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Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored CD4+ T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Babcock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Metabolic bariatric surgery (MBS) has demonstrated safety in its usage in the adolescent population and can aid in curbing the rising obesity epidemic. However, long-term data surrounding durability of MBS in this population is limited. This study aims to examine both short and long-term outcomes of MBS in adolescents, as well as identify patient characteristics and demographics that may impact operative safety and durability., Methods: The New York Statewide Planning and Research Cooperative System was utilized to identify patients 12-19 y old who underwent a bariatric procedure from 2007 to 2018. Patients were followed for the need for revisional or conversion (RC) procedures. Safety was defined by 30-d readmission, length of stay (LOS), and in-hospital complications. Durability was characterized by the incidence of RC after the initial procedure. Variables that were significantly associated with each outcome on univariable analysis were selected for in multivariable regression models., Results: 2241 adolescents underwent MBS in the study time frame; 58.46% of them underwent sleeve gastrectomy (SG). The median LOS was 1.66 ± 1.04 d. The overall in-hospital complication rate was 3.44%; 30-d readmission rate was 3.17%. Roux-en-Y Gastric Bypass (RYGB) patients were more likely to have a 30-d readmission than SG (OR = 1.75 95% CI 1.03-2.96). Factors associated with in hospital complications were preexisting hypertension (OR = 2.008 95% CI 1.141-3.535) and hypothyroidism (OR = 2.459 95% CI 1.132-5.341). Overall, the RC rate was 6.65%. RC rate following laparoscopic adjustable gastric banding (LAGB), RYGB, and SG was 27.33%, 2.08%, and 1.22%, respectively. The incidence of RC was significantly different between patients undergoing different types of bariatric surgery (P-value<0.0001), and it was significantly higher after LAGB comparing to RYGB (HR = 16.16, 95% CI: 7.56-34.51) as well as comparing to SG (HR = 9.22, 95% CI: 5.07-16.78). Insurance status, race or ethnicity, and socioeconomic disadvantage were not significantly associated with 30-d readmissions, in-hospital complications, LOS, or RC., Conclusions: Adolescent patients experience a low rate of postoperative adverse events following MBS. These procedures remain durable over time for this patient cohort. These positive results are regardless of race, ethnicity, and insurance status. This study identifies that female patients and LAGB patients are at highest risk for need for eventual RC, suggesting the need for closer postoperative follow-up for these specific patient cohorts., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: While prior literature demonstrates gender-based differences in surgical residents' self-assessments, limited data exist examining these effects at the medical student level. This study aimed to understand how self-ratings of clinical performance differ across genders for clerkship students., Methods: This was a retrospective study examining the results of an institutional Clinical Performance Examination administered at the end of the clerkship year. Students were tasked with obtaining a history and physical examination and developing an assessment and plan based on standardized patient cases. After the examination, students were asked to estimate the percentile rating of their performance. Female and male students' true scores, self-rated percentiles, and differences between true and self-rated percentiles were compared., Results: One hundred twenty three male and 113 female medical students were included in the analysis. Female medical students performed statistically significantly better overall (79.65% versus 78.23%, P = 0.0039), in history skills (76.90% versus 75.19%, P = 0.012), and in communication skills (94.05% versus 92.58%, P = 0.0085). No statistically significant differences were seen between self-rated percentiles between male and female students. However, when comparing the difference between self-rated and true percentile scores (Δ = self-rated - true percentile), male students were more likely to rate themselves higher than their true percentile on history (male students Δ = 12.26 versus female students Δ = -1.24, P = 0.00076) and communication metrics (male students Δ = 14.12 versus female students Δ = 6.05, P = 0.037)., Conclusions: Despite higher performance, female students rate themselves similarly to male medical students, suggesting a pattern of underestimation. Faculty must recognize that gender-based differences in self-evaluations begin at the medical student level, potentially impacting future trainee development., (Published by Elsevier Inc.)

Background: The severe respiratory manifestations observed in severe coronavirus disease 2019 (COVID-19) cases are often associated with an excessive inflammatory response. Dexamethasone, a synthetic glucocorticoid, exerts its anti-inflammatory effects by inhibiting the transcription of pro-inflammatory genes and suppressing the activity of various immune cells. This mechanism has implications for mitigating the cytokine storm observed in severe COVID-19 cases. Early on in the pandemic, the Recovery Collaborative working group showed a mortality benefit of using dexamethasone in decreasing mortality in patients with COVID-19 requiring respiratory support. However, the optimal dosage of corticosteroids remains debatable. Several studies that compare different doses of dexamethasone in COVID-19 exist, but the results are conflicting., Aim: To review the latest evidence regarding dosage, safety, and efficacy of dexamethasone in severe COVID-19., Methods: We followed preferred reporting items for systematic reviews and meta-analysis guidelines. A detailed literature search was conducted across PubMed, Google Scholar, and Medline to include publications up to March 2024. Our keywords included "COVID-19" "SARS-CoV-2" "dexamethasone" "corticosteroid" "steroid" and "glucocorticoid"-along with their combinations. We employed the Cochrane Risk of Bias Tool and the Newcastle-Ottawa scale to evaluate the integrity and potential of bias in the included studies. A meta-analysis was conducted using a random-effects model, assessing pooled odds ratios and mean differences, with heterogeneity gauged by the I 2 statistic and the χ 2 tests., Results: No statistical differences were found in 28-day all-cause mortality [pooled odds ratio (OR) = 1.109, 95%CI: 0.918-1.340], 60-day all-cause mortality (OR = 0.873, 95%CI: 0.744-1.024; I 2 = 47.29%), mean length of hospital stay (mean difference = -0.08 days, 95%CI: -0.001 to 0.161) and adverse events (OR = 0.877, 95%CI: 0.707-1.087)., Conclusion: Differing doses of corticosteroids have no clinical implications on mortality, mean length of hospital stay, and adverse events in COVID-19 patients. Additional research is required in patients requiring invasive or non-invasive ventilation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Occult nodal disease (OND) during clinically-N0 salvage total laryngectomy (TL) can be detected with the Neck-Imaging-Reporting-and-Data-Systems (NI-RADS). However, some patients will still have OND revealed on final pathology., Methods: A retrospective study on all patients who had OND during salvage TL with elective neck dissection (END) between 2009 and 2021 was performed. Repeat CT and PET scan interpretation was performed to evaluate their preoperative imaging for suspicious features., Results: Among 81 salvage TL patients undergoing END, 12 (16%) had OND and a total of 26 occult nodes were identified. On pathology, the average node length [SD] was 0.6 cm [0.3]. On CT, 31% (8 of 26) had rounded morphology. On PET, most had SUV max below blood pool. One patient scored NI-RADS 2; the rest scored 1., Conclusions: On re-review of preoperative imaging, occult nodes were subtle and challenging to identify. Despite no clear impact on survival, performing an END may provide prognostic information., (© 2024 Wiley Periodicals LLC.)

Background & Aims: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC., Methods: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility., Results: TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy., Conclusions: This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Abstract: Various pathologies could lead to occult gastrointestinal (GI) bleeding. Here we report the case of a 73-year-old woman who presented with hematochezia and syncope, and was found to have a large bleeding GI stromal tumor incidentally from 99m Tc-RBC scintigraphy. This study was done after negative workup with CT angiography, colonoscopy, and capsule endoscopy for the source of GI bleeding. Final pathology confirmed the mass being a low-grade GI stromal tumor after exploratory laparotomy., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Postoperative constipation after bariatric surgery is a common complaint, decreasing patient quality of life. No literature exists examining the efficacy of a preoperative bowel regimen in reducing postoperative constipation in this cohort. This study aims explore the efficacy of a well-established bowel regimen, polyethylene glycol (PEG), in reducing constipation frequency and severity after bariatric surgery., Methods: This was a retrospective study of adult patients undergoing primary and revisional bariatric procedures. The use of PEG bowel prep for bariatric patients was introduced as an institutional quality improvement measure. Patients during the first 3 months after PEG implementation were surveyed for postoperative constipation. For the year after implementation, patients were followed for 30-day emergency room visits or hospitalization secondary to constipation. This cohort was compared to historical controls from the previous year. Student t-tests were used for statistical analysis., Results: During the 3-month exploratory phase, 28/49 (57.14%) patients fully completed the bowel regimen. In total, 0/56 (0%) patients reported preoperative constipation, and 5/28 (17.9%) patients reported constipation at the 3-week follow-up. In the 1 year post-implementation cohort, 2/234 (0.85%) patients had constipation-related occurrences at 30-day follow-up, compared to 8/219 patients (3.65%) in the historical cohort (p = 0.04)., Conclusions: The implementation of a PEG-based bowel regimen did not eliminate self-reported constipation. However, there were significant differences in rates of constipation-related ED visits and hospital readmissions, suggesting that the bowel regimen decreases rates of severe constipation. Finally, patient compliance was limited. Future work should aim towards increasing compliance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Preliminary evidence demonstrates female surgeons have improved post-operative outcomes compared to male colleagues despite underrepresentation in surgery. This study explores the effect of patient-surgeon gender discordance on outcomes in three specialties with high female patient populations: bariatric, foregut, colorectal., Methods: This is a retrospective study using the New York State (NYS) SPARCS database and first study evaluating outcomes based on surgeon/patient concordance in NYS. Bariatric, foregut, and colorectal surgery cases from 2013 to 2017 were identified., Results: Bariatric: female patients (FP) with CC had lower 30-day readmissions but higher complications compared with DC. Male patients (MP) with CC trended towards higher 30-day readmissions but lower complications compared with DC. FP received significantly better influence from CC in 30-day readmission, but disadvantages in complications. There was no significant difference in LOS or ED visits between CC and DC groups for either FP or MP. Foregut: FP with CC had lower LOS, 30-day readmissions, and 30-day ED visits compared with DC. MP showed opposite trends between CC and DC, although non-significant. The benefit from concordance was pronounced in FP compared to MP in LOS, 30-day readmissions, and 30-day ED visit. Concordance vs discordance did not significantly affect complications within either FP or MP group. Colorectal: the difference between CC and DC was not significant within FP or MP groups in any outcomes. When comparing the difference of 30-day readmissions in CC vs DC between FP and MP, there is a significant difference., Conclusion(s): Overall, our results show DC between patient and surgeon has significant effect on patient outcomes. A negative effect is seen for female patients in certain specialties, most pronounced in foregut surgery. This emphasizes need for surgeons to be conscious of care provided to opposite gender patients and underscores increasing female surgeons in high FP fields., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes., (© 2024. The Author(s).)

Introduction: Determining the need for surgical management of blunt bowel and mesenteric injury (BBMI) remains a clinical challenge. The Faget score and Bowel Injury Prediction Score (BIPS) have been suggested to address this issue. Their efficacy in determining the need for surgery was examined., Methods: A retrospective review of all adult blunt trauma patients hospitalized at a level 1 trauma center between January 2009 and August 2019 who had small bowel, colon, and/or mesenteric injury was conducted. We further analyzed those who underwent preoperative computed tomography (CT) scanning at our institution. Final index CT reports were retrospectively reviewed to calculate the Faget and BIPS CT scores. All images were also independently reviewed by an attending radiologist to determine the BIPS CT score., Results: During the study period, 14,897 blunt trauma patients were hospitalized, of which 91 had BBMI. Of these, 62 met inclusion criteria. Among patients previously identified as having BBMI in the registry, the retrospectively applied Faget score had a sensitivity of 39.1%, specificity of 81.2%, positive predictive value (PPV) of 85.7%, and negative predictive value (NPV) of 31.7% in identifying patients with operative BBMI. The retrospectively applied BIPS score had a sensitivity of 47.8%, specificity of 87.5%, PPV of 91.7%, and NPV of 36.8% in this cohort. When CT images were reviewed by an attending radiologist using the BIPS criteria, sensitivity was 56.5%, specificity 93.7%, PPV 96.3%, and NPV 42.8%., Conclusions: Existing BBMI scoring systems had limited sensitivity but excellent PPV in predicting the need for operative intervention for BBMI. Attending radiologist review of CT images using the BIPS scoring system demonstrated improved accuracy as opposed to retrospective application of the BIPS score to radiology reports., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: The spatial anatomy of hematopoiesis in the bone marrow (BM) has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized BM core biopsy tissue specimens, providing a rich resource for studying the intact human BM topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence-based digital whole slide image analysis and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of foci with increased lymphocytes, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human BM states using intact archival tissue specimens., (© 2023 by The American Society of Hematology.)

Objective: This study aims to explore how timing of interval of cholecystectomy (IC) after percutaneous transhepatic cholecystostomy tube (PTC) placement impacts post-operative outcomes., Methods: A retrospective database analysis of New York State SPARCs database of IC between 2005 and 2015. The timing for IC ranged between > 1 week and < 2 years. Patients undergoing this procedure were further divided into quartiles using 4-time intervals; 1-5 weeks (Q1), 5-8 weeks (Q2), 8-12 weeks(Q3), and > 12 weeks(Q4). The study's primary outcome was hospital length of stay (LOS). Secondary outcomes included discharge status, 30-day readmission, 30-day ED visit, and 90-day reoperation, surgery type, complication, and bile duct injury. Multivariable regression models were used to compare patients across the four-time intervals after adjusting for confounding factors., Results: A total of 1038 patients with a history of PTC followed by IC between > 1 week and < 2 years were included in the final analysis. The median time to IC was 7.7 weeks. Q2 and Q3 both had a significantly higher median LOS of 3 days versus Q1 and Q4 at median of 5 days (p < 0.0001). Patients from racial and ethnic minorities (e.g., African Americans and Hispanics) were more likely to get their IC after 12 weeks (p < 0.05). Further, Black patients had a significantly higher median LOS than White, non-Hispanic patients (8 days vs 4 days, p < 0.0001) and were more likely to have open procedure. Multivariable regression analysis identified shorter LOS during Q2 (Ratio, 0.76, 95%, 0.67-0.87, p < 0.0001), and Q3 (Ratio 0.75, 95% CI, 065-0.86, p < 0.0001) compared to those who got their IC in Q4. Similar findings exist when comparing Q2 and Q3 to those receiving treatment during Q1., Conclusion: A time interval of 5-12 weeks between PTC and IC was associated with a decreased LOS. This study also suggests the persistence of racial disparities among these patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk., Methods: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR., Results: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004)., Conclusion: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Gastroesophageal reflux disease (GERD) is a possible side effect of sleeve gastrectomy (SG). However, procedure selection for patients with GERD and risk factors for morbidity after bypass surgeries is complex. For patients with a preoperative GERD diagnosis, literature related to worsening postoperative symptoms is discordant., Objective: This study evaluated the effects of SG on patients with pre-operative GERD confirmed through pH testing., Setting: University Hospital, United States., Methods: This was a single-center case-series. SG patients with preoperative pH testing were compared based on DeMeester scoring. Preoperative demographics, endoscopy results, need for conversion surgery, and changes in gastrointestinal quality of life (GIQLI) scores were compared. Two-sample independent t-tests assuming unequal variances were used for statistical analysis., Results: Twenty SG patients had preoperative pH testing. Nine patients were GERD positive; median DeMeester score 26.7 (22.1-31.15). Eleven patients were GERD negative, with a median DeMeester score of 9.0 (4.5-13.1). The two groups had similar median BMI, preoperative endoscopic findings and use of GERD medications. Concurrent hiatal hernia repair was performed in 22% of GERD positive vs. 36% of GERD negative patients, (p = 0.512). Two patients in the GERD positive cohort required conversion to gastric bypass (22%), while none in the GERD negative cohort did. No significant postoperative differences were noted in GIQLI, heartburn, or regurgitation symptoms., Conclusion: Objective pH testing may allow the differentiation of patients who would be higher risk for need for conversion to gastric bypass. For patients with mild symptoms, but negative pH testing, SG may represent a durable option., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although numerous putative oncogenes have been associated with the etiology of head and neck squamous cell carcinoma (HNSCC), the mechanisms by which these oncogenes and their downstream targets mediate tumor progression have not been fully elucidated. We performed an integrative analysis to identify a crucial set of targets of the oncogenic transcription factor p63 that are common across multiple transcriptomic datasets obtained from HNSCC patients, and representative cell line models. Notably, our analysis revealed FST which encodes follistatin, a secreted glycoprotein that inhibits the transforming growth factor TGFβ/activin signaling pathways, to be a direct transcriptional target of p63. In addition, we found that FST expression is also driven by epidermal growth factor receptor EGFR signaling, thus mediating a functional link between the TGF-β and EGFR pathways. We show through loss- and gain-of-function studies that FST predominantly imparts a tumor-growth and migratory phenotype in HNSCC cells. Furthermore, analysis of single-cell RNA sequencing data from HNSCC patients unveiled cancer cells as the dominant source of FST within the tumor microenvironment and exposed a correlation between the expression of FST and its regulators with immune infiltrates. We propose FST as a prognostic biomarker for patient survival and a compelling candidate mediating the broad effects of p63 on the tumor and its associated microenvironment., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)

Study Design: Systematic Review., Objectives: To synthesize previous studies evaluating racial disparities in spine surgery., Methods: We queried PubMed, Embase, Cochrane Library, and Web of Science for literature on racial disparities in spine surgery. Our review was constructed in accordance with Preferred Reporting Items and Meta-analyses guidelines and protocol. The main outcome measures were the occurrence of racial disparities in postoperative outcomes, mortality, surgical management, readmissions, and length of stay., Results: A total of 1753 publications were assessed. Twenty-two articles met inclusion criteria. Seventeen studies compared Whites (Ws) and African Americans (AAs) groups; 14 studies reported adverse outcomes for AAs. When compared with Ws, AA patients had higher odds of postoperative complications including mortality, cerebrospinal fluid leak, nervous system complications, bleeding, infection, in-hospital complications, adverse discharge disposition, and delay in diagnosis. Further, AAs were found to have increased odds of readmission and longer length of stay. Finally, AAs were found to have higher odds of nonoperative treatment for spinal cord injury, were more likely to undergo posterior approach in the treatment of cervical spondylotic myelopathy, and were less likely to receive cervical disk arthroplasty compared with Ws for similar indications., Conclusions: This systematic review of spine literature found that when compared with W patients, AA patients had worse health outcomes. Further investigation of root causes of these racial disparities in spine surgery is warranted., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiomyocyte differentiation continues throughout murine gestation and into the postnatal period, driven by temporally regulated expression changes in the transcriptome. The mechanisms that regulate these developmental changes remain incompletely defined. Here, we used cardiomyocyte-specific ChIP-seq of the activate enhancer marker P300 to identify 54,920 cardiomyocyte enhancers at seven stages of murine heart development. These data were matched to cardiomyocyte gene expression profiles at the same stages and to Hi-C and H3K27ac HiChIP chromatin conformation data at fetal, neonatal, and adult stages. Regions with dynamic P300 occupancy exhibited developmentally regulated enhancer activity, as measured by massively parallel reporter assays in cardiomyocytes in vivo, and identified key transcription factor-binding motifs. These dynamic enhancers interacted with temporal changes of the 3D genome architecture to specify developmentally regulated cardiomyocyte gene expressions. Our work provides a 3D genome-mediated enhancer activity landscape of murine cardiomyocyte development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC)., Purpose: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization., Materials and Methods: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs., Results: N = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively., Conclusion: In patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes., Clinical Trial Number: NCT04172714., (© 2023. The Author(s).)

The discovery of meningeal lymphatic vessels that drain the CNS has prompted new insights into how immune responses develop in the brain. In this study, we examined how T cell responses against CNS-derived antigen develop in the context of infection. We found that meningeal lymphatic drainage promotes CD4 + and CD8 + T cell responses against the neurotropic parasite Toxoplasma gondii in mice, and we observed changes in the dendritic cell compartment of the dural meninges that may support this process. Indeed, we found that mice chronically, but not acutely, infected with T. gondii exhibited a significant expansion and activation of type 1 and type 2 conventional dendritic cells (cDC) in the dural meninges. cDC1s and cDC2s were both capable of sampling cerebrospinal fluid (CSF)-derived protein and were found to harbor processed CSF-derived protein in the draining deep cervical lymph nodes. Disrupting meningeal lymphatic drainage via ligation surgery led to a reduction in CD103 + cDC1 and cDC2 number in the deep cervical lymph nodes and caused an impairment in cDC1 and cDC2 maturation. Concomitantly, lymphatic vessel ligation impaired CD4 + and CD8 + T cell activation, proliferation, and IFN-γ production at this site. Surprisingly, however, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to concurrent activation of T cells at non-CNS-draining sites during chronic infection. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses against T. gondii but remains dispensable for immune protection of the brain., Competing Interests: MK, MC, IB, LS, KS, SB, SL, IS, TH No competing interests declared, (© 2022, Kovacs et al.)

Purpose: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 ( 90 Y) (scout 90 Y) microspheres with those of technetium-99m macroaggregated albumin (MAA) in predicting the therapeutic 90 Y (Rx 90 Y) dose for patients with hepatocellular carcinoma (HCC)., Materials and Methods: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout 90 Y. Rx 90 Y activity was administered 3 days after mapping. Using paired t test and Pearson correlation, the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), predicted mean tumor dose (TD), and nontumoral liver dose (NTLD) by MAA and scout 90 Y were compared with those by Rx 90 Y. Bland-Altman plots compared the level of agreement between the TNR and LSF of scout 90 Y and MAA with that of Rx 90 Y. The safety of scout 90 Y was evaluated by examining the discrepancy in extrahepatic activity between MAA and scout 90 Y., Results: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx 90 Y. Scout 90 Y had a moderate LSF, strong TNR, strong TD, and very strong NTLD in correlation with those of Rx 90 Y. Furthermore, the TNR and LSF of scout 90 Y had a stronger agreement with those of Rx 90 Y than with those of MAA. In the nonsegmental subgroup, MAA had no significant correlation with the TD and NTLD of Rx 90 Y, whereas scout 90 Y had a very strong correlation with both of these factors. In the segmental subgroup, both MAA and scout 90 Y had a strong linear correlation with the TD and NTLD of Rx 90 Y., Conclusions: Compared with MAA, scout 90 Y is a more accurate surrogate for Rx 90 Y biodistribution for nonsegmental therapies., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Background: The pioneer transcription factor (TF) GATA4 (GATA Binding Protein 4) is expressed in multiple cardiovascular lineages and is essential for heart development. GATA4 lineage-specific occupancy in the developing heart underlies its lineage specific activities. Here, we characterized GATA4 chromatin occupancy in cardiomyocyte and endocardial lineages, dissected mechanisms that control lineage specific occupancy, and analyzed GATA4 regulation of endocardial gene expression., Methods: We mapped GATA4 chromatin occupancy in cardiomyocyte and endocardial cells of embryonic day 12.5 (E12.5) mouse heart using lineage specific, Cre-activated biotinylation of GATA4. Regulation of GATA4 pioneering activity was studied in cell lines stably overexpressing GATA4. GATA4 regulation of endocardial gene expression was analyzed using single cell RNA sequencing and luciferase reporter assays., Results: Cardiomyocyte-selective and endothelial-selective GATA4 occupied genomic regions had features of lineage specific enhancers. Footprints within cardiomyocyte- and endothelial-selective GATA4 regions were enriched for NKX2-5 (NK2 homeobox 5) and ETS1 (ETS Proto-Oncogene 1) motifs, respectively, and both of these TFs interacted with GATA4 in co-immunoprecipitation assays. In stable NIH3T3 cell lines expressing GATA4 with or without NKX2-5 or ETS1, the partner TFs re-directed GATA4 pioneer binding and augmented its ability to open previously inaccessible regions, with ETS1 displaying greater potency as a pioneer partner than NKX2-5. Single-cell RNA sequencing of embryonic hearts with endothelial cell-specific Gata4 inactivation identified Gata4 -regulated endocardial genes, which were adjacent to GATA4-bound, endothelial regions enriched for both GATA4 and ETS1 motifs. In reporter assays, GATA4 and ETS1 cooperatively stimulated endothelial cell enhancer activity., Conclusions: Lineage selective non-pioneer TFs NKX2-5 and ETS1 guide the activity of pioneer TF GATA4 to bind and open chromatin and create active enhancers and mechanistically link ETS1 interaction to GATA4 regulation of endocardial development.

Purpose: The primary objective of the REMEMBR Y90 study is to evaluate the efficacy of Yttrium-90 (Y90) radioembolization in patients with breast cancer metastases to the liver as a 2nd or 3rd line treatment option with systemic therapy by assessing liver-specific and overall progression-free survival. Secondary objectives include quality of life, overall survival benefit, and toxicity in relation to patients' tumor biology., Materials and Methods: This trial is a multi-center, prospective, Phase 2, open-label, IRB-approved, randomized control trial in the final phases of activation. Eligible patients include those over 18 years of age with metastatic breast cancer to the liver with liver-only or liver-dominant disease, and history of tumor progression on 1-2 lines of chemotherapy. 60 patients will be randomized to radioembolization with chemotherapy versus chemotherapy alone. Permissible regimens include capecitabine, eribulin, vinorelbine, and gemcitabine within 2 weeks of enrollment for every patient. Patients receiving radioembolization will receive lobar or segmental treatment within 1-6 weeks of enrollment depending on their lesion. After final radioembolization, patients will receive clinical and imaging follow-up every 12-16 weeks for two years, including contrast-enhanced computed tomography or magnetic resonance imaging of the abdomen and whole-body positron emission tomography/computed tomography., Discussion: This study seeks to elucidate the clinical benefit and toxicity of Y90 in patients with metastatic breast cancer to the liver who are receiving minimal chemotherapy. Given previous data, it is anticipated that the use of Y90 and chemotherapy earlier in the metastatic disease course would improve survival outcomes and reduce toxicity., Level of Evidence: Level 1b, Randomized Controlled Trial., Trial Registration Number: NCT05315687 on clinicaltrials.gov., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that establishes a life-long chronic infection largely restricted to the central nervous system (CNS). Constant immune pressure, notably IFN-γ-STAT1 signaling, is required for preventing fatal pathology during T. gondii infection. Here, we report that abrogation of STAT1 signaling in microglia, the resident immune cells of the CNS, is sufficient to induce a loss of parasite control in the CNS and susceptibility to toxoplasmic encephalitis during the early stages of chronic infection. Using a microglia-specific genetic labeling and targeting system that discriminates microglia from blood-derived myeloid cells that infiltrate the brain during infection, we find that, contrary to previous in vitro reports, microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostatic to "disease-associated microglia" (DAM) phenotype conserved across several neuroinflammatory models, including T. gondii infection, and (ii) the expression of anti-parasitic cytosolic molecules that are required for eliminating T. gondii in a cell-intrinsic manner. Further, genetic deletion of Stat1 from microglia during T. gondii challenge leads to fatal pathology despite largely equivalent or enhanced immune effector functions displayed by brain-infiltrating immune populations. Finally, we show that microglial STAT1-deficiency results in the overrepresentation of the highly replicative, lytic tachyzoite form of T. gondii, relative to its quiescent, semi-dormant bradyzoite form typical of chronic CNS infection. Our data suggest an overall protective role of CNS-resident microglia against T. gondii infection, illuminating (i) general mechanisms of CNS-specific immunity to infection (ii) and a clear role for IFN-STAT1 signaling in regulating a microglial activation phenotype observed across diverse neuroinflammatory disease states., Competing Interests: The authors have declared that no competing interests exist.

Objectives: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients., Methods: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging., Results: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients., Conclusions: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE., Competing Interests: Conflicts of interest and sources of funding: N.B.D. reports a grant from Boston Scientific, consulting fees from Boston Scientific, and honoraria from MedLearning. L.B. reports a grant from AAA Novartis, and participation on an advisory board for AAA Novartis. R.K.J.B. reports participation on an advisory board for Covera Health. E.C.G. reports consulting fees from Advanced Accelerator Applications. R.F.H. reports funding from National Institutes of Health/National Cancer Institute, and a leadership role as Chairman of the Radiopharmaceutical Therapy Subcommittee of the American Association of Physicists in Medicine. T.A.H. reports grants or contracts from Philips and Clovis Oncology, consulting fees from Curium and ITM, and participation on advisory boards for Ipsen and Blue Earth Diagnostics. D.A.P. reports grants from Siemens, Nordic Nanovector, Progenics, and 511 Pharma, and consulting fees from Siemens, 511 Pharma, Progenics, Actinium, and Ipsen. B.S.-B. reports a grant from Blue Earth Diagnostics, honoraria from PETNET and Blue Earth Diagnostics, and a leadership role as Society of Nuclear Medicine and Molecular Imaging (SNMMI) co-chair of outreach committee secretary of American College of Nuclear Medicine, Central Chapter SNMMI, and Academic Council SNMMI. R.M.S. reports a grant from Endocyte Inc. For the remaining authors, none were declared., (Copyright © 2022 Clinical Nuclear Medicine and American Journal of Clinical Oncology.)

Objectives: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients., Methods: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging., Results: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients., Conclusions: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE., Competing Interests: Conflicts of interest and sources of funding: N.B.D. reports a grant from Boston Scientific, consulting fees from Boston Scientific, and honoraria from MedLearning. L.B. reports a grant from AAA Novartis, and participation on an advisory board for AAA Novartis. R.K.J.B. reports participation on an advisory board for Covera Health. E.C.G. reports consulting fees from Advanced Accelerator Applications. R.F.H. reports funding from National Institutes of Health/National Cancer Institute, and a leadership role as Chairman of the Radiopharmaceutical Therapy Subcommittee of the American Association of Physicists in Medicine. T.A.H. reports grants or contracts from Philips and Clovis Oncology, consulting fees from Curium and ITM, and participation on advisory boards for Ipsen and Blue Earth Diagnostics. D.A.P. reports grants from Siemens, Nordic Nanovector, Progenics, and 511 Pharma, and consulting fees from Siemens, 511 Pharma, Progenics, Actinium, and Ipsen. B.S.-B. reports a grant from Blue Earth Diagnostics, honoraria from PETNET and Blue Earth Diagnostics, and a leadership role as Society of Nuclear Medicine and Molecular Imaging (SNMMI) co-chair of outreach committee secretary of American College of Nuclear Medicine, Central Chapter SNMMI, and Academic Council SNMMI. R.M.S. reports a grant from Endocyte Inc. For the remaining authors, none were declared., (Copyright © 2022 Clinical Nuclear Medicine and American Journal of Clinical Oncology.)

Bioinformatics is an amalgamation of biology, mathematics and computer science. It is a science which gathers the information from biology in terms of molecules and applies the informatic techniques to the gathered information for understanding and organizing the data in a useful manner. With the help of bioinformatics, the experimental data generated is stored in several databases available online like nucleotide database, protein databases, GENBANK and others. The data stored in these databases is used as reference for experimental evaluation and validation. Till now several online tools have been developed to analyze the genomic, transcriptomic, proteomics, epigenomics and metabolomics data. Some of them include Human Splicing Finder (HSF), Exonic Splicing Enhancer Mutation taster, and others. A number of SNPs are observed in the non-coding, intronic regions and play a role in the regulation of genes, which may or may not directly impose an effect on the protein expression. Many mutations are thought to influence the splicing mechanism by affecting the existing splice sites or creating a new sites. To predict the effect of mutation (SNP) on splicing mechanism/signal, HSF was developed. Thus, the tool is helpful in predicting the effect of mutations on splicing signals and can provide data even for better understanding of the intronic mutations that can be further validated experimentally. Additionally, rapid advancement in proteomics have steered researchers to organize the study of protein structure, function, relationships, and dynamics in space and time. Thus the effective integration of all of these technological interventions will eventually lead to steering up of next-generation systems biology, which will provide valuable biological insights in the field of research, diagnostic, therapeutic and development of personalized medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bhat, Sethi, Rah, Kumar and Afroze.)

A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC., Implications: This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors., (©2022 American Association for Cancer Research.)

Background: Accurate identification and discrimination of post treatment changes from recurrent disease remains a challenge for patients with intracranial malignancies despite advances in molecular and magnetic resonance imaging. We have explored the ability of readily available Rubidium-82 chloride ( 82 RbCl) positron emission tomography (PET) to identify and distinguish progressive intracranial disease from radiation necrosis in patients previously treated with radiation therapy., Methods: Six patients with a total of 9 lesions of either primary (N.=3) or metastatic (N.=6) intracranial malignancies previously treated with stereotactic radiation surgery (SRS) and persistent contrast enhancement on MRI underwent brain 82 RbCl PET imaging. Two patients with arteriovenous malformations previously treated with SRS, also had brain 82 RbCl PET imaging for a total of 11 lesions studied. Histological confirmation via stereotactic biopsy/excisional resection was obtained for 9 lesions with the remaining 2 classified as either recurrent tumor or radiation necrosis based on subsequent MRI examinations. 82 RbCl PET time activity curve analysis was performed which comprised lesion SUVmax, contralateral normal brain SUVmax, and tumor to background ratios (TBmax)., Results: 82 RbCl demonstrates uptake greater than normal brain parenchyma in all lesions studied. Time activity curves demonstrated progressive uptake of 82 RbCl in all lesions without evidence of washout. While recurrent disease demonstrated a greater mean SUVmax compared to radiation necrosis, no statistically significant difference between lesion SUVmax nor TBmax was found (P>0.05)., Conclusions: 82 RbCl PET produces high-contrast uptake of both recurrent disease and radiation necrosis compared to normal brain. However, no statistically significant difference was found between recurrent tumor and radiation necrosis.

Microglia, the resident immune cells of the central nervous system (CNS), are poised to respond to neuropathology. Microglia play multiple roles in maintaining homeostasis and promoting inflammation in numerous disease states. The study of microglial innate immune programs has largely focused on exploring neurodegenerative disease states with the use of genetic targeting approaches. Our understanding of how microglia participate in immune responses against pathogens is just beginning to take shape. Here, we review existing animal models of CNS infection, with a focus on how microglial physiology and inflammatory processes control protozoan and viral infections of the brain. We further discuss how microglial participation in over-exuberant immune responses can drive immunopathology that is detrimental to CNS health and homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Study Design: Systematic review., Objectives: Synthesize previous studies evaluating clinical utility of preoperative Hb/Hct and HbA1c in patients undergoing common spinal procedures: anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), posterior lumbar fusion (PLF), and lumbar decompression (LD)., Methods: We queried PubMed, Embase, Cochrane Library, and Web of Science for literature on preoperative Hb/Hct and HbA1c and post-operative outcomes in adult patients undergoing ACDF, PCF, PLF, or LD surgeries., Results: Total of 4,307 publications were assessed. Twenty-one articles met inclusion criteria., Pcf and Acdf: Decreased preoperative Hb/Hct were significant predictors of increased postoperative morbidity, including return to operating room, pulmonary complications, transfusions, and increased length of stay (LOS). For increased HbA1c, there was significant increase in risk of postoperative infection and cost of hospital stay., Plf: Decreased Hb/Hct was reported to be associated with increased risk of postoperative cardiac events, blood transfusion, and increased LOS. Elevated HbA1c was associated with increased risk of infection as well as higher visual analogue scores (VAS) and Oswestry disability index (ODI) scores., Ld: LOS and total episode of care cost were increased in patients with preoperative HbA1c elevation., Conclusion: In adult patients undergoing spine surgery, preoperative Hb/Hct are clinically useful predictors for postoperative complications, transfusion rates, and LOS, and HbA1c is predictive for postoperative infection and functional outcomes. Using Hct values <35-38% and HbA1c >6.5%-6.9% for identifying patients at higher risk of postoperative complications is most supported by the literature. We recommend obtaining these labs as part of routine pre-operative risk stratification., Level of Evidence: III.

Abstract: Von Hippel-Lindau (VHL) is a rare predominantly hereditary syndrome characterized by multiple benign and malignant tumors that can affect different organ systems. We present representative images of a 68Ga-DOTATATE PET/CT in a patient with confirmed VHL gene mutation, which demonstrates a constellation of findings commonly seen in these patients in one single imaging modality., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To Evaluate the correlation between tumor dosimetric parameters with objective tumor response (OR) and overall survival (OS) in patients with surgically unresectable colorectal liver metastasis (CRLM) undergoing resin-based Ytrrium-90 selective internal radiation therapy (Y90 SIRT)., Materials and Methods: 45 consecutive patients with CRLM underwent resin-based Y90 SIRT in one or both hepatic lobes (66 treated lobes total). Dose volume histograms were created with MIM Sureplan ® v.6.9 using post-treatment SPECT/CT. Dosimetry analyses were based on the cumulative volume of the five largest tumors in each treatment session and non-tumoral liver (NTL) dose. Receiver operating characteristic (ROC) curve was used to evaluate tumor dosimetric factors in predicting OR by Response Evaluation Criteria for Solid Tumors at 3 months post-Y90. Additionally, ROC curve was used to evaluate non-tumoral liver dose as a predictor of grade ≥ 3 liver toxicity and radioembolization induced liver disease (REILD) 3 months post Y90. To minimize for potential confounding demographic and clinical factors, univariate and multivariate analysis of survival with mean tumor dose as one of the factors were also performed. Kaplan-Meier estimation was used for OS analysis from initial Y90 SIRT., Results: 26 out of 45 patients had OR with a median OS of 17.2 months versus 6.8 months for patients without OR ( p < 0.001). Mean tumor dose (TD) of the five largest tumors was the strongest predictor of OR with an area under the curve of 0.73 ( p < 0.001). Minimum TD, and TD to 30%, 50%, and 70% of tumor volume also predicted OR ( p 's < 0.05). Mean TD ≥ 100 Gy predicted a significantly prolonged median OS of 19 vs. 11 months for those receiving TD < 100 Gy ( p = 0.016). On univariate analysis, mean TD < 100 Gy, presence of any genomic mutation, presence of MAPK pathway mutation, bilobar hepatic metastases and diffuse metastatic disease (>10 lesions per liver lobe) were found to be predictors of shorter median OS. On multivariate analysis, mean TD < 100 Gy, presence of any genomic mutation, and diffuse hepatic metastatic disease were found to be independent predictors of shorter OS. Overall, six (13.3%) patients developed grade ≥ 3 liver toxicity post Y90 of whom two (4.4%) patients developed REILD. No dose threshold predicting grade ≥ 3 liver toxicity or REILD was identified., Conclusions: Mean TD ≥ 100 Gy in patients with unresectable CRLM undergoing resin-based Y90 SIRT predicts OR and prolonged OS.

Purpose: To evaluate the relationship between Yttrium-90 (Y90) tumour dose and response rate in patients with hepatocellular carcinoma (HCC) who undergo Y90 radiation segmentectomy (Y90-RS) and to determine implication on overall survival (OS)., Materials and Methods: Post Y90-RS Bremsstrahlung single-photon emission computed tomography/CT of 105 HCC patients with 110 treatments performed with glass microspheres was retrospectively analysed. The dose-volume histogram of the targeted tumour was determined with commercially available dosimetry software. Tumour response at 3 months was evaluated using modified Response Evaluation Criteria in Solid Tumours. Tumour dose thresholds associated with the objective response with 80% specificity were then used to evaluate implication on OS using Kaplan-Meier estimation and log-rank analysis., Results: Tumour dose thresholds to predict objective response with 80% specificity were the following: maximum tumour dose (748 Gy), mean tumour dose (568 Gy), minimum tumour dose of 30% tumour volume (608 Gy), minimum tumour dose of 50% tumour volume (565 Gy), minimum tumour dose of 70% tumour volume (464 Gy) and minimum tumour dose of 100% tumour volume (213 Gy). These parameters all significantly predicted tumour response with areas under the ROC curve of >0.6. Mean tumour dose of ≥250 Gy predicted median OS of 43.67 vs. 17.87 months for others (P = 0.026). Minimum dose ≥180 Gy to 100% of tumour volume predicted median OS of 44.93 vs. 35.87 months for others (P = 0.043)., Conclusion: In patients with HCC undergoing Y90-RS, mean tumour dose ≥250 Gy and minimum tumour dose of ≥180 Gy to 100% of tumour volume are both significantly correlated with higher objective tumour response and prolonged survival., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To compare the efficacies of glass and resin-based Yttrium-90 microspheres by comparing absorbed tumor dose (TD) with both tumor response (TR) and overall survival (OS) in patients with chemorefractory intrahepatic cholangiocarcinoma (ICC)., Methods: Post-Y90 treatment bremsstrahlung SPECT/CT of 38 consecutive patients receiving 45 treatments (21 resin microspheres, 24 glass microspheres) were analyzed retrospectively. MIM software v6.9.4 (MIM Software Inc, Cleveland, OH) was used to calculate targeted tumors' dose volume histogram. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response 3 months post-treatment. Kaplan Meier estimation was used for survival analysis. T-test was used to compare the devices on various dosimetric parameters., Results: Thresholds for TD to predict TR with ≥ 80% specificity were as follows: mean TD (Resin: 78.9 Gy; Glass: 254.7 Gy), maximum TD (Resin: 162.9 Gy; Glass: 591 Gy), minimum TD (Resin: 53.7 Gy; Glass: 149.1 Gy). Microsphere type had no effect on survival from first Y90 (Resin: 11.2 mo; Glass 10.9 mo [p = 0.548]). In patients receiving resin microspheres, mean TD ≥ 75 Gy or maximum TD ≥ 150 Gy was associated with median OS of 20.2 mo compared to 6.5 mo for those receiving less (p = 0.001, 0.002, respectively). For patients treated with glass microspheres, those receiving a mean TD ≥ 150 Gy had a median OS of 14.6 mo vs. 2.6 mo for those receiving less (p = 0.031)., Conclusion: TD thresholds predictive of TR and OS differ significantly between glass and resin microspheres. However, microsphere type has no impact on survival in patients with chemorefractory ICC., Level of Evidence: Level 3, Retrospective Study.

The forward genetic screen is a powerful, unbiased method to gain insights into biological processes, yet this approach has infrequently been used in vivo in mammals because of high resource demands. Here, we use in vivo somatic Cas9 mutagenesis to perform an in vivo forward genetic screen in mice to identify regulators of cardiomyocyte (CM) maturation, the coordinated changes in phenotype and gene expression that occur in neonatal CMs. We discover and validate a number of transcriptional regulators of this process. Among these are RNF20 and RNF40, which form a complex that monoubiquitinates H2B on lysine 120. Mechanistic studies indicate that this epigenetic mark controls dynamic changes in gene expression required for CM maturation. These insights into CM maturation will inform efforts in cardiac regenerative medicine. More broadly, our approach will enable unbiased forward genetics across mammalian organ systems., (© 2021. The Author(s).)

Background: A hyperkinetic gallbladder is defined as a hepatobiliary iminodiacetic acid (HIDA) scan ejection fraction (EF) of >80%. This condition is poorly described, and there is no current consensus on optimal management. The intent of this study was to determine if cholecystectomy improves symptoms in patients with a hyperkinetic gallbladder when compared to those managed nonoperatively and if there were variables predictive of symptom improvement with or without cholecystectomy., Materials and Methods: This retrospective study included patients from 3 academic hospitals in the Atlanta metro area between the years 2006 and 2018. All patients with an EF >80% were included. Following voluntary exclusion patients were contacted by phone. Each patient was administered a questionnaire regarding their surgical history, medical management, and current symptom profile via Otago score. Institutional Institutional Review Board approval was obtained., Results: 4785 HIDA scans were performed, and 194 reported an EF >80% (incidence 15.7%). 96% of these scans were reported as normal by the radiologist. 68 patients were able to be contacted by phone and completed the questionnaire. 18 patients underwent cholecystectomy, and 89% reported that their symptoms attributed to gallbladder disease were no longer present. 50 patients did not undergo cholecystectomy, and alternate diagnoses, medication prescriptions, diet modification, emergency department visits, and Otago score were higher in this cohort., Discussion: Patients who undergo cholecystectomy for a diagnosis of hyperkinetic gallbladder, on average, report improvement in symptoms when compared to patients managed nonoperatively. This study supports the practice of reporting and managing hyperkinetic gallbladders as a pathologic entity.

Lung cancer is genetically diverse and a major health burden. Non-small cell lung cancer (NSCLC) accounts for 80% of total lung cancer cases and 20% cases are Small cell lung cancer (SCLC). The present case-control association study focused on the cost effective high throughput genotyping using Agena MassARRAY matrix-assisted laser desorption/ionization-time of flight, mass spectrometry (MALDI-TOF) platform to analyze the genetic association of candidate genetic variants. We performed multiplex PCR and genotyped twelve single nucleotide polymorphisms (SNPs) in 723 samples (162 NSCLC cases and 592 healthy controls). These genetic variants were selected from literature for their association with various cancers worldwide and this is the first study from the region to examine these critically important genetic variants. With prospective case-control association study design, twelve variants from ten genes were evaluated. Amongst these six variants, TCF21 (rs12190287), ERCC1 (rs2298881, 11615), ERCC5 (rs751402), ARNTL (rs4757151), BRIP1 (rs4986764) showed significant association with NSCLC risk (p ≤ 0.003) in Jammu and Kashmir population. In-silico findings of these genetic variants showed remarkable functional roles that needs in-vitro validations. It is further anticipated that such case control studies will help us in understanding the missing heritability of non-small cell lung cancer.

Background: The coronavirus disease 2019 (COVID-19) pandemic has made it more challenging for patients to undergo yttrium-90 (Y-90) radioembolization (RE). Same day Y-90 RE provides an opportunity to minimize logistical challenges and infection risk associated with COVID-19, thus improving patient access., Aim: To describe the use of same day Y-90 RE with routine single photon emission computed tomography/computed tomography (SPECT/CT) in order to optimize therapy., Methods: All patients were selected for Y-90 RE through a multidisciplinary tumor board, and were screened and tested for COVID-19 infection per institutional protocol. A same day procedure was developed, consisting of angiography, imaging, and Y-90 resin particle delivery. Routine SPECT/CT after technetium-99m macroaggregated albumin (Tc-99m MAA) administration was performed for assessment of arterial supply, personalized dosimetry, and extrahepatic activity. Post-treatment Y-90 bremsstrahlung SPECT/CT was performed for confirmation of particle delivery, by utilization of energy windowing to limit signal from previously administered Tc-99m MAA particles., Results: A total of 14 patients underwent same day Y-90 RE between March and June 2020. Mean lung shunt fraction was 6.13% (range 3.5%-13.1%). Y-90 RE was performed for a single lesion in 7 patients, while the remaining 7 patients had treatment of multifocal lesions. The largest lesion measured 8.3 cm. All patients tolerated the procedure well and were discharged the same day., Conclusion: Same day Y-90 RE with resin-based microspheres is feasible, and provides an opportunity to mitigate infection risk and logistical challenges associated with the COVID-19 pandemic and beyond. We recommend consideration of SPECT/CT, especially among patients with complex malignancies, for the potential to improve outcomes and eligibility of patients to undergo same day Y-90 RE., Competing Interests: Conflict-of-interest statement: No authors received specific funding for the development of this manuscript. Kokabi N conducts Y-90 radioembolization research partially funded by Sirtex Medical Ltd; Duszak R receives research support from the Harvey L. Neiman Health Policy Institute., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: To quantify the relationship of the tumor-to-normal ratio (TNR) attained from the technetium-99m macroaggregated albumin (MAA) and posttreatment yttrium-90 bremsstrahlung (Y90-Brem) single-photon emission computerized tomography (SPECT)/computer tomography (CT) studies in patients with hepatocellular carcinoma (HCC) treated with glass microspheres., Materials and Methods: Retrospectively, a total of 190 consecutive patients with HCC who underwent 204 MAA and Y90-Brem SPECT/CT for glass microsphere Y90 radiation segmentectomy (Y90-RS) or lobar treatment (Y90-RLT) between 2013 and 2018 were included. Semi-automated regions-of-interests were drawn around the targeted tumor and nontumoral liver tissue on the SPECT/CT studies. TNR values from MAA and Y90-Brem SPECT/CT were compared using paired t-tests, Pearson correlation, and median with interquartile ranges (IQR)., Results: The mean TNR for MAA and Y90-Brem SPECT/CT was 2.96 ± 1.86 (median, 2.64; IQR, 2.50) and 2.29 ± 1.10 (median, 2.06; IQR, 1.05), respectively (P < .0001). The mean Y90-RLT TNR was 2.88 ± 1.67 (median, 2.59; IQR, 0.83) and 2.17 ± 0.89 (median, 1.98; IQR, 0.81) for MAA and Y90-Brem SPECT/CT, respectively (P < .0001). The mean Y90-RS TNR was 3.02 ± 2.01 (median, 2.87; IQR, 3.01) and 2.39 ± 1.25 (median, 2.11; IQR, 1.28) for MAA and Y90-Brem SPECT/CT, respectively (P = .0003). TNR attained from MAA and Y90 SPECT/CT studies showed a moderate correlation in a positive linear fashion for the overall (r = 0.54; P < .001), Y90-RLT (r = 0.66, P < .001), and Y90-RS cohorts (r = 0.48, P < .001)., Conclusions: The TNR attained from Y90-Brem SPECT/CT is often underestimated, positively correlated, and less variable than that attained from MAA SPECT/CT., (Copyright © 2021 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to evaluate the effects of tumour dose on tumour response and overall survival (OS) in patients with chemo-refractory metastatic breast cancer (MBC) to the liver undergoing yttrium-90 radioembolisation (Y90 RE)., Materials and Methods: In 20 consecutive patients with chemo-refractory MBC to the liver undergoing 33 total Y90 RE resin treatments, volumes of interest were drawn around the five largest tumours of the targeted liver lobe on post-Y90 RE Bremsstrahlung single-photon emission computed tomography/computed tomography using MIM software v.6.9 (MIM Software, Cleveland, Ohio, USA) and dose-volume histograms were calculated. Response Evaluation Criteria in Solid Tumours (RECIST) was used to determine tumour response at 3 months. Receiver operating characteristics (ROC) curves were used to determine thresholds for various dosimetry parameters. Kaplan-Meier estimation was used to determine OS., Results: Overall, 11 of 33 (33%) Y90 RE treatments resulted in complete or partial response according to RECIST criteria with a median OS of 20.97 months compared to 11.73 months for nonresponders (P = 0.003). Mean tumour dose, defined as the aggregate tumour dose of up to the five largest tumours in the targeted lobe, was the most predictive of tumour response with the highest area under the ROC curve of 0.967. Mean tumour dose >70 Gy had 91% sensitivity and 100% specificity for predicting tumour response. Patients with mean tumour dose >70 Gy experienced a median OS of 16.1 months vs. 12.8 months for those who did not (P = 0.008)., Conclusion: For patients with chemo-refractory breast cancer with liver metastases, achieving a mean tumour dose >70 Gy is a significant predictor of tumour response and prolonged OS., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To compare lung shunt fraction (LSF) prior to Y-90 radioembolization calculated using planar imaging versus SPECT/CT in patients with hepatocellular carcinoma (HCC)., Methods: A single institution retrospective analysis of technetium-99m macroaggregated albumin (Tc-99m MAA) LSF studies for 293 consecutive patients with HCC between 2013 and 2018 was performed. LSF using planar imaging (PLSF) was compared to retrospectively calculated LSF using SPECT/CT (SLSF) via semiautomated segmentation using MIM v.6.9. Sub-analyses of patients were performed based on PLSF range, tumor size, BCLC stage, and Child-Pugh (C-P) score. Mean LSF absolute discrepancy between sub-groups was analyzed. Comparisons were performed using paired t tests and linear regression analysis., Results: Mean PLSF, 8.27%, was greater than mean SLSF, 3.27% (p < 0.001). When categorizing patients by PLSF ranges of < 10%, 10-19.9%, and ≥ 20%, PLSF remained greater than SLSF in all subgroups (p's < 0.001). Patients with PLSF ≥ 20% had a greater absolute discrepancy with SLSF (13.31%) compared to patients with PLSF < 20% (4.74%; p < 0.0001). LSF absolute discrepancy was greater for patients with a maximum liver tumor size ≥ 5.0 cm (5.59%) compared to a liver tumor size < 5.0 cm (4.40%; p = 0.0076). For all BCLC grades and C-P scores, PLSF was greater than SLSF. A greater LSF discrepancy existed for patients with a worse C-P score (C-P A: 4.78%, C-P B/C: 6.12%; p = 0.0081), but not BCLC stage (0/A/B: 4.87%, C: 4.56%; p = 0.5993)., Conclusion: In patients with HCC, SLSF is significantly lower compared to PLSF, with a greater discrepancy among patients with a PLSF ≥ 20%, tumor size ≥ 5 cm, and worse C-P score., Level of Evidence: Level 3, Retrospective Study.

Telomeres are highly repetitive regions capping the chromosomes and composed of multiple units of hexa-nucleotides, TTAGGG, making their quantification difficult. Most of the methods developed to estimate telomeres are extensively cumbersome or expensive. The quantitative polymerase chain reaction (qPCR) based assay is relatively easy and cheaper method that applies SyBr Green dye chemistry to measure telomere length. SyBr Green dye fluoresces after intercalation into the double stranded DNA (dsDNA), thus detection of unspecific products has been a limitation as it may affect quantitation of telomeres. To overcome this limitation of SyBr Green dye, we developed a dual labeled fluorescence probe based quantitative polymerase chain reaction (qPCR) to measure the telomere length. This highly efficient, yet cost effective and easy method, utilizes a probe that targets primarily the telomeric DNA and this increases accuracy of an existing qPCR method., (Copyright © 2020. Published by Elsevier B.V.)

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 ( Actn2 ) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2 -based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling., Competing Interests: The authors declare no conflict of interest.

Mass spectrometry enhanced by nanotechnology can achieve previously unattainable sensitivity for characterizing urinary pathogen-derived peptides. We utilized mass spectrometry enhanced by affinity hydrogel particles (analytical sensitivity = 2.5 pg/mL) to study tick pathogen-specific proteins shed in the urine of patients with (1) erythema migrans rash and acute symptoms, (2) post treatment Lyme disease syndrome (PTLDS), and (3) clinical suspicion of tick-borne illnesses (TBI). Targeted pathogens were Borrelia, Babesia, Anaplasma, Rickettsia, Ehrlichia, Bartonella, Francisella, Powassan virus, tick-borne encephalitis virus, and Colorado tick fever virus. Specificity was defined by 100% amino acid sequence identity with tick-borne pathogen proteins, evolutionary taxonomic verification for related pathogens, and no identity with human or other organisms. Using a cut off of two pathogen peptides, 9/10 acute Lyme Borreliosis patients resulted positive, while we identified zero false positive in 250 controls. Two or more pathogen peptides were identified in 40% of samples from PTLDS and TBI patients (categories 2 and 3 above, n = 59/148). Collectively, 279 distinct unique tick-borne pathogen derived peptides were identified. The number of pathogen specific peptides was directly correlated with presence or absence of symptoms reported by patients (ordinal regression pseudo-R 2  = 0.392, p = 0.010). Enhanced mass spectrometry is a new tool for studying tick-borne pathogen infections.

Various Genome-wide association studies (GWAS) have reported the association of variant rs2494938 with lung cancer. However, genetic association of LRFN2 genetic variation with non-small cell lung cancer (NSCLC) in North Indian population remained unexplored. We conducted a case-control association study using TaqMan-based chemistry in which a total of 619 individuals, 189 NSCLC cases and 430 controls, were genotyped to explore the association of rs2494938 genetic variant of the LRFN2 gene with NSCLC patients from North India. The allele 'G' (risk allele) of the genetic variant rs2494938 was significantly associated with the NSCLC [OR = 1.51 (1.18-1.93 at 95% CI); p value = 0.0009]. Genetic association was also explored by applying different genetic models (Dominant, Additive). These results suggest that rs2494938 polymorphism of the LRFN2 gene is a risk factor in the North Indian populations to develop NSCLC. The LD (Linkage Disequilibrium) plot demonstrates the variant and its LD SNPs ( r 2  > 0.8) and the variant has direct regulatory effect, which could affect the overall physiology of the gene. These findings could be used as diagnostic and prognostic markers in clinical studies of lung cancer patients in North Indian population groups. The present study also provides an important evidence on the genetic etiology of NSCLC in North Indian populations and further expounds GWAS findings on the role of LRFN2 in lung cancer risk. This study provides the holistic view about the non-small cell lung cancer in Jammu and Kashmir, North Indian population and it can be a hallmark of cancer if verified on a very large sample size (cohort)., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© King Abdulaziz City for Science and Technology 2020.)

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D.

Purpose: The complication profile following repeat Y-radioembolization (RE) is not well understood, and repeat RE is sometimes avoided because of concerns for RE-induced liver disease (REILD) and liver toxicity. The purpose of this study was to examine the incidence of REILD and liver toxicity following repeat Y-RE and to identify potential risk factors., Methods: A retrospective analysis of patients undergoing repeat RE to the same hepatic lobe between 2013 and 2018 was performed. Baseline factors were evaluated as predictors of liver toxicity, mortality, and REILD, which was defined as the presence symptomatic ascites or jaundice in the absence of biliary obstruction within 8 weeks following RE. Post-RE complications were graded according to the Common Terminology Criteria for Adverse Events version 5., Results: A total of 39 patients underwent repeat RE with 14 (35.9%) experiencing Common Terminology Criteria for Adverse Events toxicity of grade 2 or greater, 3 (10.3%) grade 3, and no grade 4 or greater. A Model for End Stage Liver Disease score of 8 or greater was associated with grade 2 toxicity or greater (26.7% vs 75%; P = 0.013). Only 3 patients (7.7%) experienced REILD due to symptomatic ascites without jaundice. Greater than 2 REs were associated with a greater rate of 6-month mortality (12% vs 58.3%, P = 0.003), 12-month mortality (28% vs 75%, P = 0.007), and REILD (0% vs 21.4%, P = 0.016). Age, sex, microsphere type, cirrhosis, Child-Pugh, and Eastern Cooperative Oncology Group status were not significantly associated with complications, REILD, or survival., Conclusions: Repeat Y-RE appears to be well tolerated with a low rate of high-grade adverse events and REILD.

Head and neck squamous cell carcinoma (HNSCC) is a disease of significant morbidity and mortality and rarely diagnosed in early stages. Despite extensive genetic and genomic characterization, targeted therapeutics and diagnostic markers of HNSCC are lacking due to the inherent heterogeneity and complexity of the disease. Herein, we have generated the global histone mark based epigenomic and transcriptomic cartogram of SCC25, a representative cell type of mesenchymal HNSCC and its normal oral keratinocyte counterpart. Examination of genomic regions marked by differential chromatin states and associated with misregulated gene expression led us to identify SCC25 enriched regulatory sequences and transcription factors (TF) motifs. These findings were further strengthened by ATAC-seq based open chromatin and TF footprint analysis which unearthed Krüppel-like Factor 4 (KLF4) as a potential key regulator of the SCC25 cistrome. We reaffirm the results obtained from in silico and chromatin studies in SCC25 by ChIP-seq of KLF4 and identify ΔNp63 as a co-oncogenic driver of the cancer-specific gene expression milieu. Taken together, our results lead us to propose a model where elevated KLF4 levels sustains the oncogenic state of HNSCC by reactivating repressed chromatin domains at key downstream genes, often by targeting super-enhancers.