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Prostate cancer is one of the most heritable human cancers. Genome-wide association studies have identified at least 185 prostate cancer germline risk alleles, most noncoding. We used integrative three-dimensional (3D) spatial genomics to identify the chromatin interaction targets of 45 prostate cancer risk alleles, 31 of which were associated with the transcriptional regulation of target genes in 565 localized prostate tumors. To supplement these 31, we verified transcriptional targets for 56 additional risk alleles using linear proximity and linkage disequilibrium analysis in localized prostate tumors. Some individual risk alleles influenced multiple target genes; others specifically influenced only distal genes while leaving proximal ones unaffected. Several risk alleles exhibited widespread germline-somatic interactions in transcriptional regulation, having different effects in tumors with loss of PTEN or RB1 relative to those without. These data clarify functional prostate cancer risk alleles in large linkage blocks and outline a strategy to model multidimensional transcriptional regulation.SignificanceMany prostate cancer germline risk alleles are enriched in the noncoding regions of the genome and are hypothesized to regulate transcription. We present a 3D genomics framework to unravel risk SNP function and describe the widespread germline-somatic interplay in transcription control. This article is highlighted in the In This Issue feature, p. 2711.

ObjectivesThis study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).BackgroundLQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.MethodsA retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.ResultsA total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p

Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II-associated (RNA Pol II-associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins - CTCF and cohesins - and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant PCa (mCRPC) specimens, we show that AR locus amplification contributes to the transcriptional upregulation of the AR gene by increasing the total number of chromatin interaction modules comprising the AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, ZBTB16), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes - VPS53, FAM57A, and GEMIN4. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a reversible cause of left ventricular (LV) dysfunction in infants. The LV function is expected to improve serially and return to normal by 1 year after surgical repair. The pattern of improvement in LV function has not been serially analyzed after ALCAPA repair. We report our preliminary experience with serial assessment of LV function in infants undergoing ALCAPA repair utilizing speckle tracking echocardiography.

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelialmesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/[beta]-catenin pathway, but not NF-[kappa]B and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates [beta]-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of [beta]-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3[beta], leading to the degradation of [beta]-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3[beta] and [beta]-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/[beta]-catenin pathway, and the NLRP12/STK38/GSK3[beta] signaling axis could be a promising therapeutic target for CRC., Introduction With more than 1.2 million newly diagnosed cases per year, colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death worldwide (1). [...]

Total anomalous pulmonary venous connection (TAPVC) is a critical congenital heart disease which is often missed on prenatal echocardiography because of the decreased pulmonary blood flow in fetal life. Improvement in technology has resulted in increasing prenatal diagnosis of this condition. We report a foetus with infra cardiac TAPVC in whom prenatal diagnosis was facilitated by the use of STIC technology.

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

Zinc–air batteries (ZABs) have garnered significant interest as a viable substitute for lithium-ion batteries (LIBs), primarily due to their impressive energy density and low cost. However, the efficacy of zinc–air batteries is heavily dependent on electrocatalysts, which play a vital role in enhancing reaction efficiency and stability. This scholarly review article highlights the crucial significance of electrocatalysts in zinc–air batteries and explores the rationale behind employing Fe-Co-Ni-Zn-based metal–organic framework (MOF)-derived hybrid materials as potential electrocatalysts. These MOF-derived electrocatalysts offer advantages such as abundancy, high catalytic activity, tunability, and structural stability. Various synthesis methods and characterization techniques are employed to optimize the properties of MOF-derived electrocatalysts. Such electrocatalysts exhibit excellent catalytic activity, stability, and selectivity, making them suitable for applications in ZABs. Furthermore, they demonstrate notable capabilities in the realm of ZABs, encompassing elevated energy density, efficacy, and prolonged longevity. It is imperative to continue extensively researching and developing this area to propel the advancement of ZAB technology forward and pave the way for its practical implementation across diverse fields.

Background: The aortic and pulmonary valves are both tricuspid valves. All cusps of the aortic valve can be imaged in the parasternal short-axis view but the pulmonary valve cusps are not routinely imaged during trans-thoracic echocardiography. Methods: We evaluated the feasibility of imaging all three pulmonary valve cusps in the short-axis by a modified parasternal view in 100 consecutive children below the age of 5 years. Results: A satisfactory short-axis imaging of the pulmonary valve was possible in 96 of 100 consecutive children in whom a complete echocardiogram study was performed. This detected abnormalities in the pulmonary valve in 10 children. This included bicuspid pulmonary valves, tricuspid pulmonary valves with unequal cusps, and a quadricuspid pulmonary valve. Visualization of the pulmonary valve permitted preoperative planning of pulmonary valve repair in one infant with a concomitant large ventricular septal defect. Conclusion: An adequate visualisation of the pulmonary valve leaflets by a modified parasternal view during trans-thoracic echocardiography was feasible in a vast majority of young children. The modified pulmonary short-axis view should hence be included as the part of a comprehensive pediatric echocardiographic protocol.

The investigation of using medicinal plants for the production and application of silver nanoparticles (AgNPs) has attracted growing research interest. In this study, AgNPs are synthesized from the stem barks of the Pyrus pashia medicinal plant using a biosynthetic strategy. The reaction conditions were optimized under ambient conditions, including concentration, temperature, time, and pH, and various techniques were employed, such as UV-visible, FTIR, XRD, FESEM, and TEM, to characterize the synthesized AgNPs. The AgNPs produced through this biosynthesis method were found to be spherical and polydispersed, with an average size of 23.92 ± 7.04 nm. The synthesized AgNPs demonstrated an enhanced DPPH free radical scavenging capacity compared to the aqueous extract, with IC50 values of 10.67 ± 0.05 µg/mL and 13.66 ± 0.35 µg/mL, respectively. In the agar well diffusion method, the synthesized AgNPs showed higher antibacterial activity than that of the extract against Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Salmonella typhi (ATCC 14028), and Shigella sonnei (ATCC 25931). Based on these findings, the study suggests that green synthesized AgNPs from P. pashia could be used for biomedical applications.

This paper explores English language teachers’ perception of critical pedagogy and equity promotion in lingo-cultural diverse classroom. The study concerns how the teachers find multicultural students’ problems and address them in the classroom. The study further investigates how teachers use dimensions of equity (multicultural education, social justice education and culturally responsive pedagogy) to promote social harmony, critical awareness and independent learning. In the study, I have used narrative inquiry as a research method, selected six participants purposively from public schools of Kathmandu and collected information from in-depth semi-structured interviews. I have employed multiple layers of thematic analysis, interpreted narrative data and developed six different themes: facility and access, classroom management, language and behavior, classroom activities, feedback and reinforcement and evaluation procedures. On the basis of this study, what I found that school environment, classroom activities, evaluation procedures and feedback and reinforcement are the major factors for the influence of their students’ participation. The school management has major role to facilitate and encourage teachers for the promotion of students centered methods such as project based learning and collaborative learning. Along all these aforementioned themes, teachers have prominent role to run active participatory classroom activities through student friendly activities like language games and healthy academic debate. Not only that, teachers are equally responsible to identify at-risk students and address their issues immediately to promote independent learning. Furthermore, to evaluate students’ progress, intra-personal comparative evaluation procedure is found more effective than inter-personal comparative evaluation procedures to encourage them to strive ahead with self-respect. The study expects relevant recommendations in the field of content-based child-friendly teaching learning activities where students participate actively enjoy the activities and learn from self and others.

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR.

Spatiotemporal imaging correlation (STIC) technology has been employed to visualize the fetal heart for close to two decades, but the additional value of the technology remains debatable. The value of the technology in identifying the morphology of the cardiac valves is being recognized. We report a 21-week gestational age fetus with common arterial trunk where STIC imaging enabled us to identify a bicuspid arterial valve.

Congenital JET (junctional ectopic tachycardia) is a rare and often difficult to treat tachyarrhythmia in young infants. The addition of Ivabradine to standard Congenital JET therapy has been shown to improve arrhythmia control. However, Ivabradine has not been reported as a single drug in the control of congenital JET. We report a pre-term neonate in whom Ivabradine monotherapy was successful in treating congenital JET.

The multi-inflammatory syndrome in children is a poorly understood febrile illness potentially linked to an immune response to COVID-19 infection. The disease is characterized by fever and elevated acute-phase reactants. A number of children with clinical and laboratory evidence of cardiovascular involvement have normal echocardiograms by conventional assessment. The peak left atrial longitudinal strain obtained by atrial deformation analysis could potentially be diagnostic of this condition in children who do not have abnormalities identified on conventional assessment.

Uniatrial but biventricular atrioventricular connection is a rare congenital cardiac abnormality where the left atria-ventricular connection is absent and the right atrio-ventricular connection straddles the crest of the muscular ventricular septum. This anomaly has been referred to as double outlet right atrium and the atrio-ventricular valve as a common atrioventricular valve in the past.In the absence of a primary atrial septal defect, the atrio-ventricular junction is not a common junction and the valve cannot hence be described as a common trio-ventricular valve. We demonstrate this paradox by an illustrative case and contrast this with two other cases where a common atrio-ventricular valve was predominantly committed to the right atrium.

The present study aims to look into ecological classroom practices adopted by teachers while teaching English language courses at colleges in Kathmandu, Nepal. The study specifically explains how three high school English teachers in the class felt about ecology of language teaching, how they experienced teaching, and how they provided meaning to it. Three high school English teachers’ experiences were recalled through an in-depth phenomenological interview. The results revealed that the need of classroom ecology was not emphasized. The teachers' experiences in the form of narratives, collected, transcribed, coded, thematic analyses and presented in the notion of emerging themes that English language teaching helped to explore the effective classroom ecological practices in detail. The study is expected to contribute in making EFL teaching successful in linguistic landscapes of Nepal.