Miracle-dz/UniFAR-FTUs huggingface dataset:
GPNMB expression identifies TSC1/2/mTOR‐associated and MiT family translocation‐driven renal neoplasms

GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration‐associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration‐associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB‐transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
REXO4 acts as a biomarker and promotes hepatocellular carcinoma progression.

Background Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality and the most common form of liver cancer. REXO4 (RNA exonuclease 4 homolog) downregulation has previously been linked to enhanced chemosensitivity in breast cancer cells. The present study sought to comprehensively clarify the functional role of REXO4 in HCC. Methods REXO4 expression levels in HCC tumor tissues and control tissue samples were established by analyzing data from the Gene Expression Omnibus (GEO) database. The expression of REXO4 was then knocked down in HCC cell lines to explore its functional role in these cells, while a gene set enrichment analysis (GSEA) approach was used to assess the functional regulator network associated with REXO4, and the Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm was used to determine the relationship between this gene and immune cell infiltration of tumor tissues. The relationship between REXO4 and metabolic pathway was analyzed by oil red O staining. Cell Counting Kit-8 assays, colony formation, wound-healing assay, and a nude mouse subcutaneous tumor model were used to evaluate the function of REXO4 in HCC. Results REXO4 was highly upregulated in HCC tumors and cell lines, and was an effective predictor of HCC patient prognosis. The results indicated that the knockdown of REXO4 inhibited the proliferation and progression of HCC in vitro and in vivo. GSEA approaches also revealed REXO4 to be associated with tumor progression. Furthermore, REXO4 was associated with the degree of increase of intratumoral immune cell infiltration in HCC tissues and cells, and this gene was also linked with altered lipid metabolism in HCC cells. Conclusions In summary, these analyses revealed REXO4 to be upregulated in HCC and to be associated with poor patient prognosis. In addition, this gene was closely linked to key cancer hallmark pathways and was revealed to play an important role in the susceptibility of liver tumors to immune cell infiltration and activation. Thus, targeting REXO4 may be a promising approach to treating patients with HCC in the near future.
Capillary module haemodynamics and mechanisms of blood flow regulation in skeletal muscle capillary networks: Experimental and computational analysis

The capillary module (CM), consisting of parallel capillaries from terminal arteriole to post‐capillary venule, is classically considered to be the building block of complex capillary networks. In skeletal muscle, CMs form interconnected columns spanning thousands of microns, which we recently described as the capillary fascicle. However, detailed evaluation of CM haemodynamics has not been described, and may provide insight into mechanisms of blood flow regulation in the microcirculation. We used intravital videomicroscopy from resting extensor digitorum longus muscle in rats (n = 9 networks, 112 capillary modules), as well as dual‐phase computational modelling of blood flow in simulated CM geometries. We found that the mean driving pressure across CMs was 3.236 ± 1.833 mmHg. Red blood cell (RBC) flow was independent of CM resistance, and the ratio of blood flow in adjacent modules was not correlated with their ratio of resistances. In simulated CM geometries, increases to driving pressure produced a direct linear increase to RBC and plasma flow, with no changes to RBC distribution; increases to arteriolar inflow haematocrit resulted in increased RBC flow, but with viscosity‐dependent increases to CM resistance. CM RBC flow heterogeneity was higher than plasma flow heterogeneity in experimental data, in contrast to simulated geometries, suggesting that time‐dependent flow variability may have important consequences for RBC distribution. In summary, these findings suggest that CMs are active participants in microvascular flow regulation, likely achieved through adjustments to CM driving pressure using pre‐ and post‐capillary loci of flow control. Increases to CM viscosity may be important during the regulation of functional hyperaemia.
Parents and newborn “togetherness” after birth

ABSTRACT Purpose Zero separation is a family-centred approach where newborns should be accompanied by their parents, regardless of the type of birth or health status. To our knowledge, few studies have described the way this approach is realized in clinical practice. This study describes situations of separation between mother/partner and newborn after birth on the labour ward, maternity ward and at the neonatal unit. Method An observation study was conducted during four months at a Swedish hospital. All caregivers at the three units were given the task of collecting the data. A semantic thematic analysis was performed with an inductive approach. Results Six themes emerged from the analysis. Two themes were common to all three units, one theme was common to two units and three themes emerged at only one unit. The themes describe various causes of separation, such as organizational and economic barriers, clinical routines, parents’ own decisions, shortage of collaboration within and between units, as well as a shortage of interprofessional communication. Conclusion Our study shows that there is still a gap between the latest evidence-based knowledge of the importance of zero separation and current practice in newborn care. There is a need for continuous collaboration between all units responsible for the care of mother and newborn.
Behavioral and social interventions to promote optimal HIV prevention and care continua outcomes in the United States

Purpose of review This review reports on trends in behavioral and social intervention research in the United States published over the past year (2020–2021) investigating HIV prevention and care outcomes, organized by the level of intervention focus – individual, dyadic, and organizational. Recent findings Researchers have continued to develop and evaluate behavioral and social interventions to reduce HIV acquisition risk and disease progression. With few exceptions, social and behavioral interventions have primarily focused on individuals as the unit of behavior change. Interventions operating at the individual-, dyadic-, and organizational-level have made strides to reduce HIV transmission risk and disease progressing by addressing mental health, substance use, stigma, peer and romantic relationships, and, to some extent, structural vulnerabilities. Summary Social and behavioral interventions continue to be critical in addressing HIV inequities in the United States. An important gap in the literature is the need for multilevel interventions designed and implemented within existing community-based organizations and local healthcare settings. We call on researchers to continue to attend to the structural, environmental, and economic vulnerabilities that shape HIV inequities in the development of multilevel approaches necessary to realize the full potential of existing and emerging HIV prevention and care strategies.
RadSigBench: a framework for benchmarking functional genomics signatures of cancer cell radiosensitivity

Abstract Multiple transcriptomic predictors of tumour cell radiosensitivity (RS) have been proposed, but they have not been benchmarked against one another or to control models. To address this, we present RadSigBench, a comprehensive benchmarking framework for RS signatures. The approach compares candidate models to those developed from randomly resampled control signatures and from cellular processes integral to the radiation response. Robust evaluation of signature accuracy, both overall and for individual tissues, is performed. The NCI60 and Cancer Cell Line Encyclopaedia datasets are integrated into our workflow. Prediction of two measures of RS is assessed: survival fraction after 2 Gy and mean inactivation dose. We apply the RadSigBench framework to seven prominent published signatures of radiation sensitivity and test for equivalence to control signatures. The mean out-of-sample R2 for the published models on test data was very poor at 0.01 (range: −0.05 to 0.09) for Cancer Cell Line Encyclopedia and 0.00 (range: −0.19 to 0.19) in the NCI60 data. The accuracy of both published and cellular process signatures investigated was equivalent to the resampled controls, suggesting that these signatures contain limited radiation-specific information. Enhanced modelling strategies are needed for effective prediction of intrinsic RS to inform clinical treatment regimes. We make recommendations for methodological improvements, for example the inclusion of perturbation data, multiomics, advanced machine learning and mechanistic modelling. Our validation framework provides for robust performance assessment of ongoing developments in intrinsic RS prediction.
Effects of dietary and exercise treatments on HDL subclasses in lactating women with overweight and obesity: a secondary analysis of a randomised controlled trial

Abstract Childbearing decreases HDL-cholesterol, potentially contributing to the increased risk of CVD in parous women. Large HDL particles (HDL-P) are associated with lower risk of CVD. In this secondary analysis of a randomised controlled trial, we investigated the effects of 12-week dietary and exercise treatments on HDL-P subclass concentration, size and apoA1 in lactating women with overweight/obesity. At 10–14 weeks postpartum, 68 women with pre-pregnant BMI 25–35 kg/m2 were randomised to four groups using 2 × 2 factorial design: (1) dietary treatment for weight loss; (2) exercise treatment; (3) both treatments and (4) no treatment. Lipoprotein subclass profiling by NMR spectroscopy was performed in serum at randomisation and after 3 and 12 months, and the results analysed with two-way ANCOVA. Lipid concentrations decline naturally postpartum. At 3 months (5–6 months postpartum), both diet (P = 0·003) and exercise (P = 0·008) reduced small HDL-P concentration. Concurrently, exercise limited the decline in very large HDL-P (P = 0·002) and the effect was still significant at 12 months (15 months postpartum) (P = 0·041). At 12 months, diet limited the decline in very large HDL-P (P = 0·005), large HDL-P (P = 0·001) and apoA1 (P = 0·002) as well as HDL size (P = 0·002). The dietary treatment for weight loss and the exercise treatment both showed effects on HDL-P subclasses in lactating women with overweight and obesity possibly associated with lower CVD risk. The dietary treatment had more effects than the exercise treatment at 12 months, likely associated with a 10 % weight loss.
Design of Compact Penta-Band and Hexa-Band Microstrip Antennas

Abstract This paper presents the design of two multi-band microstrip antennas. The antenna-1 gives Penta-Band and antenna-2 gives Hexa-band in the WLAN band. The frequency bands of the antenna-1 are Bluetooth 2.47 GHz (2.43 GHz–2.54 GHz), WiMax band 3.73 GHz (3.71 GHz–3.77 GHz), WLAN 5.1 GHz (4.99 GHz–5.13 GHz), upper WLAN 6.36 GHz (6.29 GHz–6.43 GHz), C band band 7.42 GHz (7.32 GHz–7.50 GHz) and the antenna-2 are WLAN band 2.6 GHz (2.56 GHz–2.63 GHz), 3.0 GHz (2.94 GHz–3.05 GHz), WiMax band 3.4 GHz (3.34 GHz–3.55 GHz), 4.85 GHz (4.81 GHz–4.92 GHz), WLAN 5.3 GHz (5.27 GHz–5.34 GHz) and upper WLAN 6.88 GHz. Both the antennas are fabricated and their measured results are presented to validate the simulated results. Proposed antennas have compact sizes and good radiation performances.
Rational design and synthesis of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

Abstract Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a–k, 8n–z, and phenyl urea 8l–m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics.
Composite Classic Hodgkin Lymphoma and Follicular Lymphoma

Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.
Complete chloroplast genome of Baccaurea ramiflora and its phylogenetic analysis

Abstract Baccaurea ramiflora Lour. is a popular tropical fruit tree, mainly grown in Myanmar, India, and other tropical or sub-tropical regions where it is commonly referred to as Myanmar grapes, Burmese grapes, or Latkan, respectively. Besides food, B. ramiflora is a traditional medicinal plant with several pharmaceutical effects. It is also a crucial component of Chinese Dai medicine. Here, the chloroplast genome of B. ramiflora was sequenced, assembled, and annotated. The complete chloroplast genome is 161,093 bp in length with a GC content of 36.71%. Additionally, it comprises a large single-copy region (LSC) of 89,503 bp, a small single-copy region (SSC) of 18,818 bp, and two inverted repeat regions (IRa and IRb) of 26,386 bp. In total, 128 genes were annotated, including 82 protein-coding genes, 37 tRNA genes, 8 rRNA genes, and 1 pseudogene. Phylogenetic analysis revealed that B. ramiflora is closely related to Phyllanthus emblica, Glochidion chodoense, and Phyllanthus amarus. This study provides useful genomic information for future phylogenetic studies of B. ramiflora and Phyllanthaceae family.
Genetic contributions of MHC class I antigen processing and presentation pathway to bladder cancer risk and recurrence.

Human leukocyte antigen class I (HLA class I) antigen processing and presentation pathway (APP) defines anti-tumor immune response. ERAP, TAP, tapasin (TAPBP), and IFNγ modulate APP: control HLA class I expression in the tumor and the repertoire of presented tumor antigens. At the same time, vascular endothelial growth factor (VEGF) acts as an immunomodulator in the tumor microenvironment. The objective of the current study was to examine the association of single nucleotide polymorphisms (SNPs) in the ERAP1, ERAP2, TAP1, TAP2, TAPBP, IFNG genes with the corresponding mRNA expression in bladder cancer (BC) risk and recurrence after transurethral resection of BC. Moreover, we assessed the relationship between HLA class I and VEGF plasma levels and BC recurrence. We analyzed nine SNPs in 124 BC patients using TaqMan genotyping and compared them with the data from 503 healthy individuals from the 1000 Genomes Project. In addition, we quantified the effects of SNPs on the corresponding mRNA expression in tumor and non-tumor adjacent tissue in 60 BC patients with primary and 30 with recurrent tumor by quantitative real-time PCR. Furthermore, the plasma HLA class I and VEGF levels were analyzed in BC patients and healthy controls by ELISA. IFNG (rs1861493) was associated with BC risk, TAPBP (rs3106189, rs2071888) with recurrence-free survival (RFS). Moreover, TAPBP mRNA expression was lower in tumors than in the adjacent tissue. The SNPs ERAP2 (rs251339) and TAP2 (rs241447, rs241448) variants affected mRNA expression in BC tissue. In tumor tissue, the high mRNA expression of ERAP1 was more common in BC patients with single tumors, ERAP2 in non-smokers, and TAP2 mRNA in recurrence. The lower HLA and higher VEGF plasma levels were observed in BC patients compared with healthy controls. We conclude that the genetic elements responsible for MHC class I APP may influence the BC risk, risk of recurrence, and RFS.
Three‐dimensional morphological characterization of colorectal pits from label‐free microscopy images

The prognosis of colorectal cancer (CRC), one of the most prevalent pathologies worldwide, is linked to early detection. Kudo's pit pattern classification states morphological pit patterns of the Lieberkühn crypts by analyzing the superficial mucosa, predicting the histology of colorectal lesions. Its use as a highly accurate two‐dimensional diagnostic criterion has increased, mostly involving expert endoscopists’ judgment. The processing of autofluorescence images could allow the diagnostic, bypassing staining techniques and decreasing the biopsies, resources and times involved in the inspection. That criterion could be extended by data of the pit three‐dimensional (3D) morphology. Thus, this work was aimed at obtaining 3D morphological information by quantifying geometrical and shape descriptors through software processing and analysis of widefield autofluorescence microscopy image stacks acquired by fresh colon tissue samples from a murine model of CRC. Statistical analyses included pits from control mice and from the second (2nd), fourth (4th), and eighth (8th) weeks of treatment. Statistically significant differences were found for almost all parameters between the pits from control and from the 4th treated week, stating that the major morphological changes begin after the 2nd week. In particular, pits from control or initial treatment time points were more tubular, straighter and less rough than the ones from later treatment points. Therefore, they may be more associated to normal or non‐neoplastic crypt lumens than linked to adenomas or even cancer crypts. These preliminary outcomes could be considered an advance in 3D pit morphology characterization.
Service user experiences of care recommendations from the 2014 NICE guideline for bipolar disorder: a survey

Abstract Clinical guidelines for mental health disorders produced by the National Institute of Care Excellence (NICE) emphasise a recovery-based approach clinical care with collaborative decision-making. The aim of the study was to explore service user experience of collaborative decision-making and recovery focussed care in relation to a NICE clinical guideline for bipolar disorder four years after publication. Participants with a clinical diagnosis of bipolar disorder were recruited from adult mental health services in four specialist mental health NHS Trusts through health professional or self-referral following advertisement. An online or written survey was designed with service user input to cover 40 NICE recommendations on recovery based or collaborative care. Participants completed the survey anonymously and independent of any health professional involvement. Of 222 participants, 72 (33.5%) reported to a great extent care was delivered in line with a positive recovery message; 55 (25.5%) reported that not much or no care was recovery based. Only four items (10%) on medication or the offer of crisis services were endorsed as collaborative decision-making with a health professional by >70% service users. Most decision-making in relation to the NICE clinical guideline for bipolar disorder was not delivered collaboratively and only some care was recovery focussed.