Enteroscopic Balloon Dilation of Multiple Ileal Strictures in Suspected Crohn's Disease

AbstractWith the advent of small bowel enteroscopy, the limits to the endoscopic access to the small bowel have been further exceeded, allowing histology sampling and therapeutical maneuvers. This conquest is of crucial meaning in small bowel inflammatory diseases. In this setting, enteroscopy may lead to a definite diagnosis, overcoming the limits of the anatomic disease location and of other (radiological and endoscopic imaging) techniques. Furthermore, enteroscopy permits strictures visualization and dilation, reducing or postponing the need for surgery. In this article the authors demonstrate the technique of hydrostatic balloon dilation of small bowel strictures suggestive of Crohn's disease in a patient suffering from persistent obscure gastrointestinal bleeding. This article is part of an expert video encyclopedia

Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex

The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination

Transapical off-pump echo-guided mitral valve repair with neochordae implantation mid-term outcomes

Background: The NeoChord echo-guided transapical beating heart repair is a promising early-stage minimally invasive surgical procedure for degenerative mitral valve (MV) regurgitation (DMR) correction. The technique has been improved since its inception following procedure standardization, patient selection optimization, and learning curve stabilization. We hereby present the mid-term clinical results through three years of our large single center experience. Methods: All consecutive patients with severe symptomatic DMR due to prolapse or flail of one or both mitral leaflets that underwent the NeoChord procedure between November 2013 and June 2019 were included. Patients were categorized according to MV anatomy; Type A isolated central posterior leaflet prolapse and/or flail, Type B posterior multi-segment prolapse and/or flail, Type C anterior and/or bi-leaflet prolapse or flail, Type D paracommissural prolapse and/or flail and/or significant leaflet and/or annular calcifications. Patients underwent clinical and echocardiographic follow-up at one, three, six, twelve months and yearly thereafter. Clinical outcomes and the composite primary endpoint (patient success) were defined according to Mitral Valve Academic Research Consortium (MVARC) criteria. Mitral regurgitation (MR) severity was graded as absent, mild, moderate and severe according to American Society of Echocardiography (ASE) and European Society of Cardiology (ESC) guidelines. Results: Two hundred and three patients were included; median follow-up was 24 months [interquartile range (IQR), 9–36]. Median age was 64 years (IQR, 54–74 years), median Society of Thoracic Surgeons (STS) Predicted Risk of Mortality (PROM) was 0.60% (IQR, 0.32–1.44%). There were 106 Type A patients (52.2%), 68 Type B (33.5%), 16 Type C (7.9%), and 13 Type D (6.4%). Kaplan-Meier estimate of survival was 99.0%±0.7% at one and two years and 94.0%±2.9% at three years. At one-year follow-up patient success was 91.2%±2.0% and 111 patients (74%) presented a residual MR mild or less (1+). At three-year follow-up patient success was 81.2%±3.8% and 32 patients (64%) had a residual MR mild or less (1+). Patient success was significantly different according to anatomical type (P=0.001). Echocardiographic analysis showed a significant acute left ventricle and left atrial reverse remodeling that was maintained up to three years. Conclusions: The NeoChord echo-guided transapical beating heart repair procedure demonstrated good clinical outcomes and echocardiographic results up to three-year follow-up

Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer

BACKGROUND: No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation. OBJECTIVE: To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test). RESULTS AND LIMITATIONS: FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005). CONCLUSIONS: FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa. PATIENT SUMMARY: We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.Fil: Labanca, Estefania. University of Texas; Estados UnidosFil: Yang, Jun. University of Texas; Estados UnidosFil: Shepherd, Peter D. A.. University of Texas; Estados UnidosFil: Wan, Xinhai. University of Texas; Estados UnidosFil: Starbuck, Michael W.. University of Texas; Estados UnidosFil: Guerra, Leah D.. University of Texas; Estados UnidosFil: Anselmino, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Bizzotto, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Dong, Jiabin. University of Texas; Estados UnidosFil: Chinnaiyan, Arul M.. University Of Michigan Medical School; Estados UnidosFil: Ravoori, Murali K.. University of Texas; Estados UnidosFil: Kundra, Vikas. University of Texas; Estados UnidosFil: Broom, Bradley M.. University of Texas; Estados UnidosFil: Corn, Paul G.. University of Texas; Estados UnidosFil: Troncoso, Patricia. University of Texas; Estados UnidosFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Logothethis, Christopher J.. University of Texas; Estados UnidosFil: Navone, Nora. University of Texas; Estados Unido

An early European experience with transapical off-pump mitral valve repair with NeoChord implantation

OBJECTIVES: Transapical off-pump NeoChord repair is a novel minimally invasive surgical procedure to treat degenerative mitral valve regurgitation. The aim was to evaluate 1-year clinical results of the NeoChord procedure in a consecutive cohort of patients. METHODS: Between February 2013 and July 2016, 213 patients were enrolled in the NeoChord Independent International Registry. All patients presented severe mitral regurgitation due to flail/prolapse of 1 or both leaflets, and they all completed postoperative echocardiographic assessment up to 1 year. We identified the primary end point as composed of procedural success, freedom from mortality, stroke, reintervention, recurrence of severe mitral regurgitation, rehospitalization and decrease of at least 1 New York Heart Association functional class at 1-year follow-up. We also compared outcomes according to the anatomical classification (Type A: isolated central posterior leaflet disease; Type B: posterior multisegment disease; Type C: anterior, bileaflet, paracommissural disease with/without leaflet/annular calcifications). RESULTS: The median age was 68 years (interquartile range 56-77), and the median EuroSCORE II was 1.05% (interquartile range 0.67-1.76). The number of Type A, B and C patients was 82 (38.5%), 98 (46%) and 33 (15.5%), respectively. Procedural success was achieved in 206 (96.7%) patients. At 1-year follow-up, overall survival was 98 ± 1%. Composite end point was achieved in 84 ± 2.5% for the overall population and 94 ± 2.6%, 82.6 ± 3.8% and 63.6 ± 8.4% in Type A, Type B and Type C patients, respectively (P &lt; 0.0001). CONCLUSIONS: These results demonstrate that the NeoChord procedure is safe, effective and reproducible. Clinical and echocardiographic efficacy is maintained up to 1 year with significant differences among the anatomical groups. Specific anatomical selection criteria are necessary to achieve stable results

Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.Fil: Labanca, Estefania. University of Texas; Estados UnidosFil: Bizzotto, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sanchis, Pablo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Anselmino, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Yang, Jun. University of Texas; Estados UnidosFil: Shepherd, Peter D. A.. University of Texas; Estados UnidosFil: Paez, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Antico Arciuch, Valeria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Lage Vickers, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Hoang, Anh G.. University of Texas; Estados UnidosFil: Tang, Ximing. University of Texas; Estados UnidosFil: Raso, Maria Gabriela. University of Texas; Estados UnidosFil: Titus, Mark. University of Texas; Estados UnidosFil: Efstathiou, Eleni. University of Texas; Estados UnidosFil: Cotignola, Javier Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Araujo, John. University of Texas; Estados UnidosFil: Logothetis, Christopher. University of Texas; Estados UnidosFil: Vazquez, Elba Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Navone, Nora. University of Texas; Estados UnidosFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P =.01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments