Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy

Summary Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems

The Great Recession of 2007 and the Housing Market Crash: Why Did So Many Builders Fail? Lessons for the Local Homebuilding Industry

The “Great Recession” of 2007 created havoc in the homebuilding industry, more than any other previous economic down cycle. Countless seasoned local homebuilders across the country did not survive. The impact of their failure on the economy, community, employment, lenders, suppliers, and subcontractors was devastating. While previous studies have sought to identify the symptoms and causes of business failure, very little research has been done on home builder business failure due to acts, omissions, characteristics, or other events which are non-financial. Specifically, those that are attributable to the failed entities' top management and leadership during the housing crisis and the Great Recession. Therefore, the purpose of this qualitative inquiry is to uncover those nonfinancial factors and help to fill the gap in the literature. Additionally, we seek to find specific strategies that could be incorporated into the business models of local homebuilders which allow them to anticipate and navigate turbulent economic times. The ultimate goal of such strategies, however, is to shield the organizations of those builders from the negative effects of recessions and allow them to thrive in the aftermath

The Great Recession of 2007 and the Housing Market Crash: Why Did So Many Builders Fail?

The “Great Recession” of 2007 created havoc in the homebuilding industry, more than any other previous economic down cycle. Countless seasoned local homebuilders across the country did not survive. The impact of their failure on the economy, community, employment, lenders, suppliers, and subcontractors was devastating. While previous studies have sought to identify the symptoms and causes of business failure, very little research has been done on home builder business failure due to acts, omissions, characteristics, or other events which are non-financial. Specifically, those that are attributable to the failed entities\u27 top management and leadership during the housing crisis and the Great Recession. Therefore, the purpose of this qualitative inquiry is to uncover those nonfinancial factors and help to fill the gap in the literature Additionally, we seek to find specific strategies that could be incorporated into the business models of local homebuilders which allow them to anticipate and navigate turbulent economic times. The ultimate goal of such strategies, however, is to shield the organizations of those builders from the negative effects of recessions and allow them to thrive in the aftermath

Dravet Syndrome in Lebanon: First Report on Cases with SCN1A Mutations

Dravet syndrome, also known as severe myoclonic epilepsy in infancy, is a rare disease characterized by the appearance of different types of seizures in a healthy baby, triggered by various factors and stressful events. We report 8 Lebanese cases referred for molecular analysis of the SCN1A gene. Results were positive in 7 cases and revealed de novo variants at the heterozygous state in different exons of the gene for all except one, where the variant was intronic. Four variants were novel. Confirmation of Dravet syndrome is important for a better follow-up and treatment, preventing the occurrence of status epilepticus and severe neurological deterioration

Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases

International audienc

Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer

International audienceImportance: Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers.Objective: To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer.Design, setting, and participants: This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022.Interventions: The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning).Main outcomes and measures: The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival.Results: A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms.Conclusions and relevance: This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates.Trial registration: ClinicalTrials.gov Identifier: NCT01874587

OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer

International audienc

Early toxicity of a phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer (OLIGOPELVIS GETUG P07)

International audiencePURPOSE:Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiotherapy as considered in the BLINDED trial, is an attractive option but with concerns about its toxicity. This article describes early toxicity with the technique.METHODS AND MATERIALS:BLINDED was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH-PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Early toxicity was defined until one year after radiotherapy. Patients quality of life was assessed using the EORTC questionnaires (QLQ-C30 and QLQ-PR25).RESULTS:Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9/67 patients (13.4%) and grade 2 one-year toxicity in 4/67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10/67 patients (14.9%) and grade 2 one-year toxicity in 4/67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. EORTC questionnaire scores at one year did not worsen significantly.CONCLUSIONS:The acute and one-year toxicity of the BLINDED protocol was satisfactory, even in patients with a past history of prostatic irradiation