bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of Immune Checkpoint Inhibitors in Various Tumor Types Treated by Low, Per-Weight, and Conventional Doses at a Tertiary Care Center in Mumbai
Authors: Patel Amol , Hande Vivek , MR Kaushik , Dange Hemendra , Das Amit Kumar , Murugesan Vigneshwaran , Bhatt Trilok , Shankaran Ramakrishnan 
Published: January 2024

PURPOSE The cost of immune checkpoint inhibitors (ICIs) limits their accessibility to a small number of patients with cancer in low- and middle-income countries. Early-phase clinical trials have shown target inhibition and high activity at doses lower than those registered and evaluated in clinical trials. Here, we report everyday experience of using ICIs in 100 Indian patients, many of whom received lower doses of ICIs. METHODS Consecutive patients who received at least one dose of an ICI irrespective of tumor type at a tertiary care hospital in Mumbai, India, that was able to access ICIs for its patients were enrolled. The objectives were to study the doses used over a 3-year time period, and the effectiveness of therapy, assessed primarily by the overall response rate (ORR), overall survival (OS), and progression-free survival were secondary end points. RESULTS Twenty-five patients were treated with conventional doses of ICIs, 29 patients received lower doses per body weight, and 46 patients received low-dose treatment. The median number of cycles received was 5 (range, 1-28). Seventy-eight patients received ICIs in a palliative setting. The median follow-up time was 10.2, 9.8, and 3.9 months for those receiving fixed approved dosing, per body weight dosing, and low-dose treatment, respectively. There was a trend with time to prescribe lower doses. Response evaluation was available for 92 patients. Twenty-one (five-adjuvant and 16-palliative) patients received ICIs only. The ORR did not differ statistically among different dosing groups, but comparisons are confounded by inclusion of different ICIs, different tumor sites, and concurrent treatments. The median OS was 6.8 (range, 4.6-9.0) months. CONCLUSION Adoption of per-body weight and lower dosing of ICIs appears to give acceptable outcomes. Lower dosing can improve access and timely delivery of ICIs in low- and middle-income countries.
Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study
Authors: Pinto Carmine , Orlandi Armando , Normanno Nicola , Maiello Evaristo , Calegari Maria A. , Antonuzzo Lorenzo , Bordonaro Roberto , Zampino Maria G. , Pini Sara , Bergamo Francesca , Tonini Giuseppe , Avallone Antonio , Latiano Tiziana P. , Rosati Gerardo , Cogoni Alessio Aligi , Ballestrero Alberto , Zaniboni Alberto , Roselli Mario , Tamberi Stefano , Barone Carlo 
Published: January 2024

PURPOSE The intensity of anti-EGFR–based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively ( P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months ( P = .39). The overall survival was 35.7 versus 30.7 months ( P = .119) and 31.0 versus 25.2 months ( P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.
Cancer-Associated Thrombosis: Management of a Patient With an Isolated Calf Deep Vein Thrombosis
Authors: Soff Gerald A. 
Published: January 2024

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Venous thromboembolism occurs frequently in patients with cancer and is the second leading cause of death, after the cancer itself. There is a well-established consensus of the need for anticoagulation in patients with a proximal deep vein thrombosis or pulmonary embolism. But with improved imaging technology and widescale use of contrast imaging for cancer staging, many incidental pulmonary emboli are detected in patients with cancer. Furthermore, many isolated distal deep vein thromboses and subsegmental pulmonary emboli are identified. There have been questions if these small or asymptomatic thromboses require anticoagulation management similar to more proximal or symptomatic thromboses. In this Oncology Grand Rounds, we will review the existing evidence for these situations. We will also review management strategies for cancer-associated thrombosis, reflecting the evolving drugs and evidence over the past 20 years.
Update on Adrenarche—Still a Mystery
Authors: Augsburger Philipp , Liimatta Jani , Flück Christa E 
Published: January 2024

Abstract

Context
Adrenarche marks the timepoint of human adrenal development when the cortex starts secreting androgens in increasing amounts, in healthy children at age 8–9 years, with premature adrenarche (PA) earlier. Because the molecular regulation and significance of adrenarche are unknown, this prepubertal event is characterized descriptively, and PA is a diagnosis by exclusion with unclear long-term consequences.

Evidence Acquisition
We searched the literature of the past 5 years, including original articles, reviews, and meta-analyses from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms adrenarche, pubarche, DHEAS, steroidogenesis, adrenal, and zona reticularis.

Evidence Synthesis
Numerous studies addressed different topics of adrenarche and PA. Although basic studies on human adrenal development, zonation, and zona reticularis function enhanced our knowledge, the exact mechanism leading to adrenarche remains unsolved. Many regulators seem involved. A promising marker of adrenarche (11-ketotestosterone) was found in the 11-oxy androgen pathway. By current definition, the prevalence of PA can be as high as 9% to 23% in girls and 2% to 10% in boys, but only a subset of these children might face related adverse health outcomes.

Conclusion
New criteria for defining adrenarche and PA are needed to identify children at risk for later disease and to spare children with a normal variation. Further research is therefore required to understand adrenarche. Prospective, long-term studies should characterize prenatal or early postnatal developmental pathways that modulate trajectories of birth size, early postnatal growth, childhood overweight/obesity, adrenarche and puberty onset, and lead to abnormal sexual maturation, fertility, and other adverse outcomes.
Approach to the Peripubertal Patient With Short Stature
Authors: Torres-Santiago Lournaris , Mauras Nelly 
Published: January 2024

Abstract

Context
The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)–insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth.

Evidence Acquisition
Extensive literature review through PubMed and other search engines.

Evidence Synthesis
Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments.

Conclusion
The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized.
Efficacy and Safety of Denosumab vs Zoledronic Acid in OI Adults: A Prospective, Open-Label, Randomized Study
Authors: Lin Xiaoyun , Hu Jing , Zhou Bingna , Wang Xiaojie , Zhang Qian , Jiang Yan , Wang Ou , Xia Weibo , Xing Xiaoping , Li Mei 
Published: January 2024

Abstract

Context
The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established.

Objective
To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI.

Methods
This was a prospective, open-label study. Patients were randomized to receive denosumab 60 mg every 6 months or zoledronic acid 5 mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated.

Results
A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of β-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group.

Conclusion
Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.
Granulosa Cells Alone, Without Theca Cells, Can Mediate LH-induced Oocyte Meiotic Resumption
Authors: Norris Rachael P , Jaffe Laurinda A 
Published: January 2024

Abstract
Signaling in the granulosa cells of mammalian ovarian follicles is necessary for maintaining prophase arrest in the oocyte and for mediating the resumption of meiosis in response to luteinizing hormone (LH). However, the follicle also includes an outer layer of theca cells, some of which express receptors for LH. To investigate whether theca cells are required for maintaining meiotic arrest and reinitiating meiosis in response to LH, we mechanically separated the granulosa cells and oocyte from the theca and basal lamina. This was accomplished by cutting a slit in the outer surface of isolated follicles such that the mural granulosa cells and cumulus-oocyte complex were extruded from the theca shell, forming a lawn of cells on an organotypic membrane. The remnant of theca cells and basal lamina was then removed. The separation of the granulosa cells from the theca cells and basal lamina was demonstrated by immunofluorescence localization of endomucin (blood vessels of the theca) and laminin gamma (basal lamina). Cells comprising these granulosa cell-oocyte complexes expressed LH receptors and were connected by gap junctions. Oocytes within these granulosa cell complexes maintained meiotic arrest and resumed meiosis in response to LH, showing that the granulosa cells alone, without theca cells, transduce these signals. This semi-intact and mostly 2-dimensional preparation could facilitate imaging studies of follicle physiology.
Face-valid phenotypes in a mouse model of the most common mutation in EEF1A2-related neurodevelopmental disorder
Authors: Marshall Grant F. , Fasol Melissa , Davies Faith C. J. , Le Seelleur Matthew , Fernandez Alvarez Alejandra , Bennett-Ness Cavan , Gonzalez-Sulser Alfredo , Abbott Catherine M. 
Published: January 2024

ABSTRACT
De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects. Both E122K homozygotes and Eef1a2-null mice developed progressive motor abnormalities, with E122K homozygotes reaching humane endpoints by P31. The null phenotype is driven by progressive spinal neurodegeneration; however, no signs of neurodegeneration were observed in E122K homozygotes. The E122K protein was relatively stable in neurons yet highly unstable in skeletal myocytes, suggesting that the E122K/E122K phenotype is instead driven by loss of function in muscle. Nevertheless, motor abnormalities emerged far earlier in E122K homozygotes than in nulls, suggesting a toxic gain of function and/or a possible dominant-negative effect. This mouse model represents the first animal model of an EEF1A2 missense mutation with face-valid phenotypes and has provided mechanistic insights needed to inform rational treatment design.
RhoU forms homo-oligomers to regulate cellular responses
Authors: Clayton Natasha S. , Hodge Richard G. , Infante Elvira , Alibhai Dominic , Zhou Felix , Ridley Anne J. 
Published: January 2024

ABSTRACT
RhoU is an atypical member of the Rho family of small G-proteins, which has N- and C-terminal extensions compared to the classic Rho GTPases RhoA, Rac1 and Cdc42, and associates with membranes through C-terminal palmitoylation rather than prenylation. RhoU mRNA expression is upregulated in prostate cancer and is considered a marker for disease progression. Here, we show that RhoU overexpression in prostate cancer cells increases cell migration and invasion. To identify RhoU targets that contribute to its function, we found that RhoU homodimerizes in cells. We map the region involved in this interaction to the C-terminal extension and show that C-terminal palmitoylation is required for self-association. Expression of the isolated C-terminal extension reduces RhoU-induced activation of p21-activated kinases (PAKs), which are known downstream targets for RhoU, and induces cell morphological changes consistent with inhibiting RhoU function. Our results show for the first time that the activity of a Rho family member is stimulated by self-association, and this is important for its activity.
A Ramp versus Step Transition to Constant Work Rate Exercise Decreases Steady-State Oxygen Uptake
Authors: MARINARI GABRIELE , IANNETTA DANILO , HOLASH ROBERT JOHN , TRAMA ROBIN , FARICIER ROBIN , ZAGATTO ALESSANDRO M. , KEIR DANIEL A. , MURIAS JUAN M. 
Published: January 2024

ABSTRACT
Within the initial minutes of square-wave exercise transitions above the moderate-intensity domain, the reliance on the anaerobic energy sources may induce some levels of metabolic instability; however, no study has attempted to limit metabolic instability at exercise onset by manipulating the exercise transition phase to a target work rate (WR).

Purpose
This study aimed to investigate whether a ramp-to-constant WR (rCWR) transition compared with a square-wave-to-constant WR (CWR) transition within the heavy-intensity domain can reduce metabolic instability and decrease the oxygen cost of exercise.

Methods
Fourteen individuals performed (i) a ramp-incremental test to task failure, (ii) a 21-min CWR within the heavy-intensity domain, and (iii) an rCWR to the same WR. Oxygen uptake (V̇O2), lactate concentration ([La−]), and muscle oxygen saturation (SmO2) were measured. V̇O2 and V̇O2 gain (V̇O2-G) during the first 10-min steady-state V̇O2 were analyzed. [La−] before, at, and after steady-state V̇O2 and SmO2 during the entire 21-min steady-state exercise were also examined.

Results
V̇O2 and V̇O2-G during rCWR (2.49 ± 0.58 L·min−1 and 10.7 ± 0.2 mL·min−1·W−1, respectively) were lower (P < 0.001) than CWR (2.57 ± 0.60 L·min−1 and 11.3 ± 0.2 mL·min−1·W−1, respectively). [La−] before and at steady-state V̇O2 during the rCWR condition (1.94 ± 0.60 and 3.52 ± 1.19 mM, respectively) was lower than the CWR condition (3.05 ± 0.82 and 4.15 ± 1.25 mM, respectively) (P < 0.001). [La−] dynamics after steady-state V̇O2 were unstable for the rCWR (P = 0.011). SmO2 was unstable within the CWR condition from minutes 4 to 13 (P < 0.05).

Conclusions
The metabolic disruption caused by the initial minutes of square-wave exercise transitions is a primary contributor to metabolic instability, leading to an increased V̇O2-G compared with the rCWR condition approach. The reduced early reliance on anaerobic energy sources during the rCWR condition may be responsible for the lower V̇O2-G.
Reducing discrimination against service users with psychosis through brief contact-based video interventions: a randomised controlled trial
Authors: Mankiewicz Pawel D , Tan Audrina SY 
Published: January 2024

Background/Aims Internationally, mental health service users, particularly those with psychosis, face discriminatory attitudes and behaviours from the public. It is crucial for mental health services to deliver interventions that alleviate the stigma directed toward their patients. This study evaluates the efficacy of a brief indirect contact-based intervention designed for this purpose in Singapore. Methods A randomised controlled trial was conducted among 168 participants, who were allocated to video intervention, transcript intervention and active control groups. Stigmatising behaviour levels were measured at pre-intervention, post-intervention and at a 30-day follow up. Group differences in attitudes were analysed using a 3x3 two-way mixed subjects ANOVA, with significance set at P<0.05. Results There were no significant differences in declared discriminatory behaviour between the investigated conditions (P=0.23). The video intervention did not produce superior results to the transcript, while the results of both interventions did not differ significantly from those of the control condition. Additionally, no significant interaction of each condition with time was observed at the post-intervention and follow-up periods (P=0.5). Conclusions Individual contact-based interventions may not sustainably reduce discrimination towards mental health service users. Services should prioritise strategies to specifically target the societal mechanisms that maintain stigmatising behaviour towards people with psychosis.
Assessing the person-centered care framework and assessment tool (PCC-AT) in HIV treatment settings in Ghana: A pilot study protocol
Authors: Posner Jessica E. , Duffy Malia , Madevu-Matson Caitlin , Casella Amy , Tagoe Henry , Nagai Henry , Sharer Melissa 
Published: January 2024

Introduction
Evidence suggests that person-centered care (PCC) has the potential to overcome inequities in access to HIV services, support quality care that is responsive to diverse needs while increasing efficiencies and resilience of the health system. Despite emerging evidence on the effectiveness of PCC, there is limited information available on how to assess it in diverse clinical settings. This work builds upon a systematic literature review published elsewhere by this study team to develop a PCC framework for HIV treatment service delivery.

Objectives
The PCC framework informed the development of the PCC assessment tool (PCC-AT) to assess the degree to which PCC activities are operationalized in diverse HIV treatment settings. The study objectives are to assess: (1) content validity of the PCC framework; (2) PCC-AT score consistency and reliability between health facility staff and clients; and (3) PCC-AT feasibility in HIV treatment settings.

Methods
The study team will pilot the PCC-AT among staff in five health facilities and conduct subsequent focus group discussions (FGDs) to determine PCC-AT feasibility. Key informant interviews (KIIs) with clients will explore content validity among PLHIV relative to each subdomain of the PCC-AT and provide a basis to compare score concordance. Quantitative data among health facility staff will examine how many and which cadres participated in the PCC-AT pilot and FGD, years of experience, gender, and the time required to complete the PCC-AT. Information on clients will include total time accessing treatment at the study health facility, years since diagnosis, age and gender. Qualitative data analysis, using descriptive coding with NVivo or a similar software, will be drawn from transcripts from the PCC-AT pilots, FGDs and KIIs.

Discussion
PCC assessment is a novel approach that aims to help health facilities assess and strengthen their ability to deliver PCC services to improve client outcomes.