ANKRD1 expression is aberrantly upregulated in the mdm mouse model of muscular dystrophy and induced by stretch through NFκB.

The muscular dystrophy with myositis (mdm) mouse model results in a severe muscular dystrophy due to an 83-amino-acid deletion in the N2A region of titin, an expanded sarcomeric protein that functions as a molecular spring which senses and modulates the response to mechanical forces in cardiac and skeletal muscles. ANKRD1 is one of the muscle ankyrin repeat domain proteins (MARPs) a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. The aberrant over-activation of Nuclear factor Kappa B (NF-κB) and the Ankyrin-repeat domain containing protein 1 (ANKRD1) occurs in several models of progressive muscle disease including Duchenne muscular dystrophy. We hypothesized that mechanical regulation of ANKRD1 is mediated by NF-κB activation in skeletal muscles and that this mechanism is perturbed by small deletion of the stretch-sensing titin N2A region in the mdm mouse. We applied static mechanical stretch of the mdm mouse diaphragm and cyclic mechanical stretch of C2C12 myotubes to examine the interaction between NF-κΒ and ANKRD1 expression utilizing Western blot and qRTPCR. As seen in skeletal muscles of other severe muscular dystrophies, an aberrant increased basal expression of NF-κB and ANKRD1 were observed in the diaphragm muscles of the mdm mice. Our data show that in the mdm diaphragm, basal levels of NF-κB are increased, and pharmacological inhibition of NF-κB does not alter basal levels of ANKRD1. Alternatively, NF-κB inhibition did alter stretch-induced ANKRD1 upregulation. These data show that NF-κB activity is at least partially responsible for the stretch-induced expression of ANKRD1.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer. FUNDING: Gilead Sciences.

Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

PURPOSE: Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer. METHODS: In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. RESULTS: Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%). CONCLUSION: SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

Obstrucción intestinal por íleo biliar: reporte de un caso

El íleo biliar (IB) se define como la obstrucción intestinal mecánica intraluminal por uno o más cálculos biliares que han emigrado a través de una fístula biliodigestiva, establecida como complicación de una colelitiasis. Presentamos el caso de una mujer de 59 años con antecedente de hipertensión arterial, con diagnóstico tomográfico preoperatorio de obstrucción intestinal por íleo biliar (triada de Rigler), por lo que es intervenida quirúrgicamente de emergencia, decidiéndose realizar una enterolitotomía y programar su segunda intervención en dos meses. El IB es una causa infrecuente de obstrucción intestinal en pacientes de edad avanzada, con una elevada morbi-mortalidad. Requiere un alto índice de sospecha ante un cuadro de oclusión intestinal intermitente y antecedente de cólicos biliares. La triada de Rigler solo está presente en un tercio de los pacientes, para lo cual la tomografía es el estudio de elección. El tratamiento es controversial, pero el más empleado es la enterolitotomía.

Gallstone ileus (BI) is defined as intraluminal mechanical intestinal obstruction by one or more gallstones; who have emigrated through a biliodigestive fistula, established as a complication of cholelithiasis. We present the case of a 59-year-old woman with a history of arterial hypertension, with a preoperative tomographic diagnosis of intestinal obstruction due to biliary ileus (Rigler's triad), for which she underwent emergency surgery, deciding to perform an enterolithotomy and schedule her second intervention in two months. BI is an uncommon cause of intestinal obstruction in elderly patients, with high morbidity and mortality. It requires a high index of suspicion in the presence of intermittent intestinal obstruction and a history of biliary colic. Rigler's triad is only present in a third of patients, for which tomography is the study of choice. Treatment is controversial, but the most widely used is enterolithotomy.

Manejo del delirium en el paciente oncológico y su repercusión en la toma de decisiones compartidas / Management of delirium in cancer patients and its impact on shared decisions

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Mitral valve prolapse morphofunctional features by cardiovascular magnetic resonance: more than just a valvular disease.

INTRODUCTION: Mitral valve (MV) prolapse (MVP) is a primary valvular abnormality. We hypothesized that additionally there are concomitant abnormalities of the left ventricle (LV) and MV apparatus in this entity even in the absence of significant mitral regurgitation (MR). OBJECTIVE: To characterize MV and LV anatomic and functional features in MVP with preserved LV ejection fraction, with and without significant MR, using cardiovascular magnetic resonance (CMR). METHODS: Consecutive MVP patients (n = 80, mean 52 years, 37% males) with preserved LV ejection fraction, and 44 controls (46 years, 52% males) by CMR were included, as well as 13 additional patients with "borderline" MVP. From cine images we quantified LV volumes, MV and LV anatomic measurements (including angle between diastolic and systolic annular planes, annular displacement, and basal inferolateral hypertrophy) and, using feature tracking, longitudinal and circumferential peak systolic strains. RESULTS: Significant MR was found in 46 (56%) MVP patients. Compared with controls, MVP patients had LV enlargement, basal inferolateral hypertrophy, higher posterior annular excursion, and reduced shortening of the papillary muscles. LV basal strains were significantly increased, particularly in several basal segments. These differences remained significant in patients without significant MR, and many persisted in "borderline" MVP. CONCLUSIONS: In patients with MVP and preserved LV ejection fraction there is LV dilatation, basal inferolateral hypertrophy, exaggerated posterior annular displacement and increased basal deformation, even in the absence of significant MR or overt MVP. These findings suggest that MVP is a disease not only of the MV but also of the adjacent myocardium.

Endocarditis infecciosa, una entidad que precisa de los niveles asistenciales geriátricos / Endocarditis; an entity that requires geriatric care models

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SIRT1 Regulation in Ageing and Obesity.

Ageing and obesity have common hallmarks: altered glucose and lipid metabolism, chronic inflammation and oxidative stress are some examples. The downstream effects of SIRT1 activity have been thoroughly explored, and their research is still in expanse. SIRT1 activation has been shown to regulate pathways with beneficiary effects on 1) ageing and obesity-associated metabolic disorders such as metabolic syndrome, insulin resistance and type-II diabetes with, 2) chronic inflammatory processes such as arthritis, atherosclerosis and emphysema, 3) DNA damage and oxidative stress with impact on neurodegenerative diseases, cardiovascular health and some cancers. This knowledge intensified the interest in uncovering the mechanisms regulating the expression and activity of SIRT1. This review focuses on the upstream regulatory mechanisms controlling SIRT1, and how this knowledge could potentially contribute to the development of therapeutic interventions.

Pancitopenia en el curso de infección por SARS-CoV-2 / Pancytopenia during SARS-CoV-2 infection

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Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial.

BACKGROUND: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. METHODS: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. RESULTS: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. CONCLUSIONS: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. TRIAL REGISTRATION: NCT02802748 , registered 16 June 2016.

Parkinsonismo inducido por fármacos / Drug-induced Parkinsonism

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