline control where no incentives are offered. Findings support the hypothesis that the cognitive control system in early adolescence is flexibly modulated by social value., (© 2021 John Wiley & Sons Ltd.)

Introduction: This longitudinal study designed and tested the validity of a new measure of prosocial risk taking - risks that individuals take in order to help others., Methods: The sample was racially and ethnically diverse adolescents in the rural Southeastern United States (N = 867; Mage = 12.82 years, 10-14 years at Wave 1; 50% Girls, 33% White non-Latinx, 27% Latinx, 20% Black, 20% Mixed/Other race/ethnicity). Adolescents completed self-report measures of the new prosocial risk-taking scale at baseline and one- and two-year follow-ups., Results: Confirmatory factor analysis demonstrated excellent model fit with a 6-item single factor score. Further, the scale demonstrated good test-retest reliability at one and two-year follow ups. The scale also demonstrated convergent validity, such that prosocial risk taking was positively correlated with prosocial tendencies, empathy, and sensation seeking, and negatively correlated with negative risk-taking behavior and risk tolerance. Finally, we found significant differences by race/ethnicity (but not by gender) in prosocial risk taking, which were not attributable to measurement invariance, and should be interpreted in the context of ongoing societal inequalities between youth., Conclusions: The new Prosocial Risk-Taking Scale yielded reliable scores in our sample. It may be used in future research to investigate individual differences in adolescents' prosocial risk taking, developmental change in prosocial risk taking, and the significance of prosocial risk taking for adolescents' emotional and social adaptation., (Copyright © 2021 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.)

The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Lessons Learned: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination., Background: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors., Methods: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab., Results: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation., Conclusion: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)

Purpose: Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points., Methods: Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily., Results: Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma., Conclusion: These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.

Background: Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation., Methods: This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform., Results: Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m 2 prexasertib and 700 mg LY3300054. Dose-limiting toxicities included one episode each of febrile neutropenia (Arm C) and grade 4 neutropenia lasting > 5 days (Arm B). One patient had immune-related AST/ALT elevation after 12 cycles. Three patients with CCNE1-amplified, high-grade serous ovarian cancer (HGSOC) achieved partial response (PR), 2 lasting > 12 months; a fourth such patient maintained stable disease > 12 months. Analysis of peripheral blood demonstrated evidence of CD8 + T-cell activation in response to treatment., Conclusions: Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples., Trial Registration: ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination-directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA -mutated PARP inhibitor-resistant high-grade serous ovarian cancer (HGSOC)., Patients and Methods: Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks)., Results: Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor-resistant HGSOC, one achieved PR (-90%) and five had SD ranging 16-72 weeks (CBR 86%)., Conclusion: Olaparib with ceralasertib demonstrated preliminary activity in ATM -mutated tumors and in PARP inhibitor-resistant BRCA1/2 -mutated HGSOC. These data warrant additional studies to further confirm activity in these settings., Competing Interests: Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported. Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition., Patients and Methods: This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1-5 and 15-19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments., Results: Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m 2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1 -mutant, PARP inhibitor-resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure., Conclusions: Prexasertib combined with olaparib has preliminary clinical activity in BRCA -mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress., (©2021 American Association for Cancer Research.)

Purpose: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1 / TSC2 or MTOR mutations., Patients and Methods: Patients with tumors with inactivating TSC1 / TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations., Results: Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%-22%]. Median progression-free survival was 2.3 months (95% CI, 1.8-3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5-12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2 -inactivating mutations and PEComa-like pathologic features., Conclusions: Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study. See related commentary by Kato and Cohen, p. 3807 ., (©2021 American Association for Cancer Research.)

Background: Acute hepatopancreatic necrosis disease (AHPND) is caused by toxin-producing strains of Vibrio parahaemolyticus which contain deadly binary toxins PirA vp and PirB vp encoded in pVA1 plasmid. The polyclonal antibodies against PirB vp protein could be used to develop immunochromatographic test strip for in-field diagnosis of AHPND., Results: In this study, PirB vp gene was amplified, cloned, and expressed in E. coli. The expressed protein was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot probed with 6xHis antibodies. Then, the recombinant PirB vp (rPirB vp ) was purified using Ni-Sepharose column. Rabbits were immunized with the purified rPirB vp , and produced antibodies were analyzed using Ouchterlony double immunodiffusion. The antibody titration and antibody purification were performed by ELISA and affinity chromatography, respectively. Finally, antibody specificity and sensitivity were evaluated by dot blotting. The present study showed a high titer of polyclonal antibodies in rabbit serum after immunization and the titer increased steadily during the immunization schedule. The highest titer of antibody reached up to 2,560,000 with LOD of 0.1 ng/mL. The purified antibodies showed no cross-reactivity with proteins from other Vibrio species, and the detection threshold ranged from 6.25 to 12.5 ng toxin/dot., Conclusion: This study highlights the production of high titer and specific polyclonal antibodies as an initial material towards the development of lateral-flow strip test.

Adolescence is often characterized by heightened risk-taking behaviors, which are shaped by social influence from parents and peers. However, little is understood about how adolescents make risky decisions under conflicting influence. The valuation system in the brain may elucidate how adolescents differentially integrate conflicting social information. Twenty-eight adolescents (M age  = 12.7 years) completed a social influence task during a functional magnetic resonance imaging scan. Behaviorally, adolescents took more risks only when their parent endorsed risky decisions but not when their peers endorsed risky decisions. At the neural level, adolescents showed enhanced vmPFC-striatum functional connectivity when they made risky decisions that followed their parents' risky decisions. Results suggest that parents' decisions may guide youths' risk-taking behavior under conflicting influence., (© 2020 Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Acute Hepatopancreatic Necrosis Disease (AHPND) is a newly emerging shrimp disease with mortality up to 100 percent caused by Vibrio parahaemolyticus which carries a plasmid encoding for two toxins, ToxA and ToxB. In 2013, the Global Aquaculture Alliance (GAA) estimated shrimp farming decline in Asia accounted for 1-billion US dollar lost. Currently, diagnosis using PCR method does not meet the demand of in situ detection, which is based on antigen-antibody interaction, has not been developed yet. In this present study, we proceeded to create the toxin and its antibody for lateral flow development. First, recombinant toxin ToxA was generated by gene manipulation. After that, purified ToxA was used to immunize rabbits. Finally, antisera from rabbits and protein-A purified antibodies were evaluated for titer, specificity, and detection threshold. Results showed that recombinant ToxA was overexpressed in soluble fraction at 37 o C with 1mM IPTG. Purification by affinity chromatography was able to isolate recombinant ToxA with the purity up to 94.49%. In ELISA experiment, the immunized antisera reached a titer of up to 1/5,210,000 with 1µg/ml of antigen, and detection threshold was 100ng recombinant toxin. After purification, the detection threshold of purified polyclonal antibodies was 25ng toxin per dot. These results laid a groundwork for the development of AHPND detection kit based on antigen - antibody interactions.

Purpose: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma., Methods: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy., Results: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m 2 IV + AT7519 21 mg/m 2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug., Conclusions: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.

Purpose: DLYE5953A is an antibody-drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors., Patients and Methods: This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies., Results: Sixty-eight patients received DLYE5953A (median, four cycles; range, 1-27). No dose-limiting toxicities were identified during dose escalation (0.2-2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non-small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg ( n = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients., Conclusions: DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target., (©2020 American Association for Cancer Research.)

Adolescents often need to reconcile discrepancies between their own attitudes and those of their parents and peers, but the social contexts under which adolescents conform to the attitudes of others, or the neurocognitive processes underlying decisions to conform, remain unexplored. This fMRI study assessed the extent to which early adolescents (n = 39, ages 12-14) conform to their parents' and peers' conflicting attitudes toward different types of behavior (unconstructive and constructive) and in response to different types of influence (negative and positive). Overall, adolescents exhibited low rates of conformity, sticking with their pre-existing attitudes 65 % of the time. When they did conform, adolescents were more likely to conform to their peers' attitudes towards constructive than unconstructive behaviors, exhibiting decreased activation in the ventromedial prefrontal cortex, dorsal anterior cingulate cortex, insula, and inferior frontal gyrus during peer conformity toward constructive over unconstructive behaviors. Adolescents were also more likely to conform when their parents and peers endorsed relatively more positive influence than negative influence, exhibiting increased activation in the temporoparietal junction when considering conforming to negative over positive influence. These results highlight early adolescents' ability to stick with their own opinions when confronted with opposing attitudes and conform selectively based on the social context., (Published by Elsevier Ltd.)

In this study, we consider a technological approach to obtain a high perpendicular magnetic anisotropy of the Co/Pd multilayers deposited on nanoporous TiO 2 templates of different types of surface morphology. It is found that the use of templates with homogeneous and smoothed surface relief, formed on silicon wafers, ensures conservation of perpendicular anisotropy of the deposited films inherent in the continuous multilayers. Also, their magnetic hardening with doubling of the coercive field is observed. However, inhomogeneous magnetic ordering is revealed in the porous films due to the occurrence of magnetically soft regions near the pore edges and/or inside the pores. Modeling of the field dependences of magnetization and electrical resistance indicates that coherent rotation is the dominant mechanism of magnetization reversal in the porous system instead of the domain-wall motion typical of the continuous multilayers, while their magnetoresistance is determined by electron-magnon scattering, similarly to the continuous counterpart. The preservation of spin waves in the porous films indicates a high uniformity of the magnetic ordering in the fabricated porous systems due to a sufficiently regular pores array introduced into the films, despite the existence of soft-magnetic regions. The results are promising for the design and fabrication of future spintronic devices.

This study tested the pathways supporting adolescent development of prosocial and rebellious behavior. Self-report and structural brain development data were obtained in a three-wave, longitudinal neuroimaging study (8-29 years, N = 210 at Wave 3). First, prosocial and rebellious behavior assessed at Wave 3 were positively correlated. Perspective taking and intention to comfort uniquely predicted prosocial behavior, whereas fun seeking (current levels and longitudinal changes) predicted both prosocial and rebellious behaviors. These changes were accompanied by developmental declines in nucleus accumbens and medial prefrontal cortex (MPFC) volumes, but only faster decline of MPFC (faster maturity) related to less rebellious behavior. These findings point toward a possible differential susceptibility marker, fun seeking, as a predictor of both prosocial and rebellious developmental outcomes., (© 2019 The Authors Child Development published by Wiley Periodicals, Inc. on behalf of Society for Research in Child Development.)

We have systematically investigated the magnetization reversal characteristics and magnetoresistance of continuous and nanoporous [Co/Pd] 5 -IrMn multilayered thin films with perpendicular magnetic anisotropy at different temperatures (4-300 K). For their nanostructuring, porosity was induced by means of deposition onto templates of anodized titania with small (∼30 nm in diameter) homogeneously distributed pores. The magnetization reversal and magnetoresistance of the porous films were found to be closely related to the splitting of the ferromagnetic material into regions with different magnetic properties, in correlation with the complex morphology of the porous system. Independent magnetization reversal is detected for these regions, and is accompanied by its strong impact on the magnetic order in the capping IrMn layer. Electron-magnon scattering is found to be a dominant mechanism of magnetoresistance, determining its almost linear field dependence in a high magnetic field and contributing to its magnetoresistance behavior, similar to magnetization reversal, in a low magnetic field. Partial rotation of IrMn magnetic moments, consistent with the magnetization reversal of the ferromagnet, is proposed as an explanation for the two-state resistance behavior observed in switching between high-resistive and low-resistive values at the magnetization reversal of the porous system studied.

Heightened risk taking in adolescence has long been attributed to valuation systems overwhelming the deployment of cognitive control. However, this explanation of why adolescents engage in risk taking is insufficient given increasing evidence that risk-taking behavior can be strategic and involve elevated cognitive control. We argue that applying the Expected Value of Control (EVC; Shenhav, Botvinick, & Cohen, 2013) computational model to adolescent risk taking can clarify under what conditions control is elevated or diminished during risky decision making. Through this lens, we review research examining when adolescent risk taking might be due to-rather than a failure of-effective cognitive control and suggest compelling ways to test such hypotheses. This effort can not only resolve when risk taking arises from an immaturity of the control system itself versus differences in what adolescents value relative to adults, but also identify promising avenues for channeling cognitive control towards adaptive outcomes in adolescence.

Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages' unmutated common ancestor, "UCA"), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor's initial exposure and the vaccination that preceded sampling. Our data indicate that a "pluripotent" naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.

Genomic analysis of the invasive marine snail Batillaria attramentaria from Elkhorn Slough, Moss Landing, California, USA using 150 bp paired-end Illumina sequences resulted in the assembly of its complete mitogenome. The mitogenome is 16,095 bp in length and contains 2 rRNA, 13 protein-coding, and 22 tRNA genes (GenBank Accession MN557850). Gene content and organization of B. attramentaria are identical to the Turritellidae and Pachychilidae. The phylogenetic analysis of B. attramentaria resolves it in a fully supported clade with these same two families in the superfamily Cerithioidea. Nucleotide BLAST searches of the Elkhorn Slough cox1 gene of B. attramentaria yielded identical sequences from invasive populations from California and British Columbia, and native populations from northeastern and central Japan. These data show that mitogenome sequencing is a useful tool for studying the classification and phylogenetic history Cerithioidea., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Biologically embedded experiences alter developmental trajectories in ways that can influence health, learning, and/or behavior. These systematic differences in experiences may contribute to different biological outcomes as individuals grow and develop, including at the neural level. Previous studies of biologically embedded experiences on neurodevelopment have focused on large-scale institutional or economic factors (e.g. socioeconomic status [SES]) and psychosocial factors (e.g. caregiving behavior). Less attention has focused on how the quality of the immediate home settings, such as the physical home environment (PHYS), influences neurodevelopment. Moreover, no study has investigated these effects in adolescents, who undergo significant physical maturation and neurodevelopment that may influence how they respond to their physical environments. The goal of the current study was to examine whether PHYS quality is biologically embedded in the developing adolescent brain as evidenced by cognitive achievement and cortical development in 56 (48% female) healthy adolescents (14-18 years (M = 16.83 years, SD = 1.17). Using in-home assessments of the physical home environment, anatomical brain scans, and indices of academic achievement, we found that adolescents who have more physical problems in the home (e.g. structural hazards, crowding, excessive noise, poorly lit) have thinner prefrontal cortices, which was associated with lower levels of reading achievement, independent of SES and psychosocial factors. By conducting home visits to assess physical characteristics of adolescents' home, we highlight a typically overlooked aspect of the home environment that has relevance for adolescents' cognitive and brain development., (© 2019 John Wiley & Sons Ltd.)

Purpose: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance., Experimental Design: Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed., Results: Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying BRCA1 mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability., Conclusions: Prexasertib exhibits monotherapy activity in PARP inhibitor-resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition., (©2019 American Association for Cancer Research.)

Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo . LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1-expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors., Patients and Methods: Adults with previously treated, advanced, NY-ESO-1-positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 10 8 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 10 8 vg, 10 9 vg, 10 10 vg x 4 doses)., Results: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma ( n = 24), ovarian ( n = 8), melanoma ( n = 6), and lung cancer ( n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti-NY-ESO-1-specific CD4 + and/or CD8 + T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti-NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis., Conclusions: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer., (©2019 American Association for Cancer Research.)

Although prosocial behavior is preferentially directed toward the in-group across many species, prioritizing the outcomes of both the in- and out-group earlier in development can reduce intergroup biases. The current study examined the role of corticostriatal recruitment and connectivity in buffering the effect of intergroup bias on costly giving behavior during childhood and adolescence, a period when other-oriented preferences and associated brain functions undergo significant change. During functional magnetic resonance imaging, youth (n = 51; 8-16 years) made decisions that could potentially benefit in-group and out-group peers at a cost to themselves. Youth were more prosocial toward in-group relative to out-group peers, but were relatively more prosocial to out-group peers when there was a greater discrepancy between potential rewards for others over oneself (i.e., higher reward inequity). Although they showed no differences in corticostriatal activation, youth evinced greater connectivity between the ventral striatum (VS) and posterior superior temporal sulcus (pSTS) when considering more inequitable prosocial decisions that favored the outcomes of out-group peers, which attenuated intergroup biases in prosocial behavior. We found no age-related differences at the behavioral or neural level, suggesting that in-group preferences already bias prosocial behavior and its neurocognitive processes by late childhood and do not change across adolescence., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A Gram-stain-negative, motile bacterium, designated strain YE3 T , was isolated from activated sludge obtained from a municipal wastewater treatment plant in Daejeon Metropolitan City, Republic of Korea. The cells were oxidase- and catalase-positive, and grew under aerobic conditions at 10-40 °C (optimum, 30 °C), with 1.0-8.0 % (w/v) NaCl (1.0 %) and at pH 5.5-9.0 (pH 7.0). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain YE3 T was most closely related to Pusillimonasharenae KACC 14927 T (98.2 % sequence similarity) and Pusillimonasginsengisoli KCTC 22046 T (98.0 %). DNA-DNA relatedness values for strain YE3 T and P. harenae KACC 14927 T , P. ginsengisoli KCTC 22046 T and P. soli KCTC 22455 T were 28.7±2.27 %, 21.3±1.16 %, and 14.0±0.67 %, respectively. The genomic G+C content of the type strain YE3 T was 59.3 mol%, as determined by whole-genome sequencing. The dominant fatty acids were C16 : 0 (39.2 %) and C17 : 0cyclo (37.5 %). The major polar lipids of strain YE3 T were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Two aminophospholipids and four unidentified lipids were also detected. Furthermore, strain YE3 T was able to oxidize thiosulfate under heterotrophic conditions. Based on the phenotypic, genotypic, chemotaxonomic and phylogenetic analyses, strain YE3 T represents a novel species of the genus Pusillimonas, for which the name Pusillimonas thiosulfatoxidans sp. nov. is proposed. The type strain is YE3 T (=KCTC 62737 T =NBRC 113113 T ).

Objective: This study was undertaken to investigate the genetic characteristics of Berkshire (BS), Landrace (LR), and Yorkshire (YS) pig breeds raised in the Great Grandparents pig farms using the single nucleotide polymorphisms (SNP) information., Methods: A total of 25,921 common SNP genotype markers in three pig breeds were used to estimate the expected heterozygosity (HE), polymorphism information content, F-statistics (FST), linkage disequilibrium (LD) and effective population size (Ne)., Results: The chromosome-wise distribution of FST in BS, LR, and YS populations were within the range of 0-0.36, and the average FST value was estimated to be 0.07±0.06. This result indicated some level of genetic segregation. An average LD (r2) for the BS, LR, and YS breeds was estimated to be approximately 0.41. This study also found an average Ne of 19.9 (BS), 31.4 (LR), and 34.1 (YS) over the last 5th generations. The effective population size for the BS, LR, and YS breeds decreased at a consistent rate from 50th to 10th generations ago. With a relatively faster Ne decline rate in the past 10th generations, there exists possible evidence for intensive selection practices in pigs in the recent past., Conclusion: To develop customized chips for the genomic selection of various breeds, it is important to select and utilize SNP based on the genetic characteristics of each breed. Since the improvement efficiency of breed pigs increases sharply by the population size, it is important to increase test units for the improvement and it is desirable to establish the pig improvement network system to expand the unit of breed pig improvement through the genetic connection among breed pig farms.

Sus scrofa provides a major source of animal protein for humans as well as being an excellent biomedical model. This study was carried out to understand, in detail, the genetic and functional variants of Jeju Native Pigs and miniature pigs through differential expression profiling of the genes controlling their immune response, growth performance, and meat quality. The Illumina HiSeq 2000 platform was used for generating 1.3 billion 90 bp paired-end reads, which were mapped to the S. scrofa genome using TopHat2. A total of 2481 and 2768 genes were differentially expressed with 8-log changes in muscle and liver samples, respectively. Five hundred forty-eight genes in muscle and 642 genes in liver samples had BLAST matches within the non-redundant database. GO process and pathway analyses showed enhanced biological processes related to the extracellular structural organization and skeletal muscle cell differentiation in muscle tissue, whereas the liver tissue shares functions related to the inflammatory response. Herein, we identify inflammatory regulatory genes in miniature pigs and growth response genes in Jeju Native Pigs, information which can provide a stronger base for the selection of breeding stock and facilitate further in vitro and in vivo studies for therapeutic purposes.

The transition from childhood to adolescence is marked by increasingly sophisticated social cognitive abilities that are paralleled by significant functional maturation of the brain. However, the role of social and neurobiological development in facilitating age differences in prosocial behavior remains unclear. Using a cross-sectional sample of children and adolescents (n = 51; 8-16 years), we examined the age-related correlates of prosocial behavior. Youth made costly and non-costly prosocial decisions to anonymous peers during a functional magnetic resonance imaging scan. Among a subsample of youth who made prosocial decisions (n = 35), we found quadratic age differences in neural activation that peaked in early adolescence relative to childhood and older adolescence. In particular, early adolescents showed heightened recruitment of the posterior superior temporal sulcus (pSTS), temporal pole and inferior frontal gyrus (IFG) when engaging in costly prosocial behavior at the expense of gaining a reward, whereas they evoked heightened pSTS and dorsolateral prefrontal cortex/IFG activation when engaging in costly vs non-costly forms of prosocial behavior. Given that we did not find age differences in prosocial behavior, this suggests that early adolescents show unique patterns of brain activation to inform similar levels of prosocial behavior., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Summary: Associations of metabolomics data with phenotypic outcomes are expected to span functional modules, which are defined as sets of correlating metabolites that are coordinately regulated. Moreover, these associations occur at different scales, from entire pathways to only a few metabolites; an aspect that has not been addressed by previous methods. Here, we present MoDentify, a free R package to identify regulated modules in metabolomics networks at different layers of resolution. Importantly, MoDentify shows higher statistical power than classical association analysis. Moreover, the package offers direct interactive visualization of the results in Cytoscape. We present an application example using complex, multifluid metabolomics data. Due to its generic character, the method is widely applicable to other types of data., Availability and Implementation: https://github.com/krumsieklab/MoDentify (vignette includes detailed workflow)., Supplementary Information: Supplementary data are available at Bioinformatics online.

Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic. Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404-21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333 ., (©2018 American Association for Cancer Research.)

Background: Untargeted mass spectrometry (MS)-based metabolomics data often contain missing values that reduce statistical power and can introduce bias in biomedical studies. However, a systematic assessment of the various sources of missing values and strategies to handle these data has received little attention. Missing data can occur systematically, e.g. from run day-dependent effects due to limits of detection (LOD); or it can be random as, for instance, a consequence of sample preparation., Methods: We investigated patterns of missing data in an MS-based metabolomics experiment of serum samples from the German KORA F4 cohort (n = 1750). We then evaluated 31 imputation methods in a simulation framework and biologically validated the results by applying all imputation approaches to real metabolomics data. We examined the ability of each method to reconstruct biochemical pathways from data-driven correlation networks, and the ability of the method to increase statistical power while preserving the strength of established metabolic quantitative trait loci., Results: Run day-dependent LOD-based missing data accounts for most missing values in the metabolomics dataset. Although multiple imputation by chained equations performed well in many scenarios, it is computationally and statistically challenging. K-nearest neighbors (KNN) imputation on observations with variable pre-selection showed robust performance across all evaluation schemes and is computationally more tractable., Conclusion: Missing data in untargeted MS-based metabolomics data occur for various reasons. Based on our results, we recommend that KNN-based imputation is performed on observations with variable pre-selection since it showed robust results in all evaluation schemes.

Objective: To determine the effects of genomic breeding values (GBV) and single nucleotide polymorphisms (SNP) on the total number of piglets born (TNB) in 3 pig breeds (Berkshire, Landrace, and Yorkshire)., Methods: After collecting genomic information (Porcine SNP BeadChip) and phenotypic TNB records for each breed, the effects of GBV and SNP were estimated by using single step best linear unbiased prediction (ssBLUP) method., Results: The heritability estimates for TNB in Berkshire, Landrace, and Yorkshire breeds were 0.078, 0.107, and 0.121, respectively. The breeding value estimates for TNB in Berkshire, Landrace, and Yorkshire breeds were in the range of -1.34 to 1.47 heads, -1.79 to 1.87 heads, and -2.60 to 2.94 heads, respectively. Of sows having records for TNB, the reliability of breeding value for individuals with SNP information was higher than that for individuals without SNP information. Distributions of the SNP effects on TNB did not follow gamma distribution. Most SNP effects were near zero. Only a few SNPs had large effects. The numbers of SNPs with absolute value of more than 4 standard deviations in Berkshire, Landrace, and Yorkshire breeds were 11, 8, and 19, respectively. There was no SNP with absolute value of more than 5 standard deviations in Berkshire or Landrace. However, in Yorkshire, four SNPs (ASGA 0089457, ASGA0103374, ALGA0111816, and ALGA0098882) had absolute values of more than 5 standard deviations., Conclusion: There was no common SNP with large effect among breeds. This might be due to the large genetic composition differences and the small size of reference population. For the precise evaluation of genetic performance of individuals using a genomic selection method, it may be necessary to establish the appropriate size of reference population.

Halomonas aestuarii Hb3, a moderately halophilic bacterium belonging to the class Gammaproteobacteria, was isolated from a tidal flat. Herein, we report the complete genome sequence of its strain Hb3. Its size is estimated at 3.54Mbp with a mean G+C content of 67.9%. The genome includes 3238 open reading frames, 65 transfer RNAs, and four ribosomal RNA gene operons. Genes related to the degradation of monoaromatic compounds, detoxification of arsenic, and production of polymers were identified. These features indicate that this strain may be important for ecological and industrial application., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments. Comparison showed that both Abs contacted the HA receptor-binding site through long heavy-chain third complementarity determining regions. Affinities of the clonal-lineage BCRs for historical influenza-virus HAs from both group 1 and group 2 viruses suggested that serial responses to seasonal influenza exposures had elicited the lineage and driven affinity maturation. We propose that appropriate immunization regimens might elicit a comparably broad response., (Copyright © 2017 Elsevier Inc. All rights reserved.)