bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the RNA m6A modification for cancer immunotherapy
Authors: Li Xinxin , Ma Shoubao , Deng Youcai , Yi Ping , Yu Jianhua 
Published: March 2022

AbstractN6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.
Computer-assisted three-dimensional quantitation of programmed death-ligand 1 in non-small cell lung cancer using tissue clearing technology
Authors: Lin Yen-Yu , Wang Lei-Chi , Hsieh Yu-Han , Hung Yu-Ling , Chen Yung-An , Lin Yu-Chieh , Lin Yen-Yin , Chou Teh-Ying 
Published: March 2022

AbstractImmune checkpoint blockade therapy has revolutionized non-small cell lung cancer treatment. However, not all patients respond to this therapy. Assessing the tumor expression of immune checkpoint molecules, including programmed death-ligand 1 (PD-L1), is the current standard in predicting treatment response. However, the correlation between PD-L1 expression and anti-PD-1/PD-L1 treatment response is not perfect. This is partly caused by tumor heterogeneity and the common practice of assessing PD-L1 expression based on limited biopsy material. To overcome this problem, we developed a novel method that can make formalin-fixed, paraffin-embedded tissue translucent, allowing three-dimensional (3D) imaging. Our protocol can process tissues up to 150 μm in thickness, allowing anti-PD-L1 staining of the entire tissue and producing high resolution 3D images. Compared to a traditional 4 μm section, our 3D image provides 30 times more coverage of the specimen, assessing PD-L1 expression of approximately 10 times more cells. We further developed a computer-assisted PD-L1 quantitation method to analyze these images, and we found marked variation of PD-L1 expression in 3D. In 5 of 33 needle-biopsy-sized specimens (15.2%), the PD-L1 tumor proportion score (TPS) varied by greater than 10% at different depth levels. In 14 cases (42.4%), the TPS at different depth levels fell into different categories (< 1%, 1–49%, or ≥ 50%), which can potentially influence treatment decisions. Importantly, our technology permits recovery of the processed tissue for subsequent analysis, including histology examination, immunohistochemistry, and mutation analysis. In conclusion, our novel method has the potential to increase the accuracy of tumor PD-L1 expression assessment and enable precise deployment of cancer immunotherapy.
Design and implementation of a novel pharmacogenetic assay for the identification of the CYP2D6*10 genetic variant
Authors: Ranadeva Nadeeka Dimuthu Kumari , Sirisena Nirmala Dushyanthi , Wetthasinghe Tithila Kalum , Noordeen Nafeesa , Dissanayake Vajira Harshadeva Weerabaddana 
Published: March 2022

Abstract
Objectives
Tamoxifen is considered to be the most widely used adjuvant therapy for hormone receptor positive breast cancer in premenopausal women. However, it is reported that nearly 30% of patients receiving tamoxifen therapy have shown reduced or no benefits. This may be due to the high inter-individual variations in the CYP2D6 gene that is involved in tamoxifen metabolism. The CYP2D6*10 gene variant (rs1065852C>T) is reported to be commonly found in Asian and South Asian populations. The present study was undertaken to design a novel pharmacogenetic assay (Single step-Tetra Arms Polymerase Chain Reaction) for the identification of the CYP2D6*10 variant and implement the designed assay by genotyping a cohort of breast cancer patients.

Results
The novel assay was successfully designed, optimized and validated using Sanger sequencing. Blood samples from 70 patients were genotyped. The following bands were observed in the gel image: Control band at 454 bp; band for C allele at 195 bp; band for T allele at 300 bp. The genotype frequencies for the CYP2D6*10 (rs1065852C>T) variant were: CC-24.28% (17/70), CT-75.71% (53/70), TT-0% (0/70). The allele frequencies were: T-allele-37.86% and C-allele-62.14%.
Community and cultural engagement for people with lived experience of mental health conditions: what are the barriers and enablers?
Authors: Baxter Louise , Burton Alexandra , Fancourt Daisy 
Published: March 2022

Abstract
Background
Community and cultural engagement can support recovery, help symptom management and increase social connections for people with lived experience of mental health conditions. However, research suggests that people with mental health conditions experience significant barriers to participation. The aim of this study was to explore barriers and enablers of participation in community and cultural activities among people with mental health conditions.

Methods
A qualitative interview study with 23 people with mild-to-moderate mental health conditions was undertaken. Data were analysed thematically, and themes were mapped to domains of the Capability, Opportunity and Motivation Model of Behaviour (COM-B).

Results
Eleven themes were identified from the analysis. Three themes involved participant Capability: physical skills, psychological traits and physical health limitations and three themes related to Opportunity: affordability and accessibility, structure and nature of the group, and support from others to attend. Five themes mapped to Motivation: creative identity, recovery and coping, enjoyment and fun, connecting with others, and information and planning. Participants were motivated to engage with community and cultural activities through “a creative identity”, belief that engagement would help recovery from mental illness, and a desire to connect with others and make friends. Motivation to participate was sustained by the enjoyable nature of activities. However, participants’ ability to engage was hampered by the expense, inaccessibility and sometimes unstructured nature of activities, and social anxiety associated with attending. Some participants had physical limitations such as fatigue or physical health problems to overcome. Interventions that could address these barriers include peer support, training for social prescribers to account for identity and previous experiences of participation, training for community organisations in providing a welcoming and structured environment, and provision of long-term sustainable funding to community organisations to subsidise attendance, transport or equipment costs.

Conclusion
People with mental health conditions may be at risk of experiencing barriers to community and cultural engagement due to existing social inequalities and social anxiety, however believing that involvement will support mental health was an enabler to participation. Future studies are needed to test the effectiveness of potential interventions to address the barriers and harness the facilitators identified here, to enable a more socially inclusive community and voluntary sector, and a potentially more responsive and effective social prescribing service in the UK for people experiencing mental health problems.
The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis
Authors: Bai Xiaojing , Mai Meiting , Yao Kai , Zhang Mengqi , Huang Yue , Zhang Wenbin , Guo Xiaorou , Xu Yixuan , Zhang Ying , Qurban Atikam , Duan Lijie , Bu Jimei , Zhang Jianfeng , Wu Junfeng , Zhao Yongfei , Yuan Xiangshan , Zu Hengbing 
Published: March 2022

AbstractPrevious studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked toneuropathologicalimpairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.
Progressive multifocal fibrosing neuropathy: description of a novel disease
Authors: Mendoza Fabian A. , Bagley Jennifer , Gochfeld Michael , Dalakas Marinos C. , Farber John L. , Jimenez Sergio A. 
Published: March 2022

AbstractEntrapment peripheral neuropathies are clinically characterized by sensory impairment and motor deficits. They are usually caused by mechanical injuries, but they are also a frequent manifestation of metabolic diseases, toxic agent exposure, or systemic fibrotic disorders. Here we describe the clinical, radiological, and histopathological features of a novel progressive fibrotic disorder characterized by progressive multifocal fibrosing neuropathy. We identified two patients who presented with severe and progressive peripheral neuropathic symptoms sequentially affecting multiple sites. These patients presented with severe and progressive multifocal, sequentially additive peripheral neuropathic symptoms. Extensive nerve conduction and radiological studies showed the sequential development of multifocal motor and sensory peripheral neuropathy in the absence of any exposure to known infectious, inflammatory, or fibrotic triggers and the lack of family history of compression neuropathies. Extensive clinical and laboratory test evaluation failed to support the diagnosis of any primary inflammatory or genetic peripheral neuropathy and there was no evidence of any systemic fibrosing disorder including Systemic Sclerosis, lacking cutaneous fibrotic changes and cardiopulmonary abnormalities. The clinical course was progressive with sequential development of motor and sensory deficits of upper and lower extremities displaying proximal predominance. Histopathological study of tissues obtained during nerve release surgeries showed severe perineural fibrosis with marked accumulation of thick collagen bundles encroaching the peripheral nerves. There was no evidence of vasculitic, inflammatory, or vascular fibroproliferative lesions. We suggest that the clinical findings described here represent a previously undescribed fibrotic disorder affecting peripheral nerves, and we propose the descriptive term "Progressive Multifocal Fibrosing Neuropathy" to refer to this novel disorder. Despite the inherent limitations of this early description, we hope this is would contribute to the identification of additional cases.
Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies
Authors: Fixemer Sonja , Ameli Corrado , Hammer Gaël , Salamanca Luis , Uriarte Huarte Oihane , Schwartz Chantal , Gérardy Jean-Jacques , Mechawar Naguib , Skupin Alexander , Mittelbronn Michel , Bouvier David S. 
Published: March 2022

AbstractThe cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD.
Prostate MRI using a rigid two-channel phased-array endorectal coil: comparison with phased array coil acquisition at 3 T
Authors: Lewis Sara , Ganti Aasrith , Argiriadi Pamela , Rosen Ally , Hectors Stefanie , Semaan Sahar , Song Christopher , Peti Steve , Segall Maxwell , George Kezia , Jaikaran Vaneela , Villa Sebastian , Kestenbaum David , Voutsinas Nicholas , Doucette John , Tewari Ashutosh , Rastinehad Ardeshir R. , Taouli Bachir 
Published: March 2022

Abstract
Background
To compare image quality, lesion detection and patient comfort of 3T prostate MRI using a combined rigid two-channel phased-array endorectal coil and an external phased-array coil (ERC-PAC) compared to external PAC acquisition in the same patients.

Methods
Thirty three men (mean age 65.3y) with suspected (n = 15) or biopsy-proven prostate cancer (PCa, n = 18) were prospectively enrolled in this exploratory study. 3T prostate MRI including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) was performed using an ERC-PAC versus PAC alone, in random order. Image quality, lesion detection and characterization (biparametric PI-RADSv2.1) were evaluated by 2 independent observers. Estimated signal-to-noise ratio (eSNR) was measured in identified lesions and the peripheral zone (PZ). Patient comfort was assessed using a questionnaire. Data were compared between sequences and acquisitions. Inter/intra-observer agreement for PI-RADS scores was evaluated.

Results
Twenty four prostate lesions (22 PCa) were identified in 20/33 men. Superior image quality was found for ERC-PAC compared to PAC for T2WI for one observer (Obs.1, p < 0.03) and high b-value DWI for both observers (p < 0.05). The sensitivity of PI-RADS for lesion detection for ERC-PAC and PAC acquisitions was 79.2 and 75% for Obs.1, and 79.1 and 66.7%, for Obs.2, without significant difference for each observer (McNemar p-values ≥0.08). Inter−/intra-observer agreement for PI-RADS scores was moderate-to-substantial (kappa = 0.52–0.84). Higher eSNR was observed for lesions and PZ for T2WI and PZ for DWI using ERC-PAC (p < 0.013). Most patients (21/33) reported discomfort at ERC insertion.

Conclusion
Despite improved image quality and eSNR using the rigid ERC-PAC combination, no significant improvement in lesion detection was observed, therefore not supporting the routine use of ERC for prostate MRI.
The influence of epidural volume extension on spinal block with hyperbaric bupivacaine for elective knee arthroplasty
Authors: Özeroğlu Ertaç , Yilmaz Fulya 
Published: March 2022

Abstract
Background
Epidural volume extension (EVE) via a combined spinal–epidural is the enhancement of a small-dose intrathecal block by an epidural injection of physiological saline solution. The aim of this study was to investigate the sensory and motor block characteristics of spinal anesthesia after EVE. Eighty patients enrolled in this prospective, randomized, double-blind study. Group I (n=40) received 10 mg hyperbaric bupivacaine and group II (n=40) first received 10 mg hyperbaric bupivacaine intrathecally and subsequently 10 mL saline via epidural catheter.

Results
In the first 30 min after combined spinal–epidural anesthesia, the maximum sensory block level was significantly higher in group II than in group I. The Bromage score was significantly higher in group II than in group I at 3–6 and 9 min of the intraoperative period. EVE increased the mean Smax significantly in group 2 than group 1 (p<0.05). Tmax was statistically similar between group 1 and group 2 (p>0.05). EVE significantly altered Time10 and Tadeq in group 2 (p<0.05).

Conclusions
EVE with saline (10 mL) offer early onset of sensory and motor block and a high level of sensory block. And also delay supplemental epidural dose requirement intraoperatively.
Vitamin D receptor gene polymorphism in Madura pregnant women with hypertension: a case control study
Authors: Setiarsih Dini , Hastuti Pramudji , Nurdiati Detty Siti 
Published: March 2022

Abstract
Background
Genetic factors are important considerations in the etiology of preeclampsia and gestational hypertension. Several previous studies have shown an association of Vitamin D receptor (VDR) gene polymorphisms with hypertension in pregnancy. However, the number of studies is still very limited and the results differ from one another.

Aim of the study
This study aimed to analyze the polymorphisms of rs2228570 and rs731236 of the VDR gene in subjects with hypertension and non-hypertension in pregnancy in Madura ethnicity.

Subjects and methods
The researchers conducted tests for two polymorphisms in the VDR gene among 210 subjects consisting of 105 pregnant women with hypertension and 105 non-hypertension pregnant women from Madura ethnicity. The rs2228570 (T>C) and rs731236 (C>T) polymorphisms were detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. All data were analyzed by T-tests and Chi-Square tests.

Results
The TT genotype frequency of rs2228570 (15.2%) in the hypertension group was higher than in the control group (6.7%) (p = 0.047). Subjects with the TT genotype at rs2228570 showed a 3.048 times greater risk of developing hypertension than the CC genotype (OR = 3.048: 1.135–8.183, p = 0.023). The T allele frequency of rs2228570 (40.5%) in the hypertension group was higher than in the control group (30.5%) (p = 0.032). Subjects with the T allele had 1.551 times greater risk of developing hypertension. There was no significant difference in genotype and allele of rs731236 between hypertension subjects and controls.

Conclusion
The TT genotype and T allele of rs2228570 in the hypertension group were risk factors for hypertension in this study. While the TT genotype and T allele at rs731236 were not risk factors for hypertension in pregnancy. Genotyping of VDR gene polymorphisms in pregnant women is expected to be useful in strategies for treating hypertension in pregnancy.
Applying implementation science frameworks to identify factors that influence the intention of healthcare providers to offer PrEP care and advocate for PrEP in HIV clinics in Colombia: a cross-sectional study
Authors: Martinez-Cajas Jorge Luis , Torres Julian , Mueses Hector Fabio , Plazas Pilar Camargo , Arrivillaga Marcela , Gomez Sheila Andrea , Galindo Ximena , Buitrago Ernesto Martinez , Llano Beatriz Eugenia Alvarado 
Published: March 2022

Abstract
Background
Few studies have used implementation science frameworks to identify determinants of PrEP prescription by healthcare providers. In this work, we developed and psychometrically examined a questionnaire using the theoretical domains framework (TDF) and the consolidated framework for implementation research (CFIR). We used this questionnaire to investigate what factors influence the intention of healthcare providers to offer PrEP care and advocate for PrEP.

Methods
We conducted a cross-sectional study in 16 HIV healthcare organizations in Colombia. A 98-item questionnaire was administered online to 129 healthcare professionals. One hundred had complete data for this analysis. We used exploratory factor analysis to assess the psychometric properties of both frameworks, and multinomial regression analysis to evaluate the associations of the frameworks’ domains with two outcomes: (1) intention to offer PrEP care and (2) intention to advocate for PrEP impmentation.

Results
We found support for nine indices with good internal consistency, reflecting PrEP characteristics, attitudes towards population needs, concerns about the use of PrEP, concerns about the role of the healthcare systems, knowledge, beliefs about capabilities, professional role, social influence, and beliefs about consequences. Notably, only 57% of the participants were likely to have a plan to care for people in PrEP and 66.7% were likely to advocate for PrEP. The perception of the need for PrEP in populations, the value of PrEP as a practice, the influence of colleagues, and seeing PrEP care as a priority was related to being less likely to be unwilling to provide or advocate for PrEP care.

Conclusion
Our findings suggested the importance of multilevel strategies to increase the provision of PrEP care by healthcare providers including adquisition of new skills, training of PrEP champions, and strength the capacity of the health system.