bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trial in progress: Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated metastatic pancreatic cancer.
Authors: McWilliams Robert R. , Kasi Pashtoon Murtaza , Foster Nathan R. , Zhu Mojun , Carr Ryan Michael , Ma Wen Wee , Hartgers Mindy L. , Jones Kayla M. , Bartusiewicz Jacqueline M. , Dong Haidong , Markovic Svetomir , Alberts Steven R , Ahn Daniel H. , Babiker Hani M. , Bekaii-Saab Tanios S. , Couch Fergus 
Published: January 2023

TPS780 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .
A phase II study of hypofractionated radiation therapy to augment immune response in patients with metastatic gastrointestinal malignancies progressing on immune therapy (ARM-GI).
Authors: Chang Hewitt , Andemicael Luchia , Anwar Moshiur Mekhail , Gordan John , Johnson Jamese , Keenan Bridget P , Kelley Robin Kate , Ko Andrew H. , Van Loon Katherine , Venook Alan P. , Fong Lawrence , Xu Melody Ju , Feng Mary Uan-Sian 
Published: January 2023

TPS817 Background: Metastatic disease remains a consistent challenge for patients with gastrointestinal (GI) malignancies. Multiple immune checkpoint inhibitors (ICI) have been FDA approved for several GI indications. Still, patients will progress on these therapies, either immediately or after initial response. Palliative radiation therapy (RT) is an effective treatment that can be delivered to symptomatic metastases. It also has been reported to lead to an abscopal effect, which is an induction of response in a distant tumor. This is thought to result from increased tumor immunogenicity, tumor microenvironment modulation, and immune cell recruitment. Thus, palliative RT could not only relieve symptoms, but also potentially reinvigorate the immune response, prolong ICI efficacy, and delay next-line systemic therapy that carries risks of unknown efficacy and tolerability. Ongoing studies seek to elucidate prognostic and predictive biomarkers of the abscopal effect. However, cohorts of patients with GI malignancies are limited, so there remains a need for research in combining RT and immunotherapy in the context of metastatic GI cancer. ARM-GI aims to study the radiation-augmented immune response in patients with metastatic GI cancers progressing on immunotherapy. Methods: ARM-GI is a phase 2, single arm study. Key eligibility criteria include confirmed metastatic GI malignancy, progressive disease per RECIST v1.1 on any ICI, and at least 2 metastases, one of which can be safely left unirradiated. The target prescription dose is 30 Gy in 5 fractions to symptomatic sites through intensity modulated RT or stereotactic body RT. Patients will continue the same immunotherapy after RT and be evaluated per RECIST v1.1 longitudinally. The primary endpoint is overall response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per iRECIST, progression free survival, overall survival, local control in radiated lesion(s), effect of distant radiation on unirradiated target lesions, incidence of new metastatic lesions, safety by CTCAE v5.0, and time to new systemic therapy. The study will enroll 28 patients, with recruitment ongoing. Serial peripheral blood samples are collected for exploratory studies that will analyze for association with disease response and quantification of changes in circulating immune cell subsets after RT compared to baseline. Clinical trial information: NCT04221893 .
Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).
Authors: Deming Dustin A. , Rodon Ahnert Jordi , Demeure Michael J. , Federman Noah , McKean Meredith , Lee Elizabeth Katherine , Spira Alexander I. , Kwiatkowski David J. , Hussein Maen A. , Gordon Erlinda Maria , Crockett David G. , Ganjoo Kristen N. , Schulte Brian , Cranmer Lee D. , Schmid Anita N. , Navarro Willis H. , Itri Loretta Marie , Iyer Gopa 
Published: January 2023

TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]
Threshold-free estimation of entropy from a Pearson matrix
Authors: Felippe H. , Viol A. , de Araujo D. B. , da Luz M. G. E. , Palhano-Fontes F. , Onias H. , Raposo E. P. , Viswanathan G. M. 
Published: January 2023

Abstract
There is demand in diverse fields for a reliable method of estimating the entropy associated with correlations. The estimation of a unique entropy directly from the Pearson correlation matrix has remained an open problem for more than half a century. All existing approaches lack generality insofar as they require thresholding choices that arbitrarily remove possibly important information. Here we propose an objective procedure for directly estimating a unique entropy of a general Pearson matrix. We show that upon rescaling the Pearson matrix satisfies all necessary conditions for an analog of the von Neumann entropy to be well defined. No thresholding is required. We demonstrate the method by estimating the entropy from neuroimaging time series of the human brain under the influence of a psychedelic.
Conserved currents for the gauge-field theory with Lorentz symmetry group and a composite theory of gravity
Authors: Öttinger Hans Christian 
Published: January 2023

Abstract
For the Yang-Mills–type gauge-field theory with Lorentz symmetry group, we propose and verify an explicit expression for the conserved currents in terms of the energy-momentum tensor. A crucial ingredient is the assumption that the gauge symmetry arises from the decomposition of a metric in terms of tetrad variables. The currents exist under the weak condition that the energy-momentum tensor and the Ricci tensor commute. We show how the conserved currents can be used to obtain a composite theory of gravity and discuss the static isotropic field around a point mass at rest.
Opposing Roles of Sphingosine 1-Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice
Authors: Asano Motochika , Kajita Kazuo , Fuwa Masayuki , Kajita Toshiko , Mori Ichiro , Akahoshi Noriyuki , Ishii Isao , Morita Hiroyuki 
Published: January 2023

Abstract
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein–coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.
State-Level Trends in Lifespan Variability in the United States, 1960–2019: A Research Note
Authors: Brown Dustin C. , Lariscy Joseph T. , Walker Benjamin H. 
Published: January 2023

Abstract
State-level disparities in life expectancy are wide, persistent, and potentially growing in the United States. However, the extent to which differences in lifespan variability by state have changed over time is unclear. This research note describes trends in lifespan variability for the United States overall and by state from 1960 to 2019 using period life table data from the United States Mortality Database. Lifespan disparity at birth (e0†) decreased over time in the United States overall from 14.0 years in 1960–1964 to 12.2 in 2015–2019. Lifespan variability decreased in all states, but states differed in the level and pace with which these changes occurred. Southern states and the District of Columbia exhibited consistently higher (i.e., less equitable) levels of lifespan variability than the nation overall. Conversely, lifespan variability was lower among several states in the Northeast (e.g., Connecticut and Massachusetts), Upper Midwest (e.g., Iowa, Minnesota, and Wisconsin), and West (e.g., California, Oregon, Utah, and Washington). We observe a particularly worrisome trend of increasing lifespan variability for the United States overall and for most states from 2010–2014 to 2015–2019. Monitoring state-level trends in lifespan variability has the potential to inform policies designed to ameliorate population health disparities.
State Courts, State Legislatures, and Setting Abortion Policy
Authors: Kim Jeong Hyun , Gunderson Anna , Lane Elizabeth A. , Bauer Nichole M. 
Published: January 2023

Abstract
On June 24, 2022, the US Supreme Court decided in Dobbs vs. Jackson Women's Health Organization (597 U.S. (2022)) to overturn the constitutional right to abortion, a seismic shift in abortion policy that makes the states key battlegrounds in fights over abortion and broader reproductive rights. This article focuses on the role of state supreme courts in setting state abortion policies. Using an original data set of state court decisions surrounding abortion from the past 20 years, the authors investigate how two overarching factors affect state supreme court decision-making on abortion. First, they track how states' political environments affect the decisions courts make about access to abortion. Second, the authors consider the scope of the abortion policy considered by the courts. The authors find that the partisan makeup of state legislatures does not influence the direction of state supreme courts' rulings on abortion issues, but it does affect the scope of abortion regulation being considered by the courts. Additionally, they find that elected judges tend to be more responsive to constituent preferences when ruling on abortion policies. Overall, these findings illustrate the multifaceted dynamics involved in state supreme courts' rulings on abortion.
Frizzled 7 modulates goblet and Paneth cell fate, and maintains homeostasis in mouse intestine
Authors: Gu Nai-Xin , Guo Yu-Ru , Lin Sey-En , Wang Yen-Hsin , Lin I.-Hsuan , Chen Yi-Fan , Yen Yun 
Published: January 2023

ABSTRACT
Intestinal homeostasis depends on interactions between the intestinal epithelium, the immune system and the microbiota. Because of these complicated connections, there are many problems that need to be solved. Current research has indicated that genes targeted by Wnt signaling are responsible for controlling intestinal stem cell fate and for modulating intestinal homeostasis. Our data show that loss of frizzled 7 (Fzd7), an important element in Wnt signaling, interrupts the differentiation of mouse intestinal stem cells into absorptive progenitors instead of secretory progenitors (precursors of goblet and Paneth cells). The alteration in canonical Wnt and Notch signaling pathways interrupts epithelial homeostasis, resulting in a decrease in physical protection in the intestine. Several phenotypes in our Fzd7-deleted model were similar to the features of enterocolitis, such as shortened intestines, decreased numbers of goblet cells and Paneth cells, and severe inflammation. Additionally, loss of Fzd7 exacerbated the defects in a chemical-induced colitis model and could initiate tumorigenesis. These findings may provide important information for the discovery of efficient therapeutic methods to treat enterocolitis and related cancers in the intestines.
Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors
Authors: Zaytseva Olga , Mitchell Naomi C. , Muckle Damien , Delandre Caroline , Nie Zuqin , Werner Janis K. , Lis John T. , Eyras Eduardo , Hannan Ross D. , Levens David L. , Marshall Owen J. , Quinn Leonie M. 
Published: January 2023

ABSTRACT
The first characterised FUSE Binding Protein family member, FUBP1, binds single-stranded DNA to activate MYC transcription. Psi, the sole FUBP protein in Drosophila, binds RNA to regulate P-element and mRNA splicing. Our previous work revealed pro-growth functions for Psi, which depend, in part, on transcriptional activation of Myc. Genome-wide functions for FUBP family proteins in transcriptional control remain obscure. Here, through the first genome-wide binding and expression profiles obtained for a FUBP family protein, we demonstrate that, in addition to being required to activate Myc to promote cell growth, Psi also directly binds and activates stg to couple growth and cell division. Thus, Psi knockdown results in reduced cell division in the wing imaginal disc. In addition to activating these pro-proliferative targets, Psi directly represses transcription of the growth inhibitor tolkin (tok, a metallopeptidase implicated in TGFβ signalling). We further demonstrate tok overexpression inhibits proliferation, while tok loss of function increases mitosis alone and suppresses impaired cell division caused by Psi knockdown. Thus, Psi orchestrates growth through concurrent transcriptional activation of the pro-proliferative genes Myc and stg, in combination with repression of the growth inhibitor tok.
Parents' experience of extended viewing in a paediatric hospice: a qualitative study
Authors: Smith Philippa , Teasdale Elizabeth , Sheppard-Law Suzanne 
Published: January 2023

Background: The rising prevalence of life-limiting conditions in children and young people warrants an evaluation of paediatric palliative care, hospice services and delivered care. Aim: First, this study aimed to develop a deeper understanding of how extended viewing is experienced by the parents of a deceased child (or young person) with a life-limiting condition, based in Australia. Second, this study aimed to evaluate the quality of bereavement care delivered during the first few days after death. Findings: A total of 17 bereaved parents of 13 children completed an interview. In-depth interviews were audio-recorded, transcribed verbatim and thematically analysed. While the authors acknowledge the complexity and individual nature of grief, four broad themes were identified, namely the importance of the ‘physical environment’ being conducive to spending time with their child; ‘seeing their child’; ‘time to say goodbye’; and ‘supportive care’. Conclusion: The findings of this study reinforce that extended viewing can provide therapeutic benefits for parents, as well as the importance of a skilled palliative care nursing workforce in assisting with grief management.
An overview of light-curing within orthodontics
Authors: Monaghan Liam , Needham Richard 
Published: January 2023

The use of light to initiate bonding reactions has become an integral part of orthodontic practice. Different technologies are available to cure dental composite, each with advantages and drawbacks. The efficacy of light-curing is affected by a range of factors and it is important for orthodontists to understand these concepts, alongside common problems with light-cure units, to aid in troubleshooting. Periodic testing of light-curing equipment can help to identify defective units that can potentially contribute to bond failure. CPD/Clinical Relevance: An understanding basic materials science in relation to dental light-curing technology is important in allowing orthodontists to maintain safe and effective equipment. The choice of light-curing equipment and method of use can influence bond strength and, therefore, treatment success.
Humour in Islamic Literature and Muslim Practices: Virtue or Vice?
Authors: Ghali Walid 
Published: January 2023

This chapter traces major normative Islamic perspectives on humour to the medieval Sufi scholars and jurists, especially to al-Ghazālī (c. 1058-1111). Al-Ghazālī acknowledges the value of a good-natured joking and moderate laughter, but he proscribes a number of humour practices including crass and mocking jokes as well as bawdy, frivolous, and impious expressions of humour. Although Sufis use humour as a teaching tool and although Muslims in general like a good laugh, al-Ghazālī’s views that unfettered joking is a ‘vice of the tongue’ and that comedians follow a dubious profession have been influential. Ghali’s chapter historicizes the existence of humour regulation in Islamic contexts and highlights the social, interpersonal, and moral concerns driving it.
Al-Bernameg : How Bassem Youssef Ridiculed Religious Fundamentalists and Survived the ‘Defamation of Religion’ Charge
Authors: Alkheder Moutaz 
Published: January 2023

In his satirical show, Al-Bernameg, the Egyptian satirist Bassem Youssef spoke truth to the power of political Islam’s movement of the Muslim Brotherhood. Although the Muslim Brotherhood was democratically elected in 2011, it had significant religious clout which made it a risky endeavour to ridicule the movement and/or its leaders. Youssef took that risk without insulting religion per se, which he accomplished by adopting various defensive and offensive strategies. He avoided tackling core Islamic values, and when he had to deal with politico-religious matters, he managed to separate the political from the religious. He also took the initiative to beat political Islamists at their own game, that is, religious insult allegations, by showing that they themselves fell into defamation of religion amidst their fierce campaign against their political opponents.