Metabolic dependencies of metastasis-initiating cells in female breast cancer.

Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.

IFNγ-induced stem-like state of cancer cells as a driver of metastatic progression following immunotherapy.

Despite the remarkable success of immune checkpoint blockade (ICB) therapy, most cancer patients still do not respond. We now find that immunotherapy can induce stem-like properties in tumors. Using mouse models of breast cancer, we observe that cancer stem cells (CSCs) show not only enhanced resistance to T cell cytotoxicity, but that interferon gamma (IFNγ) produced by activated T cells directly converts non-CSCs to CSCs. IFNγ enhances several CSC phenotypes, such as resistance to chemo- and radiotherapy and metastasis formation. We identified the branched-chain amino acid aminotransaminase 1 (BCAT1) as a downstream mediator of IFNγ-induced CSC plasticity. Targeting BCAT1 in vivo improved cancer vaccination and ICB therapy by preventing IFNγ-induced metastasis formation. Breast cancer patients treated with ICB exhibited a similar increase in CSC markers expression indicating comparable responses to immune activation in humans. Collectively, we discover an unexpected, pro-tumoral role for IFNγ that may contribute to cancer immunotherapy failure.

Association Between Insulin-Like Growth Factor-1 and Social Cognition in Huntington's Disease.

Background: Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. Results: Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF-1 levels (P = 0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). Conclusions: In HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.

3-Year Outcomes of XEN Implant Compared With Trabeculectomy, With or Without Phacoemulsification for Open Angle Glaucoma.

PRCIS: Trabeculectomy (TRAB) surgery reduces the intraocular pressure (IOP) more than the XEN45 implant over 3 years. There is no difference in the number of antiglaucoma medications between the 2 procedures. The decision to perform either TRAB or XEN45 implantation must be evaluated on a case-by-case basis, taking into account the high rate of needling of the XEN45. PURPOSE: The aim of this study was to compare the differences between the efficacy and safety of the XEN45 implant and TRAB, either alone or in combination with phacoemulsification (PHACO), in patients with open angle glaucoma (OAG) at 36 months. METHODS: A retrospective, single-center and comparative study conducted on OAG patients who underwent XEN45 implantation or TRAB from 2016 to 2018. Patients were divided into 4 groups: group 1 (XEN45 alone), group 2 (XEN45+PHACO), group 3 (TRAB alone), and group 4 (TRAB+PHACO). For statistical purposes, groups 1 and 2 were combined (XEN45 implant), whereas groups 3 and 4 were also combined (TRAB surgery). IOP, number of glaucoma medications, and adverse events were evaluated. The main outcome measure was the reduction in IOP at 36 months postoperatively. RESULTS: One hundred thirty-four patients (134 eyes; 63 XEN45 and 71 TRAB) were included. The mean (95% confidence interval) IOP reduction at the end of the study follow-up was -6.3 (-11.0 to -1.6 mm Hg, P =0.025, XEN45 alone), -8.9 (-11.0 to -6.8 mm Hg, P <0.001, TRAB alone), -2.5 (-4.5 to -0.4 mm Hg, P =0.019, XEN45+PHACO), and -5.6 (-7.7 to -3.4 mm Hg, P <0.001, TRAB±PHACO). The proportion of patients achieving an IOP≥6 and ≤16 mm Hg without treatment at the end of the 36-month follow-up were 50.8% (32/63) in the XEN45 implant and 49.3% (35/71) in the TRAB surgery group, P =0.863. The mean number of glaucoma medications was significantly reduced in all the study groups. The needling rate was 19% in XEN45 versus 5.6% in the TRAB group ( P =0.030), and 2.81% and 36.6% of eyes in the TRAB group presented anterior chamber flattening and hyphema, respectively. CONCLUSIONS: TRAB surgery lowered IOP significantly more than XEN45 implant with or without phacoemulsification over 3 years and had a significantly lower need for additional needling surgery. Both procedures reduced glaucoma medications to a similar rate. These findings are relevant to the informed consent process and patient decisions for one procedure over the other.

Corneal Endothelial Dysfunction as a Manifestation of Digoxin Toxicity.

PURPOSE: The purpose of this study was to report a case of corneal endothelial dysfunction and subsequent corneal edema in a patient with digoxin toxicity. METHOD: This was a case report. RESULTS: A 77-year-old woman diagnosed with open-angle glaucoma and treated with a topical prostaglandin analog for 5 years developed blurred vision and photopsia in both eyes. Systemic medications included digoxin, furosemide, apixaban, amlodipine, enalapril, and simvastatin. Ocular examination revealed folds in Descemet membrane and corneal stromal edema in both eyes, with normal fundoscopy. Ancillary tests revealed elevated serum digoxin levels. No intervention other than discontinuation of digoxin was initiated. The corneal edema improved after that and resolved in the next 2 weeks. CONCLUSIONS: We encountered 1 case of corneal edema secondary to corneal endothelial dysfunction in a patient with digoxin toxicity. Special care should be taken to elicit a complete history because ocular signs can be manifestations of systemic alterations with vital importance for patients.

Incidental tricuspid valve fibroelastoma associated with patent foramen ovale in a young female: Straightforward diagnosis but controversial management.

Papillary fibroelastoma is an uncommon primary cardiac tumor, predominantly associated with left-sided valvular endocardium. Affectation of tricuspid valve leaflets is rare, and management in asymptomatic patients remains controversial. We present a 30-year-old female referred for evaluation prior to bariatric surgery. A routine echocardiogram revealed a mobile cardiac mass attached to the tricuspid valve. A patent foramen ovale was also present. Tumor was surgically removed. Histology confirmed the definite diagnosis of a papillary fibroelastoma. In our case, the presence of a patent foramen ovale associated with the right-sided fibroelastoma was decisive in the decision for surgery.

Decrease in the percentage of peripheral blood CXCR3highCD4+ lymphocytes after renal transplantation.

INTRODUCTION: Previous studies suggest that infiltration into the graft of active T cells following kidney transplantation depends on the expression of chemokines and their interaction with their T-cell receptors. However, little is known about the natural history of the expression of these molecules during the early post-transplantation phase. AIM: To evaluate the percentage of CXCR3highCD4+ and CCR4highCD4+ cells, as markers of the Th1 and Th2 populations, in peripheral blood from uremic patients before transplantation and six months after maintaining an acceptable kidney graft function. MATERIAL AND METHODS: Flow cytometry was used to measure CXCR3highCD4+ and CCR4highCD4+ cells from 44 consecutive patients who received a kidney transplant at our center. Measurements were made at the time of transplantation and six months later. RESULTS: There was a significant reduction after transplantation in the CXCR3highCD4+/CCR4highCD4+ balance (10.68±20.28 vs. 2.01±3.15, p=0.001). Separate analysis of each subset showed a significant reduction after transplantation in CXCR3highCD4+ (2.37±2.75 vs. 1.49±2.66, p=0.010) but no difference in CCR4highCD4+ (0.83±1.01 vs. 1.01±1.12, p=0.812). CONCLUSION: Prior to kidney transplantation uremic patients have an immunologic activation with Th1 polarization (studied by analyzing the CXCR3highCD4+ and CCR4highCD4+ populations) that falls after transplantation. This can be monitored with the CXCR3highCD4+ lymphocyte subset. This may help understand the pathologic mechanisms intervening in immunologic dysfunction of kidney grafts.

Working memory and facial expression recognition in patients with Parkinson's disease.

Facial expression recognition impairment has been reported in Parkinson's disease. While some authors have referred to specific emotional disabilities, others view them as secondary to executive deficits frequently described in the disease, such as working memory. The present study aims to analyze the relationship between working memory and facial expression recognition abilities in Parkinson's disease. We observed 50 patients with Parkinson's disease and 49 healthy controls by means of an n-back procedure with four types of stimuli: emotional facial expressions, gender, spatial locations, and non-sense syllables. Other executive and visuospatial neuropsychological tests were also administered. Results showed that Parkinson's disease patients with high levels of disability performed worse than healthy individuals on the emotional facial expression and spatial location tasks. Moreover, spatial location task performance was correlated with executive neuropsychological scores, but emotional facial expression was not. Thus, working memory seems to be altered in Parkinson's disease, particularly in tasks that involve the appreciation of spatial relationships in stimuli. Additionally, non-executive, facial emotional recognition difficulty seems to be present and related to disease progression.

Adverse events in Spanish intensive care units: the SYREC study.

OBJECTIVE: To estimate the incidence and characteristics of adverse events (AEs) and no-harm events (NHEs) in critically ill patients. DESIGN: Observational, prospective, 24-h cross-sectional study with self-reporting. SETTING: Seventy-nine intensive care units at 76 hospitals. MEASUREMENTS: Number of events, risk of AEs and NHEs, types of incidents, severity and avoidability of incidents. RESULTS: A total of 1017 patients were included in the study; 591 (58%) were affected by one or more incidents. Of the 1424 valid incidents, 943 (66%) were NHEs and 481 (34%) were AEs. The individual risk of suffering at least one incident was 62%, at least one NHE 45% and at least one AE 29%. The median number of incidents, NHEs and AEs was 6, 3 and 2 per 100 patient-hours, respectively. Seventy-four per cent of the incidents were related to medication (24%), equipment (15%), nursing care (14%), accidental withdrawal of vascular accesses and catheters (10%) or airways and mechanical ventilation (10%). AEs resulted in temporary damage in 29% and in permanent damage or damage that compromised patients' lives or contributed to their death in 4%. Incidents were avoidable in 79% of cases (90% in NHEs and 60% in AEs, P < 0.05). CONCLUSIONS: The individual risk for incidents in critical patients is high. Many incidents did not harm patients, some caused damage and a few were related to the patient's death. Most incidents were considered avoidable.