Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.

Cardiomyopathies in Pregnancy: Trends and Clinical Outcomes in Delivery Hospitalizations in the United States (2005-2020).

BACKGROUND: Cardiomyopathy (CDM) in pregnancy is associated with maternal morbidity and mortality. OBJECTIVES: To explore trends and clinical outcomes in CDM subtypes during delivery hospitalizations. METHODS: We used the National Inpatient Sample database to identify delivery hospitalizations between 2005-2020 by CDM subtypes: peripartum (PPCM), dilated (DCM), hypertrophic (HCM), and restrictive (RCM). Maternal and fetal outcomes were identified using International Classification of Diseases, 9th and 10th Revision, Clinical Modification codes. Baseline characteristics and temporal trends of CDM subtypes were analyzed. Maternal cardiovascular, pregnancy, and fetal outcomes were evaluated by CDM subtype using univariate logistic regression. The primary outcome was in-hospital mortality. RESULTS: During 2005-2020, 37,125 out of 61,811,842 delivery hospitalizations were complicated by CDM. Among CDM-related delivery hospitalizations, the most prevalent were DCM (46%), followed by PPCM (45.6%), HCM (4.6%), and RCM (3.9%). The rates of in-hospital mortality (1.7%), adverse cardiovascular events such as acute heart failure (17%), cardiogenic shock (3.4%), and cardiac arrest (3.1%), and adverse pregnancy outcomes such as preeclampsia (14.2%) and preterm labor (11%), were highest among PPCM (all p < 0.0001). The prevalence of PPCM (49.1% to 38.5%) decreased while the prevalence of HCM (2.7% to 8.8%) and DCM (48% to 52.2%) increased over time. CONCLUSIONS: Over a 15-year period, PPCM had higher rates of in-hospital mortality, cardiovascular events, and adverse pregnancy outcomes compared to other CDM subtypes. While the prevalence of PPCM decreased over time, the prevalence of HCM and DCM increased. Hence, further research on cardiomyopathies during pregnancy and prospective studies on this vulnerable patient cohort are urgently needed.

Computer-aided diagnosis for the resect-and-discard strategy for colorectal polyps: a systematic review and meta-analysis.

BACKGROUND: The resect-and-discard strategy allows endoscopists to replace post-polypectomy pathology with real-time prediction of polyp histology during colonoscopy (optical diagnosis). We aimed to investigate the benefits and harms of implementing computer-aided diagnosis (CADx) for polyp pathology into the resect-and-discard strategy. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, and Scopus from database inception to June 5, 2024, without language restrictions, for diagnostic accuracy studies that assessed the performance of real-time CADx systems, compared with histology, for the optical diagnosis of diminutive polyps (≤5 mm) in the entire colon. We synthesised data for three strategies: CADx-alone, CADx-unassisted, and CADx-assisted; when the endoscopist was involved in the optical diagnosis, we synthesised data exclusively from diagnoses for which confidence in the prediction was reported as high. The primary outcomes were the proportion of polyps that would have avoided pathological assessment (ie, the proportion optically diagnosed with high confidence; main benefit) and the proportion of polyps incorrectly predicted due to false positives and false negatives (main harm), directly compared between CADx-assisted and CADx-unassisted strategies. We used DerSimonian and Laird's random-effects model to calculate all outcomes. We used Higgins I2 to assess heterogeneity, the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate certainty, and funnel plots and Egger's test to examine publication bias. This study is registered with PROSPERO, CRD42024508440. FINDINGS: We found 1019 studies, of which 11 (7400 diminutive polyps, 3769 patients, and 185 endoscopists) were included in the final meta-analysis. Three studies (1817 patients and 4086 polyps [2148 neoplastic and 1938 non-neoplastic]) provided data to directly compare the primary outcome measures between the CADx-unassisted and CADx-assisted strategies. We found no significant difference between the CADx-assisted and CADx-unassisted strategies for the proportion of polyps that would have avoided pathological assessment (90% [88-93], 3653 [89·4%] of 4086 polyps diagnosed with high confidence vs 90% [95% CI 85-94], 3588 [87·8%] of 4086 polyps diagnosed with high confidence; risk ratio 1·01 [95% CI 0·99-1·04; I2=53·49%; low-certainty evidence; Egger's test p=0·18). The proportion of incorrectly predicted polyps was lower with the CADx-assisted strategy than with the CADx-unassisted strategy (12% [95% CI 7-17], 523 [14·3%] of 3653 polyps incorrectly predicted with a CADx-assisted strategy vs 13% [6-20], 582 [16·2%] of 3588 polyps incorrectly diagnosed with a CADx-unassisted strategy; risk ratio 0·88 [95% CI 0·79-0·98]; I2=0·00%; low-certainty evidence; Egger's test p=0·18). INTERPRETATION: CADx did not produce benefit nor harm for the resect-and-discard strategy, questioning its value in clinical practice. Improving the accuracy and explainability of CADx is desired. FUNDING: European Commission (Horizon Europe), the Japan Society of Promotion of Science, and Associazione Italiana per la Ricerca sul Cancro.

Impact of single centre kidney-exchange transplantation to increase living donor pool in India: A cohort study involving non-anonymous allocation.

AIM: In India, 85% of organ donations are from living donors and 15% are from deceased donors. One-third of living donors were rejected because of ABO or HLA incompatibility. Kidney exchange transplantation (KET) is a cost-effective and legal strategy to increase living donor kidney transplantation (LDKT) by 25%-35%. METHODS: We report our experience with 539 KET cases and the evolution of a single-centre program to increase the use of LDKT. RESULTS: Between January 2000 and 13 March, 2024, 1382 deceased donor kidney transplantations and 5346 LDKT were performed at our centre, including 10% (n = 539) from KET. Of the 539 KET, 80.9% (n = 436) were ABO incompatible pairs, 11.1% (n = 60) were compatible pairs, and 8% (n = 43) were sensitized pairs. There were 75% 2-way (n = 2 × 202 = 404), 16.2% 3-way (n = 3 × 29 = 87), 3% 4-way (n = 4 × 4 = 16), 1.8% 5-way (n = 5 × 2 = 10), 2.2% 6-way (n = 6 × 2 = 12), and 1.8% 10-way KET (n = 10 × 1 = 10). Of the recipients 81.2% (n = 438) were male and 18.8% (n = 101) were female, while of the donors, 78.5% (n = 423) were female and 21.5% (n = 116) were male. All donors were near relatives; wives (54%, n = 291) and mothers (20%, n = 108) were the most common donors. At a median follow-up of 8.2 years, patient survival, death censored graft survival, acute rejection, and median serum creatinine levels of functioning grafts were 81.63% (n = 440), 91% (n = 494), 9.8% (n = 53) and 1.3 mg/dL respectively. We credited the success to maintaining a registry of incompatible pairs, high-volume LDKT programs, non-anonymous allocation and teamwork. CONCLUSION: This is the largest single-centre KET program in Asia. We report the challenges and solutions to replicate our success in other KET programs.

Greater Postoperative Biceps Tendon Migration After Arthroscopic Suprapectoral or Open Subpectoral Biceps Tenodesis Correlates With Lower Patient-Reported Outcome Scores.

PURPOSE: To assess the relation between tendon migration, as measured by radiostereometric analysis, and patient-reported outcome measures (PROMs) after biceps tenodesis (BT); to determine the likelihood of achieving clinically significant outcomes (CSOs) after BT; and to identify factors that impact CSO achievement. METHODS: Patients undergoing arthroscopic suprapectoral or open subpectoral BT at a single, high-volume academic medical center were prospectively enrolled. A tantalum bead sutured to the tenodesis construct was used as a radiopaque marker. Biceps tendon migration was measured on calibrated radiographs at 12 weeks postoperatively. PROMs (Constant-Murley, Single Assessment Numeric Evaluation [SANE], and Patient-Reported Outcomes Measurement Information System-Upper Extremity [PROMIS-UE] scores) were collected preoperatively and at minimum 2-year follow-up. RESULTS: Of 115 patients enrolled, 94 (82%) were included (median age, 52 years; median body mass index, 31.4). At a mean follow-up of 2.9 years, the median Constant-Murley, SANE, and PROMIS-UE scores were 33 (interquartile range [IQR], 26-35), 90 (IQR, 80-99), and 47 (IQR, 42-58), respectively. Median tantalum bead migration was 6.5 mm (IQR, 1.8-13.8 mm). There were significant correlations between migration and Constant-Murley score (r2 = 0.222; ß = -0.554 [95% confidence interval (CI), -1.027 to -0.081]; P = .022), SANE score (r2 = 0.238; ß = -0.198 [95% CI, -0.337 to -0.058]; P = .006), and PROMIS-UE score (r2 = 0.233; ß = -0.406 [95% CI, -0.707 to -0.104]; P = .009). On univariable analysis, higher body mass index was associated with achievement of substantial clinical benefit (unadjusted odds ratio [OR], 1.078 [95% CI, 1.007 to 1.161]; P = .038). Greater bead migration was negatively associated with achievement of the minimal clinically important difference (unadjusted OR, 0.969 [95% CI, 0.943 to 0.993]; P = .014) and patient acceptable symptomatic state (unadjusted OR, 0.965 [95% CI, 0.937 to 0.989]; P = .008) on all 3 instruments. CONCLUSIONS: A 1-cm increase in post-tenodesis biceps tendon migration was associated with a decrease in the Constant-Murley, SANE, and PROMIS-UE scores of 6, 2, and 4 points, respectively, at a mean of 2.9 years after surgery. Most patients achieved CSOs for these PROMs by latest follow-up, and greater biceps tendon construct migration was negatively associated with the likelihood of CSO achievement. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Early recanalization after tenecteplase versus alteplase: Experience in a large stroke network.

INTRODUCTION: Previously published data are conflicting regarding the ability of tenecteplase versus alteplase to produce early recanalization of an intracranial large vessel occlusion. We compared the performance of each thrombolytic in a stroke network. METHODS: We queried our prospectively collected code stroke registry for basilar, internal carotid, or proximal middle cerebral artery occlusion patients treated with intravenous thrombolysis from 11/17/2021-9/16/2023. The primary outcome was early recanalization, defined using angiographic or clinical criteria. Secondary and safety outcomes included 90-day functional independence and symptomatic intracranial hemorrhage. A multivariable regression analysis was performed to determine independent associations with the primary outcome. RESULTS: 233 patients, with mean age 66.9 (16.6) years and median National Institutes of Health Stroke Scale score 15 (10-21), were included. One-hundred twenty-four of 233 (53.2 %) patients were treated with alteplase while 109/233 (46.8 %) were treated with tenecteplase. Endovascular thrombectomy was performed in 82 % of subjects. Early recanalization rates were similar between the groups (alteplase 22.6 %, tenecteplase 14.7 %; p = 0.14), as were rates of 90-day independent neurological function, symptomatic intracranial hemorrhage, and mortality. Patients with an internal carotid artery occlusion or with higher presenting stroke severity were less likely to achieve early recanalization. CONCLUSIONS: Tenecteplase and alteplase have similar rates of early recanalization, 90-day functional independence, and safety outcomes in large vessel occlusion patients. Occlusion site and stroke severity predict response to thrombolysis. Future studies may investigate other factors associated with a positive response to thrombolytics as expanded treatment indications are explored.

Visualizing Multilayer Spatiotemporal Epidemiological Data with Animated Geocircles.

OBJECTIVE: The COVID-19 pandemic emphasized the value of geospatial visual analytics for both epidemiologists and the general public. However, systems struggled to encode temporal and geospatial trends of multiple, potentially interacting variables, such as active cases, deaths, and vaccinations. We sought to ask (1) how epidemiologists interact with visual analytics tools, (2) how multiple, time-varying, geospatial variables can be conveyed in a unified view, and (3) how complex spatiotemporal encodings affect utility for both experts and non-experts. MATERIALS AND METHODS: We propose encoding variables with animated, concentric, hollow circles, allowing multiple variables via color encoding and avoiding occlusion problems, and we implement this method in a browser-based tool called CoronaViz. We conduct task-based evaluations with non-experts, as well as in-depth interviews and observational sessions with epidemiologists, covering a range of tools and encodings. RESULTS: Sessions with epidemiologists confirmed the importance of multivariate, spatiotemporal queries and the utility of CoronaViz for answering them, while providing direction for future development. Non-experts tasked with performing spatiotemporal queries unanimously preferred animation to multi-view dashboards. DISCUSSION: We find that conveying complex, multivariate data necessarily involves trade-offs. Yet, our studies suggest the importance of complementary visualization strategies, with our animated multivariate spatiotemporal encoding filling important needs for exploration and presentation. CONCLUSION: CoronaViz's unique ability to convey multiple, time-varying, geospatial variables makes it both a valuable addition to interactive COVID-19 dashboards and a platform for empowering experts and the public during future disease outbreaks. CoronaViz is open-source and a live instance is freely hosted at http://coronaviz.umiacs.io.

A Neuroendocrine Tumor of Unknown Primary Origin: A Case Report and Review of the Literature.

Neuroendocrine tumors (NETs) are uncommon malignancies that develop from neuroendocrine cells which most commonly occur in the GI tract, lung, and pancreas. Treatment courses for these tumors are largely dictated by the primary origin site, which can present diagnostic and therapeutic challenges in NETs of unknown primary origin. Herein, we present a case of an NET of unknown primary origin with significant liver metastases. Our aim is to highlight the key components of the workup of NETs of unknown primary origin and detail the biochemical, histopathological, and imaging modalities as recommended by current literature. We highlight the importance of a multidisciplinary approach to both diagnosis and treatment of these patients as well as touch upon therapeutic options.

Orthostatic hypotension and subjective symptomatic orthostasis in Parkinson's disease: Associations and correlations.

Background: Both measured orthostatic hypotension and symptomatic orthostasis are common in PD but their relationship is unclear. Objective: We aim to determine clinical predictors of both measured orthostatic hypotension and reported symptomatic orthostasis in PD, including the impact of "on"/"off" status and seasons, and to determine the correlation between measured OH and subjective orthostasis. Methods: We analyzed BP readings, demographic and disease state predictors for both 1. Measured blood pressure OH criteria and 2. The subjective report of orthostatic symptoms, using logistic regression analyses from an initial "on" motor state clinical visit in all PD patient visits. We then correlated subjective orthostasis symptoms with BP measurements. We also compared intra-subject BP measures in PD patients seen in both "on" and "off" states, and when seen "on" in both summer and winter. Results: 723 consecutive visits over 2 years identified 250 unique PD individuals. Subjective orthostasis was reported by 44 % and "on" measured OH (>20 drop in SBP or 10 DBP upon standing) was seen in 30 %. Measured OH did not significantly correlate with any assessed clinical feature or specific medicine. Subjective orthostasis correlated most with older age, dementia, and L-dopa use. Subjective orthostasis correlated equally with absolute lower measured standing SBP and the drop in SBP from sitting to standing. Compared to the "off" state, "on" state showed lower sitting and standing SBP, more than DBP, but no significant change in BP drop upon standing. Seasons did not impact measured BP. Conclusions: Both OH and symptomatic orthostasis are common. Dopaminergic medications did not cause traditionally defined OH but lowered all SBP (sitting and standing) and thus reduced pulse pressure, possibly by increasing arteriole compliance simply by reducing motor tone, as this BP-lowering effect may be specific to Parkinsonism.

Accuracy of Computer-aided Diagnosis in Colonoscopy Varies according to Polyp Location. A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Computer-Aided Diagnosis (CADx) assists endoscopists in differentiating between neoplastic and non-neoplastic polyps during colonoscopy. This study aimed to evaluate the impact of polyp location (proximal vs. distal colon) on the diagnostic performance of CADx for ≤5mm polyps. METHODS: We searched for studies evaluating the performance of real-time CADx alone (i.e., independently of endoscopist judgement) for predicting the histology of colorectal polyps ≤5mm. The primary endpoints were CADx sensitivity and specificity in the proximal and distal colon. Secondary outcomes were the negative predictive value (NPV), positive predictive value (PPV), and the accuracy of the CADx alone. Distal colon was limited to the rectum and sigmoid. RESULTS: We included 11 studies for analysis with a total of 7,782 <5mm polyps. CADx specificity was significantly lower in the proximal colon compared to the distal colon (62% versus 85%; Risk ratio (RR): 0.74 [95% CI: 0.72-0.84]). Conversely, sensitivity was similar (89% vs 87% (EC-1); RR: 1.00 [95% CI: 0.97-1.03]. The NPV (64% versus 93%; RR: 0.71 [95% CI: 0.64-0.79]) and accuracy (81% vs 86%; RR: 0.95 [95% CI: 0.91-0.99]) were significantly lower in the proximal than distal colon, while PPV was higher in the proximal colon (87% vs 76%; RR: 1.11 [95% CI: 1.06-1.17]). CONCLUSION: The diagnostic performance of CADx for polyps in the proximal colon is inadequate, exhibiting significantly lower specificity compared to its performance for distal polyps. While current CADx systems are suitable for use in the distal colon, they should not be employed for proximal polyps until more performant systems are developed specifically for these lesions.

Mechanical Failure of SIGMA Total Condylar-III Revision Total Knee System Modular Femoral Component Due to Bolt Screw Breakage - Our Experience in Overcoming Broken Component Incarceration.

Introduction: The rising use of modular implants in revision total knee arthroplasty offers surgeons greater flexibility in addressing bone defects and achieving uniform gaps compared to monoblock counterparts. However, this enhanced functionality brings specific complications such as loosening and breakage at component coupling sites, leading to challenges due to mechanical failures and suboptimal fixation. Extracting broken components during revision surgery poses a significant challenge, prompting innovative techniques to facilitate extraction. Case Report: We present a rare case of modular femoral component mechanical failure in a 69-year-old male, manifesting as left knee instability and acute pain while walking 4 years following revision of total knee replacement due to infection. Radiographs revealed mechanical failure of the Sigma Total Condylar-III Revision prosthesis bolt, with intra-operative extraction efforts complicated by a lodged broken bolt. Despite initial challenges, successful extraction was achieved using mosquito forceps and a universal nail extractor. Conclusion: This case highlights the importance of documenting rare instances of mechanical failure in modular implants, emphasizing the need to understand prevalence rates and various surgical techniques for implant extraction. Our experience underscores the utility of the universal nail extractor as a valuable tool in managing difficult implant removal during revision surgery. Surgeons must remain vigilant and innovative in addressing challenges encountered during modular implant revisions.

Burden of rare genetic disorders in India: twenty-two years' experience of a tertiary centre.

BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Ammonium oxidation from concentrated synthetic wastewater and landfill leachate using partial nitritation in sequencing batch reactor.

Partial nitritation (PN) is a novel treatment for nitrogen removal using aerobic ammonium oxidation with reduced oxygen requirements compared to conventional nitrification. This study evaluated the performance of the PN process and the factors influencing nitrogen removal from landfill leachate. During the reactivation of biomass, the results showed 70% ammonium removal, but only 20% total nitrogen removal. Further analysis showed that low nitrite accumulation and high nitrate production promoted the growth of nitrite-oxidizing bacteria (NOB). The ammonium removal activity after soaking the cultivated biomass in synthetic water and leachate was measured to be 0.57, 0.1, 0.17, and 0.25 g N•g VSS-1•d-1 for synthetic wastewater and leachate soaking for synthetic wastewater, 12 h, 3 days, and 7 days, respectively. The study found abundant ammonium-oxidizing bacteria (AOB) and NOBs in biomass soaked in synthetic wastewater. However, soaking in leachate promoted AOB growth and inhibited NOB growth making leachate suitable for PN. PRACTITIONER POINTS: The study found that with a longer leachate-soaking period for biomass, ammonium removal activity increases, which in turn increases ammonium conversions during the PN process. Ammonium-oxidizing bacteria (AOB) can acclimate to landfill leachate substrate and grow with a longer soaking period. Nitrite-oxidizing bacteria (NOB) were inhibited by landfill leachate substrate, which is beneficial for nitrite accumulation. Anabolized DO can convert nitrite to nitrate rapidly, which results in higher nitrate accumulation compared to nitrite accumulation. Hence, the DO level has to be sufficiently low to prevent nitrite oxidation and nitrate accumulation.

Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer.

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Utilizing human cerebral organoids to model breast cancer brain metastasis in culture.

BACKGROUND: Metastasis, the spread, and growth of malignant cells at secondary sites within a patient's body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10-16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients. METHODS: Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid. RESULTS: We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids. CONCLUSIONS: Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.

Neurological outcomes for patients meeting radiographic criteria for DEFUSE 3 and SELECT2.

BACKGROUND: The DEFUSE 3 and SELECT2 thrombectomy trials included some patients with similar radiographic profiles, although the rates of good functional outcomes differed widely between the studies. OBJECTIVE: To report neurological outcomes for patients who meet CT and CT perfusion (CTP) inclusion criteria common to both DEFUSE 3 and SELECT2. METHODS: Retrospective study of thrombectomy patients, presenting between November 2016 and December 2023 to a large health system, with Alberta Stroke Program Early CT score ≥6, core infarction 50-69 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL. The primary outcome was 90-day modified Rankin Scale score 0-2. A logistic regression analysis was performed to identify independent predictors of the primary outcome. RESULTS: 85 patients, with mean age 64.6 (16.6) years and median National Institutes of Health Stroke Scale score 18 (15-23), were included. Thirty-eight of 85 patients (44.7%) were functionally independent at 90 days. Predictors of functional independence included age (OR=0.943, 95% CI 0.908 to 0.980; P=0.003), initial glucose (OR=0.989, 95% CI 0.978 to 1.000; P=0.044), and time last known well to skin puncture (OR=0.997, 95% CI 0.994 to 1.000; P=0.028). The area under the curve for the multivariable model predicting the primary outcome was 0.82 (95% CI 0.73 to 0.92). CONCLUSION: Nearly half of patients meeting radiographic criteria common to DEFUSE 3 and SELECT2 are functionally independent at 90 days, similar to rates reported for the treated DEFUSE 3 cohort. This might be due to their moderate core volumes and large ischemic penumbra.

High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility.

Genome-wide association studies (GWASs) have identified numerous lung cancer risk-associated loci. However, decoding molecular mechanisms of these associations is challenging since most of these genetic variants are non-protein-coding with unknown function. Here, we implemented massively parallel reporter assays (MPRAs) to simultaneously measure the allelic transcriptional activity of risk-associated variants. We tested 2,245 variants at 42 loci from 3 recent GWASs in East Asian and European populations in the context of two major lung cancer histological types and exposure to benzo(a)pyrene. This MPRA approach identified one or more variants (median 11 variants) with significant effects on transcriptional activity at 88% of GWAS loci. Multimodal integration of lung-specific epigenomic data demonstrated that 63% of the loci harbored multiple potentially functional variants in linkage disequilibrium. While 22% of the significant variants showed allelic effects in both A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cell lines, a subset of the functional variants displayed a significant cell-type interaction. Transcription factor analyses nominated potential regulators of the functional variants, including those with cell-type-specific expression and those predicted to bind multiple potentially functional variants across the GWAS loci. Linking functional variants to target genes based on four complementary approaches identified candidate susceptibility genes, including those affecting lung cancer cell growth. CRISPR interference of the top functional variant at 20q13.33 validated variant-to-gene connections, including RTEL1, SOX18, and ARFRP1. Our data provide a comprehensive functional analysis of lung cancer GWAS loci and help elucidate the molecular basis of heterogeneity and polygenicity underlying lung cancer susceptibility.

Use of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus and outcomes of inflammatory bowel disease.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) show anti-inflammatory properties. AIM: To evaluate their clinical impact on inflammatory bowel disease (IBD) outcomes. METHODS: Retrospective cohort study utilising the TriNetX database comparing IBD-specific outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) and type 2 diabetes mellitus (T2DM) on GLP-1RA compared to oral hypoglycaemic agents. The primary outcome was hospitalisation requiring intravenous steroids and IBD-related surgery within 3 years. We performed 1:1 propensity score matching (PSM) for demographics, co-morbid conditions, BMI, laboratory values, HbA1c, and IBD medications including steroids. RESULTS: We identified 1130 patients in the UC GLP-1RA cohort (mean age: 58.9 ± 11.6 years, 56.3% female, 70.2% White, 57.2% with obesity) and 1140 patients in the CD GLP-1RA cohort (mean age: 56.7 ± 11.5, 61.9% female, 73.6% White, 56.2% with obesity). After PSM, there was no difference in the risk of intravenous steroid use (aHR: 1.21, 95% CI: 0.92-1.59) but a lower risk of colectomy (aHR: 0.37, 95% CI: 0.14-0.97) between the UC GLP-1RA and control cohort. There was no difference in the risk of intravenous steroid use (aHR: 1.04, 95% CI: 0.80-1.34) but a lower risk of surgery (aHR: 0.55, 95% CI: 0.36-0.84) between the CD GLP-1RA and CD control cohort. There was no difference in the risk of oral steroid use or advanced therapy initiation in the UC and CD GLP-1RA than control cohorts. CONCLUSIONS: We found an association between lower risk of IBD-related surgery and GLP-1RA use for T2DM in patients with UC or CD.

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response.

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.