bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human 3D Ovarian Cancer Models Reveal Malignant Cell–Intrinsic and –Extrinsic Factors That Influence CAR T-cell Activity
Authors: Joy Joash D. , Malacrida Beatrice , Laforêts Florian , Kotantaki Panoraia , Maniati Eleni , Manchanda Ranjit , Annibaldi Alessandro , Hopkins Sarah , Garrobo-Calleja Ianire , Gautrot Julien , Balkwill Frances R. 
Published: May 2024

Abstract
In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment. Here, we describe the modulation of CAR T-cell activity by malignant cells and fibroblasts in human three-dimensional (3D) in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer cell spheroids, malignant cell–intrinsic resistance to CAR T-cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T-cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell–cell and cell–matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors.
Significance: Three-dimensional in vitro models of increasing complexity uncover mechanisms of resistance to CAR T cells in solid tumors, which could help accelerate development of improved CAR T-cell constructs.
Disparities and Determinants of Testing for Early Detection of Cervical Cancer among Nepalese Women: Evidence from a Population-Based Survey
Authors: Rahman Md. Shafiur , Rahman Md. Mahfuzur , Acharya Kiran , Haruyama Rei , Shah Richa , Matsuda Tomohiro , Inoue Manami , Abe Sarah K. 
Published: May 2024

AbstractBackground:Cervical cancer presents a considerable challenge in South Asia, notably in Nepal, where screening remains limited. Past research in Nepal lacked national representation and a thorough exploration of factors influencing cervical cancer screening, such as educational and socioeconomic disparities. This study aims to measure these gaps and identify associated factors in testing for early detection of cervical cancer among Nepalese women.Methods:Data from the 2019 Nepal Noncommunicable Disease Risk Factors survey (World Health Organization STEPwise approach to noncommunicable risk factor surveillance), involving 2,332 women aged 30 to 69 years, were used. Respondents were asked if they had undergone cervical cancer testing through visual inspection with acetic acid, Pap smear, or human papillomavirus test ever or in the past 5 years. The slope index of inequality (SII) and relative concentration index were used to measure socioeconomic and education-based disparities in cervical cancer test uptake.Results:Only 7.1% [95% confidence interval (CI): 5.1–9.9] Nepalese women had ever undergone cervical cancer testing, whereas 5.1% (95% CI: 3.4–7.5) tested within the last 5 years. The ever uptake of cervical cancer testing was 5.1 percentage points higher (SII: 5.1, 95% CI: −0.1 to 10.2) among women from the richest compared with the poorest households. Education-based disparities were particularly pronounced, with a 13.9 percentage point difference between highly educated urban residents and their uneducated counterparts (SII: 13.9, 95% CI: 5.8–21.9).Conclusions:Less than one in ten women in Nepal had a cervical cancer testing, primarily favoring higher educated and wealthier individuals.Impact:Targeted early detection and cervical cancer screening interventions are necessary to address these disparities and improve access and uptake.
Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models
Authors: Gough Sheryl M. , Flanagan John J. , Teh Jessica , Andreoli Monica , Rousseau Emma , Pannone Melissa , Bookbinder Mark , Willard Ryan , Davenport Kim , Bortolon Elizabeth , Cadelina Gregory , Gordon Debbie , Pizzano Jennifer , Macaluso Jennifer , Soto Leofal , Corradi John , Digianantonio Katherine , Drulyte Ieva , Morgan Alicia , Quinn Connor , Békés Miklós , Ferraro Caterina , Chen Xin , Wang Gan , Dong Hanqing , Wang Jing , Langley David R. , Houston John , Gedrich Richard , Taylor Ian C. 
Published: May 2024

Abstract

Purpose:
Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.

Experimental Design:
A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).

Results:
Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%–123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%–80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.

Conclusions:
Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2− breast cancer.
Valuing & Defending the Arts in Hong Kong
Authors: Hjort Mette 
Published: May 2024

Abstract
Focusing on a period of just over two decades (1997-2023), this essay charts how the most salient approaches to valuing and defending the arts in Hong Kong reflect the changing political circumstances of the city. I select two approaches for close analysis. Emphasizing the private and public value of the arts, the first approach reflects efforts to reinvent Hong Kong in the wake of the handover to the People's Republic of China in 1997. Influenced by significant social unrest in 2014 and 2019, and by the introduction of the National Security Law in 2020, the second approach seeks protection for the arts through collaboration with the sciences. The exceptional conditions that Hong Kong offers for meaningful arts-related work are identified to facilitate international comparisons.
India's Realignment of Higher Education
Authors: Bharucha Jamshed 
Published: May 2024

Abstract
Higher education in India has been stifled by overregulation. The opening of private universities has been severely restricted, and all but a few exempt institutions have had to comply with rigid curricular and organizational dictates. The system has been characterized by rote learning, high-stakes examination, premature specialization, and limited flexibility. In the most sweeping transformation to the system in the nation's modern history, India's new National Education Policy 2020 (NEP2020) seeks to change all that. With half of the world's university-age population residing in India, bursting with aspiration but frustrated by limited access to quality institutions, new universities are emerging. One is Sai University, the first in the nation to integrate heretofore siloed programs in arts and sciences, technology, and law into an integrated ecosystem at the undergraduate level.
The Role & Rule of Rankings
Authors: Depo Gökhan 
Published: May 2024

Abstract
This essay explores the impact of global university rankings on higher education, with a focus on their historical evolution, limitations, and flaws. I examine the detrimental consequences associated with manipulating the ranking systems, and their resultant financial repercussions, which lead to diminished trust in higher-education institutions. I call for a comprehensive evaluation, urging stakeholders-especially governments-to recognize the subjectivity and limitations inherent in rankings that inform policymaking decisions related to higher education. I propose strategies for improvement, such as broadening the criteria used for rankings, and specialized rankings that highlight the unique strengths of various types of institutions, like public engagement, student satisfaction, diversity, and sustainability. Collaboration could enhance ranking accuracy, while also acknowledging the significance of ranking systems in shaping higher-education decisions and policies.
Inter-State Applications under the European Convention on Human Rights – Situating the Instrument in the Current Human Rights Landscape
Authors: Risini Isabella , Eicke Tim 
Published: May 2024

Abstract
Recent events and developments in Europe have called for the use of the inter-State application under Article 33 the European Convention on Human Rights (echr, the Convention), a challenging situation (1) for the European Court of Human Rights (ECtHR, the Court) on many levels, including the resource situation of the Court. The inter-State application was the centerpiece of international human rights supervision in the original 1950 Convention. This contribution sketches out the evolution of the inter-State application over some seven decades of history (2) of the echr. It highlights strengths and raises awareness of existing limitations (3). One aspect that merits attention is the evidential side in this type of proceedings. Establishing a judicial record of the events under the Court’s scrutiny is a value to be appraised here in its aims and complexities.
For a Pluralism of Climate Modeling Strategies
Authors: Baldissera Pacchetti Marina , Jebeile Julie , Thompson Erica 
Published: May 2024

Abstract
The continued development of general circulation models (GCMs) toward increasing resolution and complexity is a predominantly chosen strategy to advance climate science, resulting in channeling of research and funding to meet this aspiration. Yet many other modeling strategies have also been developed and can be used to understand past and present climates, to project future climates, and ultimately to support decision-making. We argue that a plurality of climate modeling strategies and an equitable distribution of funding among them would be an improvement on the current predominant strategy for informing policymaking. To support our claim, we use a philosophy of science approach to compare the increasing resolution and complexity of general circulation models with three alternate examples: the use of machine learning techniques, the physical climate storyline approach, and Earth system models of intermediate complexity. We show that each of these strategies prioritizes a particular set of methodological aims, among which are empirical agreement, realism, comprehensiveness, diversity of process representations, inclusion of the human dimension, reduction of computational expense, and intelligibility. Thus, each strategy may provide adequate information to support different specific kinds of research and decision questions. We conclude that, because climate decision-making consists of different kinds of questions, many modeling strategies are all potentially useful and can be used in a complementary way.
The Contribution of Mesoscale Convective Systems to the Coastal Rainfall Maximum over West Africa
Authors: Wu Shun-Nan , Sakaeda Naoko , Martin Elinor , Rios-Berrios Rosimar , Russell James 
Published: May 2024

Abstract
This study examines the behaviors of coastal mesoscale convective systems (MCSs) to understand why the maximum climatological rainfall appears offshore of West Africa using satellite measurements. West Africa has a higher amount of rainfall offshore than inland during the monsoon season, but the reason for this offshore rainfall maximum remains unclear. MCSs that propagate offshore from coastal West Africa can develop into high-impact weather events in the eastern Atlantic, yet we know little about the MCS transitions across coastlines. Therefore, better understanding of how MCSs evolve during the coastal-to-maritime transition and contribute to the offshore climatological rainfall maximum over West Africa is key to advancing the knowledge of high-impact weather in this coastal region. The offshore rainfall can be contributed by either offshore-propagating MCSs generated over land or the MCSs initiated over the ocean. While continental MCSs are known to have more intense deep convection, their frequency of propagating offshore is found to be small. Instead, we find that the offshore environment supports the frequent formation of maritime MCSs, leading to their dominant contribution to offshore rainfall. However, an exception is found for the 8°–10°N offshore area, where the presence of high terrain generates MCSs with intense rainfall that more frequently propagate offshore and enhance offshore rainfall. These MCSs also often intensify their rainfall and expand in size as they move offshore. These results suggest that understanding the frequency, intensity, and transition of MCS generated over land and the ocean is key to better comprehending and simulating the rainfall activity over the coastal-to-marine transition zone.
Trajectories of Purpose in Life Across Diagnosis of Alzheimer’s Disease or Related Dementias in Older Adulthood
Authors: Mroz Emily L. , Collette Tyler , Keefe Kate , Gil Heidi , Monin Joan , Sharma Shubam 
Published: May 2024

Objectives: Sense of purpose serves as a psychological resource for late-life health. Limited research has examined how purpose changes across chronic illness diagnoses, including a diagnosis of Alzheimer’s disease and related dementias (ADRD). Method: This study leverages data from the National Health and Aging Trends Study (NHATS; N = 831) to establish trajectories of purpose across ADRD diagnosis using three-year (pre-diagnosis, year of diagnosis, post-diagnosis) timespans and two comparison groups (heart disease diagnosis, no diagnosis). Results: We observed a longitudinal decrease in purpose in the ADRD diagnosis group, t = 3.85, p = .003, d = −0.258. This contrasts with heart disease diagnosis and no diagnosis groups, where purpose did not change over time. Discussion: Older adults who receive an ADRD diagnosis may be vulnerable to a decreasing sense of purpose across their diagnosis experience. We consider social, psychological, and clinical antecedents for this trend.
Clinicoetiological Profile of Meningitis Cases in HIV-infected Patients Admitted at a Tertiary Care Hospital in Eastern India
Authors: Mandal Madhuchhanda , Chatterjee Rupak , Ghosh Subir Kumar , Mukherjee Shatavisa 
Published: May 2024

Background and Aims: Meningitis in immunocompromised patients is a significant cause of mortality and morbidity. In HIV-infected cases, it is majorly of infectious origin, with Cryptococcus neoformans and Mycobacterium tuberculosis being two opportunistic pathogens together accounting for about 75% of meningitis cases. However, other variants like bacterial, aseptic, fungal or acanthamoeba meningitis can also occur in patients with HIV. The present study aimed to observe the clinical profile and aetiology of different types of meningitis in HIV-infected patients. Methods: A cross-sectional observational study included HIV-infected patients with symptoms and signs suggestive of meningitis. Patients were then assessed according to clinical, blood and CSF biochemical, blood and CSF microbiological and/special test parameter and/or radiological parameters. Data was statistically analysed. Results: Of 120 patients included, a majority belonged to the age group 26–49 years. Common presenting features included headache, fever, photophobia, neck stiffness and altered mental status. Various aetiologies of the cases included 55% cases of cryptococcal meningitis, 38.33% cases of tubercular meningitis, 3.33% cases of tubercular/cryptococcal co-infection meningitis and 1.66% cases of syphilis and pyogenic infection each. CSF findings suggested elevated opening pressure in 64.16% cases, followed by positive serum CrAg in 63.33% cases. CSF CrAg and India ink were positive, and budding yeast cell was seen in 58.33% cases. Conclusion: Tuberculosis and cryptococcal meningitis continue to be the prevailing culprits of meningitis in individuals with HIV. As treatment is readily available for these infections, early suspicion and prompt diagnosis coupled with effective early initiation of treatment can improve the lifespan of these patients.
Prevalence of premenstrual syndrome and its associations with dietary and other lifestyle factors among university female students in Dubai: A cross-sectional study
Authors: Al Sabbah Haleama , Al Mutawa Noof , Assaf Enas A 
Published: May 2024

Background: Premenstrual syndrome is a relatively prevalent condition that affects a significant number of menstruating women worldwide. It can range from mild to severe and may interfere with daily activities. Objective: This study aims to investigate the prevalence of premenstrual syndrome and its associated factors among female university students in Dubai. Design: This study was designed as a cross-sectional study. Methods: The analysis for this study involved 217 female university students (aged ⩾18 years old) who completed a self-reported online questionnaire. Participants were recruited through simple random sampling, and the study received ethical approval from the Zayed University Ethical Committee. Results: All participants reported that they experienced at least one premenstrual syndrome symptom with different levels of severity. The prevalence rate of psychological, physical, and behavioral symptoms was 83.0%, 79.4%, and 76.6%, respectively. The most frequently reported premenstrual psychological symptoms were loss of control (69.6%). Most reported physical premenstrual symptoms included lethargy/fatigue/decreased energy (56.7%); premenstrual syndrome symptoms interfered with participants’ daily routines (45.2%). Normal body mass index, no smoking, milk consumption, cruciferous vegetables, fruits, animal foods, fish oil supplements, and no fast-food consumption were all significant factors associated with decreasing premenstrual syndrome. Conclusions: Premenstrual syndrome is a common menstrual disorder among university students that interferes with their daily routines. Dietary habits and other lifestyle factors were highly related to premenstrual syndrome. Therefore, health promotion programs are highly recommended to encourage healthy diets and lifestyles for females as early as adolescence at the school level.
Halting multiple myeloma with MALT1 inhibition: suppressing BCMA-induced NF-κB and inducing immunogenic cell death
Authors: Yao Yao , Yuan Mei , Shi Min , Li Wenyu , Sha Yuqian , Zhang Yan , Yuan Canli , Luo Jianping , Li Zhenyu , Liao Chengcheng , Xu Kailin , Niu Mingshan 
Published: May 2024

Abstract
Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 μM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.
Flow cytometric profiles with CD7 and CADM1 in CD4+ T cells are promising indicators for prognosis of aggressive ATL
Authors: Jimbo Koji , Kawamata Toyotaka , Inamoto Yoshihiro , Ito Ayumu , Yokoyama Kazuaki , Sato Aki , Fukuda Takahiro , Uchimaru Kaoru , Nannya Yasuhito 
Published: May 2024

Abstract
Adult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)–infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1–uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1–infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7–) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1–infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.