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Background: According to the “World Cancer Research Fund” and the “American Institute of Cancer Research” (WCRF/AICR) one in four cancer cases could be prevented through a healthy diet, weight control and physical activity. Objective: To explore the association between the WCRF/AICR recommendations and risk of breast cancer. Methods: During the period 2006 to 2011 we recruited 973 incident cases of breast cancer and 973 controls from 17 Spanish Regions. We constructed a score based on 9 of the WCRF/AICR recommendations for cancer prevention:: 1)Maintain adequate body weight; 2)Be physically active; 3)Limit the intake of high density foods; 4)Eat mostly plant foods; 5)Limit the intake of animal foods; 6)Limit alcohol intake; 7)Limit salt and salt preserved food intake; 8)Meet nutritional needs through diet; S1)Breastfeed infants exclusively up to 6 months. We explored its association with BC by menopausal status and by intrinsic tumor subtypes (ER+/PR+ & HER2-; HER2+; ER&PR-&HER2-) using conditional and multinomial logistic models respectively. Results: Our results point to a linear association between the degree of noncompliance and breast cancer risk. Taking women who met 6 or more recommendations as reference, those meeting less than 3 showed a three-fold excess risk (OR=2.98(CI95%:1.59-5.59)), especially for postmenopausal women (OR=3.60(CI95%:1.24;10.47)) and ER+/PR+&HER2- (OR=3.60(CI95%:1.84;7.05)) and HER2+ (OR=4.23(CI95%:1.66;10.78)) tumors. Noncompliance of recommendations regarding the consumption of foods and drinks that promote weight gain in premenopausal women (OR=2.24(CI95%:1.18;4.28); p for interaction=0.014) and triple negative tumors (OR=2.93(CI95%:1.12-7.63)); the intake of plant foods in postmenopausal women (OR=2.35(CI95%:1.24;4.44)) and triple negative tumors (OR=3.48(CI95%:1.46-8.31)); and the alcohol consumption in ER+/PR+&HER2- tumors (OR=1.52 (CI95%:1.06-2.19)) showed the strongest associations. Conclusion: Breast cancer prevention might be possible by following the “World Cancer Research Fund” and the “American Institute of Cancer Research” recommendations, even in settings like Spain, where a high percentage of women already comply with many of them. [ABSTRACT FROM AUTHOR]

Increasing evidence demonstrate that the electron transfer chain plays a critical role in controlling the effector functions of macrophages. In this work, we have generated a Ndufs4−/− murine macrophage cell lines. The Ndufs4 gene, which encodes a supernumerary subunit of complex I, is a mutational hotspot in Leigh syndrome patients. Ndufs4−/− macrophages showed decreased complex I activity, altered complex I assembly, and lower levels of maximal respiration and ATP production. These mitochondrial respiration alterations were associated with a shift towards a pro-inflammatory cytokine profile after lipopolysaccharide challenge and improved ability to phagocytose Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Objective: To determine the health status and exercise capacity of COVID-19 survivors one year after hospital discharge. Methods: This multicenter prospective study included COVID-19 survivors 12 months after hospital discharge. Participants were randomly selected from a large cohort of COVID-19 patients who had been hospitalized until 15th April 2020. They were interviewed about persistent symptoms, underwent a physical examination, chest X-ray, and a 6-minute walk test (6MWT). A multivariate analysis was performed to determine the risk factors for persistent dyspnea. Results: Of the 150 patients included, 58% were male and the median age was 63 (IQR 54–72) years. About 82% reported ≥1 symptoms and 45% had not recovered their physical health. The multivariate regression analysis revealed that the female sex, chronic obstructive pulmonary disease, and smoking were independent risk factors for persistent dyspnea. Approximately 50% completed less than 80% of the theoretical distance on the 6MWT. Only 14% had an abnormal X-ray, showing mainly interstitial infiltrates. A third of them had been followed up in outpatient clinics and 6% had undergone physical rehabilitation. Conclusion: Despite the high rate of survivors of the first wave of the COVID-19 pandemic with persistent symptomatology at 12 months, the follow-up and rehabilitation of these patients has been really poor. Studies focusing on the role of smoking in the persistence of COVID-19 symptoms are lacking. [ABSTRACT FROM AUTHOR]

Background: In-hospital care of chronic patients is based on their characteristics and risk levels. Adjusted morbidity groups (AMG) is a population stratification tool which is currently being used in Primary Care but not in Hospitals. The objectives of this study were to describe the use of hospital services by chronic patients according to their risk levels assigned by AMG and to analyze influencing variables. Material and methods: In this cross-sectional study, patients aged ≥18 years from a healthcare service area classified as chronically ill by the AMG classification system who used their referral hospital services from June 2015 to June 2016 were included. Predisposing and needs factors were collected. Univariate, bivariate and multiple linear regressions were performed. Results: Of the 9,443 chronic patients identified (52.1% of the population in the selected area), 4,143 (43.9%) used hospital care services. Their mean age was 62.1 years (standard deviation (SD) = 18.4); 61.8% were female; 9% were high risk; 30% were medium risk, and 61% were low risk. The mean number of hospital service contacts was 5.0 (SD = 6.2), with 3.8 (SD = 4.3) visits to outpatient clinic, 0.7 (SD = 1.2) visits to emergency departments, 0.3 (SD = 2.8) visits to day hospital, and 0.2 (SD = 0.5) hospitalizations. The factors associated with greater service use were predisposing factors such as age (coefficient B (CB) = 0.03; 95% confidence interval (CI) = 0.01–0.05) and Spanish origin (CB = 3.9; 95% CI = 3.2–4.6). Among the needs factors were palliative care (CB = 4.8; 95% CI = 2.8–6.7), primary caregiver status (CB = 2.3; 95% CI = 0.7–3.9), a high risk level (CB = 2.9; 95% CI = 2.1–3.6), multimorbidity (CB = 0.8, 95% CI = 0.4–1.3), chronic obstructive pulmonary disease (COPD) (CB = 1.5, 95% CI = 0.8–2.3), depression (CB = 0.8, 95% CI = 0.3–1.3), active cancer (CB = 4.4, 95% CI = 3.7–5.1), and polymedication (CB = 1.1, 95% CI = 0.5–1.7). Conclusions: The use of hospital services by chronic patients was high and increased with the risk level assigned by the AMG. The most frequent type of contact was outpatient consultation. Use was increased with predisposing factors such as age and geographic origin and by needs factors such as multimorbidity, risk level and severe diseases requiring follow-up, home care, and palliative care. [ABSTRACT FROM AUTHOR]

Background: To identify and quantify associations between baseline characteristics on hospital admission and mortality in patients with COVID-19 at a tertiary hospital in Spain. Methods and findings: This retrospective case series included 238 patients hospitalized for COVID-19 at Hospital Universitario Clínico San Cecilio (Granada, Spain) who were discharged or who died. Electronic medical records were reviewed to obtain information on sex, age, personal antecedents, clinical features, findings on physical examination, and laboratory results for each patient. Associations between mortality and baseline characteristics were estimated as hazard ratios (HR) calculated with Cox regression models. Series mortality was 25.6%. Among patients with dependence for basic activities of daily living, 78.7% died, and among patients residing in retirement homes, 80.8% died. The variables most clearly associated with a greater hazard of death were age (3% HR increase per 1-year increase in age; 95%CI 1–6), diabetes mellitus (HR 2.42, 95%CI 1.43–4.09), SatO2/FiO2 ratio (43% HR reduction per 1-point increase; 95%CI 23–57), SOFA score (19% HR increase per 1-point increase, 95%CI 5–34) and CURB-65 score (76% HR increase per 1-point increase, 95%CI 23–143). Conclusions: The patients residing in retirement homes showed great vulnerability. The main baseline factors that were independently associated with mortality in patients hospitalized for COVID-19 were older age, diabetes mellitus, low SatO2/FiO2 ratio, and high SOFA and CURB-65 scores. [ABSTRACT FROM AUTHOR]

Purpose: Several researchers have suggested that the rs243865 (16q13-q21) polymorphism in the promoter region of the metalloproteinase-2 (MMP-2) gene could be associated with an increased risk of developing age-related macular degeneration (AMD). However, previous results remain inconclusive. To clarify this controversy, we conducted a meta-analysis of the relationship between rs243865 of MMP-2 and AMD. Methods: We included 6 independent case-control studies involving 1,682 AMD patients and 2,295 healthy subjects. The association between the rs243865 polymorphism and AMD was examined by the overall odds ratio (OR) with a 95% confidence interval (CI). We used a recessive genetic model analysis, sensitivity analysis, and assessment of bias in our meta-analysis. Results: Our results showed that there was no significant association between the variant T allele (p-value = 0.10, OR [95%CI] = 0.95 [0.82–1.10]) or the CT+TT genotype (p-value = 0.16, OR [95%CI] = 0.92 [0.76–1.12]) of rs243865 MMP-2 polymorphism and the presence of AMD. Conclusions: The rs243865 MMP-2 polymorphism was not associated with an increased risk of developing AMD. The MMP-2 (-1306 C>T) promoter variant is unlikely to have a major role in AMD risk susceptibility. [ABSTRACT FROM AUTHOR]

Purpose: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. Methods: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry “El Álamo III”, dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. Results: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. Conclusions: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors. [ABSTRACT FROM AUTHOR]

The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations. [ABSTRACT FROM AUTHOR]

Mutations in the TP53 gene are very common in human cancers, and are associated with poor clinical outcome. Transgenic mouse models lacking the Trp53 gene or that express mutant Trp53 transgenes produce tumours with malignant features in many organs. We previously showed the transcriptome of a p53- deficient mouse skin carcinoma model to be similar to those of human cancers with TP53 mutations and associated with poor clinical outcomes. This report shows that much of the 682-gene signature of this murine skin carcinoma transcriptome is also present in breast and lung cancer mouse models in which p53 is inhibited. Further, we report validated gene-expression-based tests for predicting the clinical outcome of human breast and lung adenocarcinoma. It was found that human patients with cancer could be stratified based on the similarity of their transcriptome with the mouse skin carcinoma 682-gene signature. The results also provide new targets for the treatment of p53- defective tumours. [ABSTRACT FROM AUTHOR]

McArdle disease is caused by lack of glycogen phosphorylase (GP) activity in skeletal muscle. Patients experience exercise intolerance, presenting as early fatigue and contractures. In this study, we investigated the effects produced by a lack of GP on several genes and proteins of skeletal muscle in McArdle patients. Muscle tissue of 35 patients and 7 healthy controls were used to identify abnormalities in the patients' transcriptomic profile using low-density arrays. Gene expression was analyzed for the influence of variables such as sex and clinical severity. Differences in protein expression were studied by immunoblotting and 2D electrophoresis analysis, and protein complexes were examined by two-dimensional, blue native gel electrophoresis (BN-PAGE). A number of genes including those encoding acetyl-coA carboxylase beta, m-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1), were found to be downregulated in patients. Specifically, compared to controls, GS and SERCA1 proteins were reduced by 50% and 75% respectively; also, unphosphorylated GS and SERCA1 were highly downregulated. On BN-PAGE analysis, GP was present with GS in two muscle protein complexes. Our findings revealed some issues that could be important in understanding the physiological consequences of McArdle disease: (i) SERCA1 downregulation in patients could result in impaired calcium transport in type II (fast-twitch) muscle fibers, leading to early fatigability during exercise tasks involving type II fibers (which mostly use glycolytic metabolism), i.e. isometric exercise, lifting weights or intense dynamic exercise (stair climbing, bicycling, walking at a very brisk pace), (ii) GP and GS were found together in two protein complexes, which suggests a new regulatory mechanism in the activity of these glycogen enzymes. [ABSTRACT FROM AUTHOR]

Background: Mutations in the PYGM gene encoding skeletal muscle glycogen phosphorylase (GP) cause a metabolic disorder known as McArdle's disease. Previous studies in muscle biopsies and cultured muscle cells from McArdle patients have shown that PYGM mutations abolish GP activity in skeletal muscle, but that the enzyme activity reappears when muscle cells are in culture. The identification of the GP isoenzyme that accounts for this activity remains controversial. Methodology/Principal Findings: In this study we present two related patients harbouring a novel PYGM mutation, p.R771PfsX33. In the patients' skeletal muscle biopsies, PYGM mRNA levels were ~60% lower than those observed in two matched healthy controls; biochemical analysis of a patient muscle biopsy resulted in undetectable GP protein and GP activity. A strong reduction of the PYGM mRNA was observed in cultured muscle cells from patients and controls, as compared to the levels observed in muscle tissue. In cultured cells, PYGM mRNA levels were negligible regardless of the differentiation stage. After a 12 day period of differentiation similar expression of the brain and liver isoforms were observed at the mRNA level in cells from patients and controls. Total GP activity (measured with AMP) was not different either; however, the active GP activity and immunoreactive GP protein levels were lower in patients' cell cultures. GP immunoreactivity was mainly due to brain and liver GP but muscle GP seemed to be responsible for the differences. Conclusions/Significance: These results indicate that in both patients' and controls' cell cultures, unlike in skeletal muscle tissue, most of the protein and GP activities result from the expression of brain GP and liver GP genes, although there is still some activity resulting from the expression of the muscle GP gene. More research is necessary to clarify the differential mechanisms of metabolic adaptations that McArdle cultures undergo in vitro. [ABSTRACT FROM AUTHOR]

Background: In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities. Methodology: Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis. Principal Findings: Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background. Conclusions: Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders. [ABSTRACT FROM AUTHOR]