bluuebunny/crossref_metadata_2025_split huggingface dataset:
Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors
Authors: Jamison Jacob K , Zhou Mengxi , Gelmann Edward P , Luk Lyndon , Bates Susan E , Califano Andrea , Fojo Tito 
Published: June 2024

Abstract

Background
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs.

Methods
This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose.

Results
The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 17%, 20%, 33%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs.

Conclusion
In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 83% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988).
A diagnostic challenge of KIT p.V559D and BRAF p.G469A mutations in a paragastric mass
Authors: Habringer Stefan , Ihlow Jana , Kleo Karsten , Klostermann Anna , Schmidt Max , Chai Lidan , Knödler Maren , Leyvraz Serge , Sigler Christian , Sinn Bruno , Maschmeyer Georg , Jegodka Yvette , Benary Manuela , Ott Claus-Eric , Tinhofer Ingeborg , Schäfer Reinhold , Möbs Markus , Keller Ulrich , Keilholz Ulrich , Rieke Damian T 
Published: June 2024

Abstract
A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.
Tensions in Knowledge Accumulation Using Coordinated Intervention Experiments to Improve Public Policy
Authors: Bowers Jake , Greenberg Natasha , Holmes Morgan , Posner Daniel N. 
Published: June 2024

Abstract
This chapter has two main goals. It introduces and explains the value of coordinated randomized experiments for informing public policymaking with a special focus on international development, and then articulates tensions inherent in these coordinated experiments. It explains why coordination can help build the evidence base for policy innovation by helping funders and policymakers test existing theories of change in ways that facilitate the cumulation of knowledge across studies. It then articulates tensions or trade-offs that reasonable decision-makers might face given choices between coordinated and uncoordinated experiments, and provides some rough guides to help decision-makers navigate those tensions. We write from the perspective of encouraging coordinated experiments and offer practical alternatives that might be easier to implement than extant models for policy-oriented decision-makers.
SANT proteins modulate gene expression by coordinating histone H3KAc and Khib levels and regulate plant heat tolerance
Authors: Zhou Xishi , Fan Yujin , Zhu Xiying , Zhao Ruihua , He Junna , Li Pengfeng , Shang Shengping , Goodrich Justin , Zhu Jian-Kang , Zhang Cui-Jun 
Published: June 2024

Abstract
Histone post-translational modifications (PTMs), such as acetylation and recently identified lysine 2-hydroxyisobutyrylation (Khib), act as active epigenomic marks in plants. SANT domain-containing proteins SANT1, SANT2, SANT3, and SANT4 (SANT1/2/3/4), derived from PIF/Harbinger transposases, form a complex with HISTONE DEACETYLASE 6 (HDA6) to regulate gene expression via histone deacetylation. However, whether SANT1/2/3/4 coordinates different types of PTMs to regulate transcription and mediate responses to specific stresses in plants remains unclear. Here, in addition to modulating histone deacetylation, we found that SANT1/2/3/4 proteins acted like HDA6 or HDA9 in regulating the removal of histone Khib in Arabidopsis (Arabidopsis thaliana). Histone H3 lysine acetylation (H3KAc) and histone Khib were coordinated by SANT1/2/3/4 to regulate gene expression, with H3KAc playing a predominant role and Khib acting complementarily to H3KAc. SANT1/2/3/4 mutation significantly increased the expression of heat-inducible genes with concurrent change of H3KAc levels under normal and heat stress conditions, resulting in enhanced thermotolerance. This study revealed the critical roles of Harbinger transposon-derived SANT domain-containing proteins in transcriptional regulation by coordinating different types of histone PTMs and in the regulation of plant thermotolerance by mediating histone acetylation modification.
Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice
Authors: Rosario Fredrick J , Barentsen Kenneth , Powell Theresa L , Urschitz Johann , Brown Thomas L , Kanai Yoshikatsu , Jansson Thomas 
Published: June 2024

Abstract
Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific Slc7a5 overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a Slc7a5 transgene, we achieved trophoblast-specific overexpression of Slc7a5 (Slc7a5 OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific Slc7a5 overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). Slc7a5 overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of Slc7a5 activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.
Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST registry
Authors: Miyazaki Yusuke , Nakayamada Shingo , Tanaka Hiroaki , Hanami Kentaro , Fukuyo Shunsuke , Kubo Satoshi , Miyagawa Ippei , Yamaguchi Ayako , Todoroki Yasuyuki , Inoue Yoshino , Ueno Masanobu , Tanaka Yoshiya 
Published: June 2024

Abstract

Objectives
A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyse the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments.

Methods
The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA.

Results
The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (P = 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group.

Conclusions
IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.
Do increases in work uncertainty help older workers maintain higher levels of occupational future time perspective?
Authors: Rudolph Cort W , Zacher Hannes 
Published: June 2024

Abstract
In this study, we consider how changes in work uncertainty (i.e., systematic, linear trajectories that reflect over-time changes in resource, task, and input/output uncertainty) moderate the generally negative relation between employee age and occupational future time perspective (OFTP) (i.e., employeesâ&#x80;&#x99; perceptions of their remaining time, opportunities, and limitations at work). Based on the theoretical model of uncertainty regulation and propositions from socioemotional selectivity theory, we argue that increases (vs. decreases) in work uncertainty present the potential for new opportunities, particularly among older (vs. younger) workers, who can draw on their age-related strengths for dealing with uncertainty. Specifically, we argue that increases in work uncertainty allow older workers to make use of their accumulated knowledge and experience, which, in turn, helps them to maintain higher levels of OFTP. We consider longitudinal data collected among a sample of nâ&#x80;&#x85;=â&#x80;&#x85;720 employees in Germany. Considering substantive variables, variously measured across 18 months, we find evidence in partial support of the general proposition that increases in work uncertainty across three months (i.e., June through September of 2022) buffer the relation between age and OFTP collected at four subsequent timepoints (November of 2022, and June, November, and December of 2023). We discuss the implications of these findings for the future development of the model of uncertainty regulation.
Risk Assessment for Nuclear Terrorism Probability and Its Application on a Hypothetical Nuclear Facility
Authors: Kot Joeun L. , Harris Jason T. 
Published: June 2024

Abstract
Radiation protection contains the key elements of nuclear safety and security. Despite the overlap between nuclear safety and security, their objectives differ fundamentally, focusing on unintentional accidents and intentional malicious events, respectively. As such, the Potential Facility Risk Index (PFRI), originally created for security purposes, has evolved into an approach that combines conventional probabilistic risk assessment (PRA), which is a widely employed method to evaluate the safety risks of nuclear facilities. This research has developed a risk assessment model within the PFRI framework to calculate the probability of nuclear terrorism. Three essential components of the model are integrated: an analysis of historical nuclear terrorism data to determine an initial threat frequency; the target-specific factor using analytical hierarchy process (AHP) target attractiveness analysis; and the adversary motivation factor based on site-specific social influences from the Profiles of Individual Radicalization in the United States (PIRUS) dataset. Applied to a hypothetical nuclear facility, the model produces a nuclear terrorism probability of 8.97 × 10−3 y − 1. The systematic methodology proposed in the study enables the derivation of nuclear terrorism probability with results in the same risk unit as safety risk assessment. This method allows decision makers to seamlessly incorporate nuclear safety and security risk assessments, offering a comprehensive perspective. Consequently, it enriches comprehension of nuclear facility risks and establishes the groundwork for future advancements.
A randomised controlled trial of the effect of intra-articular lidocaine on pain scores in inflammatory arthritis
Authors: Rutter-Locher Zoe , Norton Sam , Denk Franziska , McMahon Stephen , Taams Leonie S. , Kirkham Bruce W. , Bannister Kirsty 
Published: June 2024

Abstract
Chronic pain in inflammatory arthritis (IA) reflects a complex interplay between active disease in a peripheral joint and central pronociceptive mechanisms. Because intra-articular lidocaine may be used to abolish joint-specific peripheral input to the central nervous system, we aimed to validate its use as a clinical tool to identify those patients with IA whose pain likely incorporates centrally mediated mechanisms. We began by investigating whether there was a placebo response of intra-articular injection in patients with IA 1:1 randomised to receive intra-articular lidocaine or control (0.9% saline). After, in a larger patient cohort not randomized to placebo vs lidocaine groups, we tested whether patients with IA could be stratified into 2 cohorts based on their response to intra-articular lidocaine according to markers of centrally mediated pain. To this end, we evaluated postlidocaine pain numerical rating scale (NRS) scores alongside baseline painDETECT, fibromyalgia criteria fulfillment, and quantitative sensory testing outcomes. Numerical rating scale scores were collected at baseline and 3-, 5-, and 10-minutes postinjection. Firstly, the placebo effect of intra-articular injection was low: compared to baseline, the mean pain NRS score 5-minutes postinjection was reduced by 3.5 points in the lidocaine group vs 1.2 points in the control group. Secondly, postlidocaine NRS scores were significantly higher in those with a high (>18) baseline painDETECT score, fibromyalgia, and low-pressure pain threshold at the trapezius (P = 0.002, P = 0.001, P = 0.005, respectively). Persistent high pain after intra-articular lidocaine injection could be used as an indicator of pronociceptive mechanisms that are centrally mediated, informing centrally targeted analgesic strategies.
Brugada syndrome following febrile episode caused by malarial infection: a case report
Authors: Aryal Egesh , Mainali Agya , Aryal Saurav 
Published: June 2024

Background:
Brugada syndrome (BrS) is a rare genetic disorder with specific electrocardiographic (ECG) patterns carrying an increased risk of sudden cardiac death.

Case presentation:
The authors present a 36-year-old gentleman who had a travel history to the Central African Republic and came to the hospital with a fever and chest pain. The lab investigation revealed Falciparum Malaria infection and the ECG pattern revealed the type 1 Brugada pattern, which was normalized with anti-malarial medication and symptomatic treatment of fever.

Discussion:
BrS is a disorder with high prevalence in males and people of the Asian continent. Patients can present with symptoms like syncope, seizure, and nocturnal agonal respiration or may be asymptomatic. The ECG pattern of BrS could be seen in the febrile phase and normalized when non-febrile, like in our patient. Prompt treatment of fever and follow-up with cardiologists would be an effective treatment of asymptomatic patients, whereas ICD is a management of choice for symptomatic patients.

Conclusion:
For a patient with chest pain, fever, and an ECG pattern of ST elevation, a clinician should think BrS one of the differential diagnoses.
Exploring Research on Competitive Para-cyclists and Its Related Factors
Authors: Villa del Bosque Gerardo , González-Devesa Daniel , Villa-Vicente José Gerardo , García-Fresneda Adrián , Suárez-Iglesias David , Ayán-Pérez Carlos 
Published: June 2024

Abstract
This scoping review aimed to explore the characteristics and performance factors of competitive para-cyclists. A systematic search for studies on competitive para-cycling on WOS, PubMed, SPORTDiscus, and Scopus was performed until December 2023. The following five methodological phases were followed: (i) identifying the research question, (ii) identifying relevant studies, (iii) study selection, (iv) charting the data, and (v) collating, summarizing, and reporting the results. A systematic search across multiple databases was performed until March 2024. Five methodological phases were employed: identifying the research question, relevant studies, study selection, charting data, and summarizing results. A total of 36 relevant studies were selected. Three main research themes emerged: sport performance (n = 15), biomechanics (n = 12), and physical and mental health (n = 9). Despite progress, gaps were identified, particularly in physiological response to exercise, fitness, and training. Biomechanics studies focused on prosthetic use and aerodynamics, mostly involving lower-limb amputees and simulated tandem competition. Injury risk in para-cycling appeared comparable to able-bodied cycling, but comprehensive studies considering confounding variables are needed. Overall, while research on para-cycling is growing, more studies with larger and diverse samples across all sport classes are essential to advance scientific understanding in this field.
Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area
Authors: Sirucek Laura , De Schoenmacker Iara , Scheuren Paulina Simonne , Lütolf Robin , Gorrell Lindsay Mary , Langenfeld Anke , Baechler Mirjam , Rosner Jan , Wirth Brigitte , Hubli Michèle , Schweinhardt Petra 
Published: June 2024

Abstract

Introduction:
In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain.

Objectives:
The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON).

Methods:
Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile).

Results:
Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed.

Conclusion:
Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.
Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection
Authors: Cyktor Joshua C. , Yeh Eunice , Ribaudo Heather , Hoeth Dianna , Naqvi Asma , Bell Tanvir , Ridker Paul M. , Fichtenbaum Carl , Daar Eric S. , Havlir Diane , Tawakol Ahmed , Lederman Michael M. , Stein James H. , Deeks Steven G. , Currier Judith S. , Hsue Priscilla Y. , Mellors John W. ,   for the A5314 Team
Published: June 2024

Background:
People with HIV-1 often have chronic inflammation leading to severe non-AIDS morbidity and mortality. The AIDS Clinical Trials Group Study A5314 sought to lower inflammation with low-dose methotrexate (LDMTX). The primary study outcomes were reported previously but here we present the impact of LDMTX on multiple measures of HIV-1 persistence.

Methods:
A5314 was a phase 2 randomized, double-blind, multicenter trial in 176 adult people with HIV-1 on virally suppressive antiretroviral therapy. LDMTX (5–15 mg/wk) was administered for 24 weeks with an additional 12 weeks of participant follow-up. The current analyses of HIV-1 persistence were restricted to 60 participants (30 LDMTX and 30 placebo) randomly selected from the total population. Plasma HIV-1 RNA, total HIV-1 DNA, and cell-associated HIV-1 RNA (CA HIV-1 RNA) were measured by sensitive quantitative PCR assays.

Results:
LDMTX treatment had no significant effect on sensitive measures of plasma HIV-1 RNA, HIV-1 DNA, CA HIV-1 RNA, or CA HIV-1 RNA/DNA ratio at any time point or from baseline to week 24. As observed in the main study, absolute peripheral CD4+ and CD8+ T-cell numbers decreased from baseline to week 24 among the 30 participants receiving LDMTX compared with placebo (median decrease of −31.5 CD4+ T cells/µL, −83.5 CD8+ T cells/µL).

Conclusions:
LDMTX had no significant effect on any measure of HIV-1 persistence in plasma or peripheral blood mononuclear cells. Further studies are needed to determine whether other immunosuppressive and/or immunoreductive interventions are safe and capable of affecting HIV-1 persistence.