Influence of cyclic changes in ovarian hormones on resting metabolic rate and appetite in women

Energy balance, when energy intake (EI) equals energy expenditure (EE), is key in the maintenance of body weight and composition. Pre-menopausal women seem to experience fluctuations on both sides of the energy balance equation and this seems to respond to changes in the ovarian hormones, estradiol (E2) and progesterone (P4) within a menstrual cycle (MC). In light of the current prevalence of overweight and obese in the female population, it seems imperative to have a better understanding of the influence of the ovarian hormones on energy regulation in pre-menopausal women. This thesis aimed to: examine the fluctuations in salivary and plasma ovarian hormones within a MC in naturally cycling (NC) women and hormonal contraceptive (HC) users; investigate whether resting metabolic rate (RMR) significantly changed throughout the MC in NC women and in HC users; explore the association between RMR and the ovarian hormones; and investigate whether appetite responses to the same breakfast changed throughout the MC phases. Ovarian hormones in plasma experienced a greater fluctuation than in saliva within a MC and this affected the correlation and the ratio between the two collection specimens. Increases in RMR in the luteal (LPh) compared to the other MC phases in NC women were observed, but were not statistically significant despite showing clinically meaningful fluctuations. Salivary P4 contributed to the variance of RMR seen in the LPh. Finally, gastric emptying (GE) time and PYY response to a standardized breakfast changed significantly across the MC; the LPh had the fastest GE time and the smallest PYY response of all the phases. P4 and E2-P4 ratio were significantly correlated to GE time. The findings suggest that NC women might experience changes in their inherent regulatory mechanisms by which energy homeostasis is achieved within a MC. Whether these regulatory changes are beneficial or not in the maintenance of body weight in the long term remains unknown

Topical azithromycin or ofloxacin for endophthalmitis prophylaxis after intravitreal injection.

Background: The number of patients who have undergone intravitreal injections has increased enormously in recent years, but a consensus is still lacking on prophylaxis for endophthalmitis. The aim of this prospective, observational study was to evaluate the prophylactic effect of azithromycin eye drops versus ofloxacin eye drops. Methods: The study was conducted in five hospitals in Spain and included all patients under going intravitreal injections of triamcinolone, bevacizumab, ranibizumab, or pegaptanib over one year. Patients received azithromycin 15 mg/g eye drops (twice daily on the day prior to injection and for another 2 days) or ofloxacin 3 mg/g eye drops (every 6 hours on the day prior to injection and for another 7 days). Results: In the azithromycin group, there were 4045 injections in 972 eyes of 701 patients. In the ofloxacin group, there were 4151 injections in 944 eyes of 682 patients. There were two cases of endophthalmitis (0.049%) in the azithromycin group and five (0.12%) in the ofloxacin group. The odds ratio of presenting with endophthalmitis in the ofloxacin group compared with the azithromycin group was 2.37 (95% confidence interval [CI] 1.32-3.72, P ,0.001). There were two cases of noninfectious uveitis after triamcinolone injection in the azithromycin group (0.049%) and two (0.048%) in the ofloxacin group; no significant differences were observed (odds ratio 0.902, 95% CI 0.622-1.407, P= 0.407). Conjunctival hyperemia was observed in 12 cases in the azithromycin group and none in the ofloxacin group. Conclusion: The risk of endophthalmitis was significantly greater with ofloxacin than with azithromycin. These findings provide a valuable addition to the ever-increasing pool of infor - mation on endophthalmitis prophylaxis after intravitreal injection, although further large-scale studies are required to provide definitive conclusions

PCIG: a web-based application to explore immune–genomics interactions across cancer types

Cancer; Application; Genomic alterationsCáncer; Aplicación; Alteraciones genómicasCàncer; Aplicació; Alteracions genòmiquesMotivation Genomic alterations can modulate the tumor immunophenotype depending on their nature and tissue of origin. Although this immune–genomic interaction may shape disease progression and response to immunotherapy, the factors governing such dynamics and the influence of each tissue-specific context remain poorly understood. Results Here, we have developed the PanCancer ImmunoGenomics (PCIG) tool, a web-based resource that provides researchers with the opportunity to mine immunome–genome relationships across several cancer types using data from the Pan-Cancer Analysis of Whole-Genomes (PCAWG) study, which comprises >2,600 samples spanning across 20 different cancer primary sites. PCIG yields an integrative analysis of the crosstalk between somatic genomic alterations and different immune features, thus helping to understand immune response-related processes.This work was supported by the Instituto de Salud Carlos III and co-funded by the European Regional Development Fund (ERDF) [CPII18/00026, PI17/01304], the CIBEREHD and CIBERNED programs from Instituto de Salud Carlos III, the Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya [2017 SGR 1035], and Fundación Científica de la Asociación Española Contra el Cáncer [GCB13131592CAST]. S.L. obtained a PFIS grant from Instituto de Salud Carlos III and co-funded by the European Regional Development Fund (ERDF) [FI18/00221]. R.E.F. is supported by a doctoral training grant from MICINN/MINECO [BES-2017-081286] and a mobility grant from Fundació Universitària Agustí Pedro i Pons. This article is based upon work from COST Action [CA17118] and supported by COST (European Cooperation in Science and Technology)

Estudio prospectivo de eficacia y seguridad de pegaptanib sodio en el tratamiento primario del edema macular secundario a trombosis venosa de la retina

Objectiu:Avaluar l'eficàcia i seguretat de pegaptanib de sodi en el tractament de l'edema macular secundari a obstrucció venosa de la retina (OVR). Mètode: Estudi prospectiu de 16 pacients amb edema macular secundari a OVR tractats mitjançant injeccions intravítrees de pegaptanib de sodi 1mg (0'05ml) a demanda amb un període de seguiment mínim de 6 mesos. Resultat: Millora significativa de l'agudesa visual i del perfil foveal en els nostres pacients. No alarmes de seguretat noves. Conclusions: Pegaptanib de sodi sembla proporcionar beneficis anatòmics i funcionals en el tractament de l'edema macular secundari a trombosis venosa de la retina.Objetivo: Evaluar la eficacia y seguridad de pegaptanib de sodio en el tratamiento del edema macular secundario a obstrucción venosa de la retina (OVR).Método: Estudio prospectivo de 16 pacientes con edema macular secundario a OVR tratados mediante inyecciones intravítreas de pegaptanib de sodio 1 mg (0'05ml) a demanda con un período de seguimiento mínimo de 6 meses. Resultado: Mejoría significativa de la agudeza visual y del perfil foveal en nuestros pacientes. No alarmas de seguridad nuevas.Conclusiones: Pegaptanib de sodio parece proporcionar beneficios anatómicos y funcionales en el tratamiento del edema macular secundario a trombosis venosa de la retina

Acute-Onset Endophthalmitis Caused by Alloiococcus otitidis following a Dexamethasone Intravitreal Implant

To report the first case of acute endophthalmitis caused by Alloiococcus otitidis after a dexamethasone intravitreal implant. A 74-year-old female was treated with intravitreal Ozurdex ® in her left eye for central retinal vein occlusion (CRVO). Best-corrected visual acuity (BCVA) in the eye was 4/20. Intravitreal injection was uneventful. At 48 h after injection, she developed ocular pain and visual acuity had dropped to light perception. Endophthalmitis associated with intravitreal injection was suspected. The patient did not show a favorable clinical response following systemic, intravitreal, and topical fortified antibiotics. We then performed a vitreous biopsy and removed the Ozurdex implant by pars plana vitrectomy. A vitreous culture was positive for A. otitidis. At the 2-month follow up, no inflammation was observed, but due to CRVO and probably aggravated by endophthalmitis, the fundus showed macular fibrosis. The final BCVA was finger counting at 30 cm in her left eye. In cases of an intravitreal implant associated with endophthalmitis, we recommend removal of the device because it may act as a permanent reservoir of organisms if it remains in the vitreous cavity

CNApp, a tool for the quantification of copy number alterations and integrative analysis revealing clinical implications.

Somatic copy number alterations (CNAs) are a hallmark of cancer, but their role in tumorigenesis and clinical relevance remain largely unclear. Here, we developed CNApp, a web-based tool that allows a comprehensive exploration of CNAs by using purity-corrected segmented data from multiple genomic platforms. CNApp generates genome-wide profiles, computes CNA scores for broad, focal and global CNA burdens, and uses machine learning-based predictions to classify samples. We applied CNApp to the TCGA pan-cancer dataset of 10,635 genomes showing that CNAs classify cancer types according to their tissue-of-origin, and that each cancer type shows specific ranges of broad and focal CNA scores. Moreover, CNApp reproduces recurrent CNAs in hepatocellular carcinoma and predicts colon cancer molecular subtypes and microsatellite instability based on broad CNA scores and discrete genomic imbalances. In summary, CNApp facilitates CNA-driven research by providing a unique framework to identify relevant clinical implications. CNApp is hosted at https://tools.idibaps.org/CNApp/

Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration?>?400?ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p?<?0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p?<?0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients

Elongin C (ELOC/TCEB1) associated von Hippel-Lindau disease.

BACKGROUND: Around 95% of patients with clinical features diagnostic of Von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the VCB-CR complex which plays a key role in oxygen sensing and degradation of hypoxia inducible factors. To date, only variants in VHL has been shown to cause VHL disease. MATERIALS AND METHODS: We undertook trio analysis by Whole-exome sequencing (WES) in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma data set was undertaken. RESULTS: A de novo pathogenic variant in ELOC (NM_005648.4:c.236A > G [p.Tyr79Cys]) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC) and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of a RCC from the proband showed similar findings to that in somatically ELOC mutated RCC (expression of hypoxia responsive proteins, no somatic VHL variants and chromosome 8 loss). CONCLUSIONS: These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant

Chromothripsis in acute myeloid leukemia: Biological features and impact on survival

Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix\uae) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p &lt; 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p &lt; 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p &lt; 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Background Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Methods Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. Results Among 1336 RCC participants (mean 61.3 years [±12SD], range 13–88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). Conclusions Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing