bluuebunny/crossref_metadata_2025_split huggingface dataset:
GRN300–001: Phase 1/1B evaluation of the safety, pharmacokinetics, and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers.
Authors: Fu Siqing , Jazaeri Amir A. , Lu Zhen , Peter Markus , Morris Stephan Wade , Bast Robert C. 
Published: June 2022

TPS5616 Background: Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of Class IIa HDACs. SIK2 is overexpressed in 30% of ovarian cancers and associated with decreased progression-free survival (Ahmed et al., 2010). Treatment with GRN-300, an orally bioavailable small-molecule inhibitor of SIK2, was shown to improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice (Zhou et al., 2017). Methods: Part 1 of the study will evaluate the safety, MTD, RP2D (Recommended Phase 2 Dose), and PK of daily GRN-300 monotherapy. For the dose-escalation enrollment of patients with advanced solid tumors of any histology, four dose levels of GRN-300 are planned: 100, 200, 300, and 400 mg BID. Subsequently, GRN-300 will be administered at the determined RP2D in an ovarian cancer expansion cohort. Part 2 will evaluate the safety, PK, and preliminary clinical activity in an open-label study of the combination of GRN-300 and paclitaxel weekly x3. Paclitaxel will be administered in one of two different dosing levels: 60 mg/m2 initially, then dose escalated to 80 mg/m2. In the combination regimen, GRN-300 will be administered at the RP2D dose as determined in Part 1 of this study. The two dose findings will be conducted independently using the BOIN design (Liu 2015, Yuan 2016). Study drug may be administered per protocol for continuous 28-day cycles until disease progression, adverse events, or other criteria as described in the protocol. Tumor biopsies and blood plasma samples including peripheral blood mononuclear cells (PBMCs) will be collected for exploratory biomarker analysis to predict and to monitor responses to GRN-300 treatment. Major eligibility criteria At least 18 years of age. Recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer (advanced solid tumors of any other histology only for the monotherapy dose escalation enrollment in Part 1) In Part 2, diagnosis of recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer for which treatment with paclitaxel is indicated. Received at least one prior second-line treatment. The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022. Clinical trial information: NCT04711161.
A phase 1/2 study of VS-6766 (RAF/MEK clamp) in combination with sotorasib (G12C inhibitor) in patients with KRAS G12C mutant non–small cell lung cancer (NSCLC) (RAMP 203).
Authors: Govindan Ramaswamy , Awad Mark M. , Gadgeel Shirish M. , Pachter Jonathan A. , Patrick Gloria , Denis Louis J. 
Published: June 2022

TPS9148 Background: KRAS is mutated (mt) in 25% of non-small cell lung cancer (NSCLC) adenocarcinoma, with KRAS G12C mt occurring in ̃13% of patients. The G12C inhibitor (G12Ci) sotorasib has recently received FDA approval for patients with KRAS G12C NSCLC. Several studies have shown that simultaneous targeting of multiple nodes in the RAS pathway may be optimal for durable pathway inhibition and response. Furthermore, acquired mutations and amplifications in the RAS pathway occur clinically upon progression on sotorasib or adagrasib. Accordingly, combination of G12Ci with a downstream blocker of the RAS pathway may be needed for more durable response. VS-6766 is a unique small molecule RAF/MEK clamp that inhibits BRAF, CRAF and MEK, enabling VS-6766 to block MEK signaling more consistently without the compensatory activation of MEK that reduces the efficacy of MEK-only inhibitors. In vitro 3D proliferation and in vivo tumor models were used to assess anti-tumor efficacy of VS-6766 ± G12Ci. In KRAS G12C mt NSCLC cell lines, VS-6766 was synergistic with both sotorasib and adagrasib in reducing tumor cell viability which correlated with deeper inhibition of RAS pathway signaling. In vivo, combination of VS-6766 with sotorasib induced strong tumor regressions in contrast to sotorasib monotherapy or sotorasib plus trametinib. Initial clinical activity of VS-6766 in KRAS G12C mt NSCLC is supported by the FRAME study [NCT03875820] results, in which 4/6 patients with KRAS G12C mt NSCLC showed tumor reduction including 1 PR. These results support the clinical evaluation of VS-6766 in combination with a G12Ci for treatment of KRAS G12C mt NSCLC. Methods: This is a Phase 1/2, multicenter, open label, dose evaluation/dose expansion study designed to evaluate the efficacy and safety of VS-6766 in combination with sotorasib in patients with KRAS G12C mt NSCLC who have not previously been treated with a KRAS G12Ci or have experienced disease progression while undergoing therapy with a KRAS G12Ci [NCT05074810]. The study will be conducted in two parts: Part A (dose evaluation) and Part B (dose expansion). Up to 3 dose levels will be evaluated in Part A to determine the Recommended Phase 2 Dose (RP2D) for Part B. Part B will assess the efficacy of the RP2D and will be conducted in 2 cohorts: patients who are G12Ci treatment naïve (cohort 1) and patients who have experienced disease progress during G12Ci therapy (Cohort 2). Patients enrolled must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1 and known KRAS G12C mutation. The study will enroll up to 121 patients with a minimum of 6 and a maximum of 12 patients in Part A and an additional 109 patients in Part B (minimum of 41 patients at RP2D stage 1 for cohort 1 and 2 or RP2D stages 1 and 2 in both cohorts). Clinical trial information: NCT05074810.
Adiposity, Insulin Resistance, Cardiorespiratory Fitness, and Bone Health in Hispanic Children
Authors: Shawar Reem S , Puyau Maurice , Shypailo Roman , Musaad Salma , Butte Nancy F , Bacha Fida 
Published: June 2022

Abstract

Context
Childhood obesity disproportionately affects Hispanic youth. The skeletal system appears to be a target organ of the adverse effects of obesity. Yet, the relationship between adiposity and bone health in youth and the modulating factors are not well understood.

Objective
This work aims to examine the relationship between adiposity, insulin resistance (IR), cardiorespiratory fitness (CRF), and bone mass in Hispanic youth.

Methods
A total of 951 Hispanic youth (50% male), aged 4 to 19 years, participated in this cross-sectional design study from the Viva La Familia Study at Children’s Nutrition Research Center. Bone mineral content (BMC) and density (BMD), lean mass (LM), total body fat mass (FM), truncal FM were obtained using dual-energy x-ray absorptiometry. Fasting glucose and insulin were obtained and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. CRF was measured using a treadmill ramp protocol. We applied linear regression models and mediation analyses.

Results
Adiposity measures were negatively related to BMC and BMD after accounting for LM and sex. IR negatively contributed whereas CRF positively contributed to the variance in BMC and BMD, more notably in the pubertal age group. In mediation analysis, HOMA-IR partially mediated the negative relationship of adiposity to BMC (standardized indirect effect [IE] = –0.0382; 95% CI, –0.0515 to –0.0264) whereas the sequential IE of HOMA-IR and CRF partially attenuated (IE = –0.0026; 95% CI, –0.0053 to –0.0005) this relationship. Similar findings were seen with BMD as the primary outcome.

Conclusion
IR mediates the negative relationship between adiposity and bone mass whereas CRF may partially attenuate it.
Vitamin D receptor absence does not enhance intestinal tumorigenesis in ApcPirc/+rats
Authors: Irving Amy A. , Waters Bayley J. , Seeman Jeremy R. , Plum Lori A. , DeLuca Hector F. 
Published: June 2022

ABSTRACT
Epidemiological observations have prompted some to posit that elevated circulating vitamin D is responsible for reduced colon cancer in individuals residing near the equator. We have previously demonstrated that vitamin D has no effect on colon cancer in two rodent models of intestinal tumorigenesis. We have now extended this line of inquiry to ask whether ablation of vitamin D receptor (VDR) affects tumorigenesis. A VDR null rat was developed using Cas9-CRISPR technology, which allowed us to investigate whether 1,25(OH)D3 signaling through its receptor plays a role in intestinal tumorigenesis. Loss of VDR expression alone did not induce tumorigenesis, even in animals exposed to the inflammatory agent dextran sodium sulfate. These VDR−/− rats were then crossed with ApcPirc/+ rats, which are predisposed to the development of intestinal neoplasms. In combination with the Pirc/+ mutation, VDR loss did not enhance tumor multiplicity, growth, or progression in the colon or small intestine. This study demonstrates that the vitamin D receptor does not impact tumor development, and strongly supports previous findings that vitamin D itself does not play a role in colon cancer development or progression. Alternative explanations are needed for the original latitude hypothesis, as well as observational data in humans.
This article has an associated First Person interview with the first author of the paper.
A prominent gene activation role for C-terminal binding protein in mediating PcG/trxG proteins through Hox gene regulation
Authors: Bi Cai-Li , Cheng Qian , Yan Ling-Yue , Wu Hong-Yan , Wang Qiang , Wang Ping , Cheng Lin , Wang Rui , Yang Lin , Li Jian , Tie Feng , Xie Hao , Fang Ming 
Published: June 2022

ABSTRACT
The evolutionarily conserved C-terminal binding protein (CtBP) has been well characterized as a transcriptional co-repressor. Herein, we report a previously unreported function for CtBP, showing that lowering CtBP dosage genetically suppresses Polycomb group (PcG) loss-of-function phenotypes while enhancing that of trithorax group (trxG) in Drosophila, suggesting that the role of CtBP in gene activation is more pronounced in fly development than previously thought. In fly cells, we show that CtBP is required for the derepression of the most direct PcG target genes, which are highly enriched by homeobox transcription factors, including Hox genes. Using ChIP and co-IP assays, we demonstrate that CtBP is directly required for the molecular switch between H3K27me3 and H3K27ac in the derepressed Hox loci. In addition, CtBP physically interacts with many proteins, such as UTX, CBP, Fs(1)h and RNA Pol II, that have activation roles, potentially assisting in their recruitment to promoters and Polycomb response elements that control Hox gene expression. Therefore, we reveal a prominent activation function for CtBP that confers a major role for the epigenetic program of fly segmentation and development.
Sperm-specific glycogen synthase kinase 3 is required for sperm motility and the post-fertilization signal for female meiosis II in Caenorhabditis elegans
Authors: Banerjee Rudra Prasanna , Srayko Martin 
Published: June 2022

ABSTRACT
In most sexually reproducing animals, sperm entry provides the signal to initiate the final stages of female meiosis. In Caenorhabditis elegans, this signal is required for completion of female anaphase I and entry into meiosis II (MII). memi-1/2/3 (meiosis-to-mitosis) encode maternal components that facilitate this process; memi-1/2/3(RNAi) results in a skipped-MII phenotype. Previously, we used a gain-of-function mutation, memi-1(sb41), to identify genetic suppressors that represent candidates for the sperm-delivered signal. Herein, we characterize two suppressors of memi-1(sb41): gskl-1 and gskl-2. Both genes encode functionally redundant sperm glycogen synthase kinase, type 3 (GSK3) protein kinases. Loss of both genes causes defects in male spermatogenesis, sperm pseudopod treadmilling and paternal-effect embryonic lethality. The two kinases locate within the pseudopod of activated sperm, suggesting that they directly or indirectly regulate the sperm cytoskeletal polymer major sperm protein (MSP). The GSK3 genes genetically interact with another memi-1(sb41) suppressor, gsp-4, which encodes a sperm-specific PP1 phosphatase, previously proposed to regulate MSP dynamics. Moreover, gskl-2 gsp-4; gskl-1 triple mutants often skip female MII, similar to memi-1/2/3(RNAi). The GSK3 kinases and PP1 phosphatases perform similar sperm-related functions and work together for post-fertilization functions in the oocyte that involve MEMI.
A unifying model for the role of the ATG8 system in autophagy
Authors: Nguyen Thanh Ngoc , Lazarou Michael 
Published: June 2022

ABSTRACT
The formation of autophagosomes and their fusion with lysosomes are key events that underpin autophagic degradation of cargoes. The core ATG8 system, which consists of the ATG8 family of ubiquitin-like proteins and the machineries that conjugate them onto autophagosomal membranes, are among the most-studied autophagy components. Despite the research focus on the core ATG8 system, there are conflicting reports regarding its essential roles in autophagy. Here, we reconcile prior observations of the core ATG8 system into a unifying model of their function that aims to consider apparently conflicting discoveries. Bypass pathways of autophagy that function independently of the core ATG8 system are also discussed.
Understanding how variable thermal environments affect the molecular mechanisms underlying temperature-sensitive phenotypes: lessons from sex determination
Authors: Paitz Ryan T. , Breitenbach Anthony T. , Marroquín-Flores Rosario A. , Bowden Rachel M. 
Published: June 2022

ABSTRACTThe thermal environment that organisms experience can affect many aspects of their phenotype. As global temperatures become more unpredictable, it is imperative that we understand the molecular mechanisms by which organisms respond to variable, and often transient, thermal environments. Beyond deciphering the mechanisms through which organisms respond to temperature, we must also appreciate the underlying variation in temperature-dependent processes, as this variation is essential for understanding the potential to adapt to changing climates. In this Commentary, we use temperature-dependent sex determination as an example to explore the mechanistic processes underlying the development of temperature-sensitive phenotypes. We synthesize the current literature on how variable thermal conditions affect these processes and address factors that may limit or allow organisms to respond to variable environments. From these examples, we posit a framework for how the field might move forward in a more systematic way to address three key questions: (1) which genes directly respond to temperature-sensitive changes in protein function and which genes are downstream, indirect responders?; (2) how long does it take different proteins and genes to respond to temperature?; and (3) are the experimental temperature manipulations relevant to the climate the organism experiences or to predicted climate change scenarios? This approach combines mechanistic questions (questions 1 and 2) with ecologically relevant conditions (question 3), allowing us to explore how organisms respond to transient thermal environments and, thus, cope with climate change.
Is vertebral shape variability in caecilians (Amphibia: Gymnophiona) constrained by forces experienced during burrowing?
Authors: Lowie Aurélien , De Kegel Barbara , Wilkinson Mark , Measey John , O'Reilly James C. , Kley Nathan J. , Gaucher Philippe , Brecko Jonathan , Kleinteich Thomas , Adriaens Dominique , Herrel Anthony 
Published: June 2022

ABSTRACT
Caecilians are predominantly burrowing, elongate, limbless amphibians that have been relatively poorly studied. Although it has been suggested that the sturdy and compact skulls of caecilians are an adaptation to their head-first burrowing habits, no clear relationship between skull shape and burrowing performance appears to exist. However, the external forces encountered during burrowing are transmitted by the skull to the vertebral column, and, as such, may impact vertebral shape. Additionally, the muscles that generate the burrowing forces attach onto the vertebral column and consequently may impact vertebral shape that way as well. Here, we explored the relationships between vertebral shape and maximal in vivo push forces in 13 species of caecilian amphibians. Our results show that the shape of the two most anterior vertebrae, as well as the shape of the vertebrae at 90% of the total body length, is not correlated with peak push forces. Conversely, the shape of the third vertebrae, and the vertebrae at 20% and 60% of the total body length, does show a relationship to push forces measured in vivo. Whether these relationships are indirect (external forces constraining shape variation) or direct (muscle forces constraining shape variation) remains unclear and will require quantitative studies of the axial musculature. Importantly, our data suggest that mid-body vertebrae may potentially be used as proxies to infer burrowing capacity in fossil representatives.
Importance of Overall Activity and Intensity of Activity for Cardiometabolic Risk in Those with and Without a Chronic Disease
Authors: DAWKINS NATHAN P. , YATES TOM , EDWARDSON CHARLOTTE L. , MAYLOR BEN , HENSON JOSEPH , HALL ANDREW P. , DAVIES MELANIE J. , DUNSTAN DAVID W. , HIGHTON PATRICK J. , HERRING LOUISA Y. , KHUNTI KAMLESH , ROWLANDS ALEX V. 
Published: June 2022

ABSTRACT

Introduction
Higher levels of physical activity are associated with lower cardiometabolic risk. However, the relative contribution of overall activity and the intensity of activity are unclear. Our aim was to determine the relative contribution of overall activity and intensity distribution of activity to cardiometabolic risk in a cross-sectional analysis of apparently healthy office workers and in people with one or more chronic disease.

Methods
Clustered cardiometabolic risk score was calculated from mean arterial pressure, high-density lipoprotein cholesterol, triglycerides and HbA1c. Open-source software (GGIR) was used to generate average acceleration and intensity gradient from wrist-worn accelerometer data for two data sets: office-workers who did not have a self-reported medical condition (n = 399, 70% women) and adults with one or more chronic disease (n = 1137, 34% women). Multiple linear regression analyses were used to assess the relative contribution of overall activity and intensity of activity to cardiometabolic risk.

Results
When mutually adjusted, both overall activity and intensity of activity were independently associated with cardiometabolic risk in the healthy group (P < 0.05). However, for the CD group, although mutually adjusted associations for average acceleration were significantly associated with cardiometabolic risk (P < 0.001), intensity was not. In healthy individuals, cardiometabolic risk was lower in those with high overall activity and/or intensity of activity, and who also undertook at least 10 min brisk walking. In those with a chronic disease, risk was lower in those who undertook at least 60 min slow walking.

Conclusions
These findings suggest interventions aiming to optimize cardiometabolic health in healthy adults could focus on increasing both intensity and amount of physical activity. However, in those with chronic disease, increasing the amount of activity undertaken, regardless of intensity, may be more appropriate.
The genetic causes of male infertility: a Middle East and North Africa perspective
Authors: Duvuru Ruthwik , Halabi Mouhammad , Omolaoye Temidayo S. , Du Plessis Stefan S. 
Published: June 2022

Male infertility is attributable to 60% of total infertility cases and about 30-50% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.
Unprecedented early-summer heat stress and forecast of coral bleaching on the Great Barrier Reef, 2021-2022
Authors: Spady Blake L. , Skirving William J. , Liu Gang , De La Cour Jacqueline L. , McDonald Cathy J. , Manzello Derek P. 
Published: June 2022

The Great Barrier Reef (GBR) is predicted to undergo its sixth mass coral bleaching event during the Southern Hemisphere summer of 2021-2022. Coral bleaching-level heat stress over the GBR is forecast to start earlier than any previous year in the satellite record (1985-present). The National Oceanic and Atmospheric Administration (NOAA) Coral Reef Watch (CRW) near real-time satellite-based heat stress products were used to investigate early-summer sea surface temperature (SST) and heat stress conditions on the GBR during late 2021. As of 14 December 2021, values of instantaneous heat stress (Coral Bleaching HotSpots) and accumulated heat stress over a 12-week running window (Degree Heating Weeks) on the GBR were unprecedented in the satellite record. Further, 89% of GBR satellite reef pixels for this date in 2021 had a positive seven-day SST trend of greater than 0.2 degrees Celsius/week. Background temperatures (the minimum temperature over the previous 29 days) were alarmingly high, with 87% of GBR reef pixels on 14 December 2021 being greater than the maximum SST over that same 29-day period for any year from 1985-2020. The GBR is starting the 2021-2022 summer season with more accumulated heat than ever before, which could have disastrous consequences for the health, recovery, and future of this critical reef system.