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Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe–S cluster biosynthesis, reducing the function of Cdkal1, an Fe–S cluster enzyme that catalyzes methylthiolation of t 6 A37 in tRNA Lys UUU to ms 2 t 6 A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms 2 t 6 A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2 −/− β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans. Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.

Iron is essential for survival of most organisms. All organisms have thus developed mechanisms to sense, acquire and sequester iron. In C. elegans, iron uptake and sequestration are regulated by HIF-1. We previously showed that hif-1 mutants are developmentally delayed when grown under iron limitation. Here we identify nhr-14, encoding a nuclear receptor, in a screen conducted for mutations that rescue the developmental delay of hif-1 mutants under iron limitation. nhr-14 loss upregulates the intestinal metal transporter SMF-3 to increase iron uptake in hif-1 mutants. nhr-14 mutants display increased expression of innate immune genes and DAF-16/FoxO-Class II genes, and enhanced resistance to Pseudomonas aeruginosa. These responses are dependent on the transcription factor PQM-1, which localizes to intestinal cell nuclei in nhr-14 mutants. Our data reveal how C. elegans utilizes nuclear receptors to regulate innate immunity and iron availability, and show iron sequestration as a component of the innate immune response.

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau ( VHL) gene, which results in the constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. Using a high throughput screen, we identify novel compounds that decrease HIF-1/2α levels and induce ferroptosis by targeting Iron Sulfur Cluster Assembly 2 (ISCA2), a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex. ISCA2 inhibition either pharmacologically or using siRNA decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. Additionally, ISCA2 inhibition triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 levels are decreased in ccRCC compared to normal kidney, and decreased ISCA2 levels are associated with pVHL loss and with sensitivity to ferroptosis induced by ISCA2 inhibition. Strikingly, pharmacological inhibition of ISCA2 using an orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells.

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene, which results in the constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. Using a high throughput screen, we identify novel compounds that decrease HIF-1/2α levels and induce ferroptosis by targeting Iron Sulfur Cluster Assembly 2 (ISCA2), a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex. ISCA2 inhibition either pharmacologically or using siRNA decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. ISCA2 inhibition also triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 levels are decreased in ccRCC compared to normal kidney, and decreased ISCA2 levels are associated with pVHL loss and with sensitivity to ISCA2 inhibition. Strikingly, pharmacological inhibition of ISCA2 using an orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells.

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Diagnosing MM presents considerable challenges, involving the identification of plasma cells in cytology examinations on hematological slides. At present, this is still a time-consuming manual task and has high labor costs. These challenges have adverse implications, which rely heavily on medical professionals’ expertise and experience. To tackle these challenges, we present an investigation using Artificial Intelligence, specifically a Machine Learning analysis of hematological slides with a Deep Neural Network (DNN), to support specialists during the process of diagnosing MM. In this sense, the contribution of this study is twofold: in addition to the trained model to diagnose MM, we also make available to the community a fully-curated hematological slide dataset with thousands of images of plasma cells. Taken together, the setup we established here is a framework that researchers and hospitals with limited resources can promptly use. Our contributions provide practical results that have been directly applied in the public health system in Brazil. Given the open-source nature of the project, we anticipate it will be used and extended to diagnose other malignancies.

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease that affects the development of adipocytes and leads to an inability to store fat in adipocytes. This study aimed to evaluate the life expectancy and the causes of death of patients with BSCL. We analyzed death certificates, and medical records of BSCL patients who died between 1997 and 2017. If the death certificate was incomplete or unavailable, we reviewed the medical records, and if they were not available too, we collected information from the patient's relatives to understand how the death happened. We calculated the potential years of life lost as a result of premature death. Twenty patients (12 female and 8 male) died between 1997 and 2017. The mean age at the time of death was 27.1±12.4 years (women 25.2±12.5 vs. men 29.9±12.6 years, p = 0.41). Life expectancy for the study population was 62.9±4.8 years. The potential number of years of life lost was 35.6±16.6 years. The causes of deaths were divided into three major groups: infections (7 patients, 35%), liver disease (7 patients, 35%), and other causes (acute pancreatitis, one patient; renal failure, three patients; sudden death/myocardial infarction, two patients). Three patients had pulmonary fibrosis. BSCL led to premature death, cutting the patients' lifespan by 30 or more years. The majority of these young patients died of liver disease or infection. Other studies are needed to understand better the mechanisms that predispose to infections, as well as to assess whether new therapies can alter the natural history of this disease.

Multiple medications in common use have been considered for the treatment of Covid-19. In this double-blind, randomized, placebo-controlled trial, ivermectin that was administered within 7 days after Covid-19 symptom onset was shown not to be of any clinical benefit.

Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies.

Background Studies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase in activity of matrix metalloproteases 1 and 3 (MMP-1 and MMP-3), and that MMP activity may be in part genetically mediated. The degree to which this might be clinically relevant in patients with rotator cuff tears has not been well characterized. Questions/purposes (1) Is genetic polymorphism of MMP-1 and MMP-3 associated with rotator cuff tears? (2) Are there haplotypes of MMP-1 and MMP-3 correlated with rotator cuff tears? (3) Compared with control subjects, do patients with rotator cuff tears have a higher proportion of relatives with the same disease? Methods We evaluated 64 patients with full-thickness rotator cuff tears and 64 asymptomatic control subjects. Patients younger 65 years, with nontraumatic tears, were included. The tear or integrity of the rotator cuff tear was evaluated by MRI or ultrasonography in all individuals. The patients and control subjects were paired by age. MMP-1 and MMP-3 genotypes were determined using the PCR-restriction fragment length polymorphism assays. Results Genetic polymorphisms in MMP-1 and MMP-3 are associated with rotator cuff tear, in which individuals with rotator cuff tears have associated genotypes 1G/2G (patients, 32 of 64 [50%], control subjects, 16 of 64 [25%]; odds ratio [OR], 4.8; 95% CI, 2.1–11.0; p < 0.001) and 2G/2G were at great risk (patients, 15 of 64 [23%], control subjects, seven of 64 [11%]; OR, 5.2; 95% CI,1.8–14.9; p < 0.001), and patients with rotator cuff tears were associated with a higher proportion of 2G allele distribution (62 of 128 [48%] versus 30 of 128 [23%]; p < 0.001). Patients with the 5A/5A genotype are at greater risk of rotator cuff tear (patients, 15 of 64 [23%]; control subjects, four of 64 [6%]; OR, 5.5; 95% CI, 1.4–20.9; p = 0.021), and there was higher 5A allele distribution in patients with rotator cuff tears (patients, 68 of 128 [53%]; control subjects, 52 of 128 [41%]; p = 0.045). Individuals with the haplotype 2G/5A were more likely to have rotator cuff tears develop (patients, 42 of 64 [66%]; control subjects, 17 of 64 [27%]; OR, 5.3; 95% CI, 2.5-11.3; p < 0.001). Patients with rotator cuff tears reported, in higher number, the existence of relatives who previously had treatment for rotator cuff tears (19 of 64 [30%] versus four of 64 [6%]; OR, 6.3; 95% CI, 2.0-19.9; p = 0.001). Conclusions The genetic polymorphism of MMP-1 and MMP-3 is associated with rotator cuff tear. Individuals with haplotype 2G/5A were more susceptible to rotator cuff tears in the population studied. Clinical Relevance Knowledge of the genetic markers related to rotator cuff tears can enable identification of susceptible individuals and increase understanding of the pathogenesis of tendon degeneration.

Background: There is scarce information on Varicella–Zoster virus genetic variability in individuals with acute central nervous system infection in Brazil. The objective of this study was the molecular characterization of Varicella–Zoster virus isolates in cerebrospinal fluid from individuals with acute central nervous system infection. Methods: Cerebrospinal fluid samples were collected from individuals evaluated in emergency and community healthcare services in São Paulo, Brazil. Varicella–Zoster virus identification was performed using commercial platforms Biofire-FilmArray Meningitis/Encephalitis (BioMérieux, Craponne, France) and XGEN-UMLTI-N9® (Mobius Life, Pinhais, Brazil). Positive samples were further characterized as wild-type or vaccine-strain by a real-time polymerase chain reaction assay that targeted a single nucleotide polymorphism in open reading frame 62. We also estimated the mean genetic distance and phylogenetic reconstruction based on open reading frames 22, 38, 54, and 62 in relation to sequences of intercontinentally circulating Varicella–Zoster virus isolates. Results: Among the 600 cerebrospinal fluid samples, we identified Varicella–Zoster virus in 30 (5%) samples. None were positive for the vaccine-strain. Twelve samples were sequenced and phylogenetically classified into Clades 1 (41.7%), 2 (25%), 3 (8.3%), 5 (16.7%), or 6 (8%). Conclusion: Enhanced characterization of circulating Varicella–Zoster virus Clades in Brazil identified previously unreported Clades 2 and 6 as well as three other Clades disseminated intercontinentally. These findings reinforce the importance of Varicella–Zoster virus molecular surveillance in cerebrospinal fluid.