C6orf10 low-frequency and rare variants in italian multiple sclerosis patients

In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value <= 5 x 10(-6)). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) <= 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs 16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 x 10(-7) and p < 1 x 10(-20)). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3' region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value ≤ 5 × 10−6). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10−7 and p < 1 × 10−20). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3′ region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS

Haemorrhagic Presentation of a Craniopharyngioma in a Pregnant Woman

Objective. Craniopharyngioma is a rare tumour, and, consequently, acute clinical presentation and diagnosis, during pregnancy, of this pathology are quite difficult to find. Only few cases are reported in the literature, and no one describes these two conditions in association. Methods. We report a particular case of craniopharyngioma presenting both of the above conditions. Results. The patient was successfully operated with endoscopic technique. Conclusions. Rare and difficult cases, created by the superposition of different clinical conditions, need multidisciplinary management, with collaboration, integration, and cooperation between different medical specialists

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers

About 100 km east of Rome, in the central Apennine Mountains, a critically endangered population of ∼50 brown bears live in complete isolation. Mating outside this population is prevented by several 100 km of bear-free territories. We exploited this natural experiment to better understand the gene and genomic consequences of surviving at extremely small population size. We found that brown bear populations in Europe lost connectivity since Neolithic times, when farming communities expanded and forest burning was used for land clearance. In central Italy, this resulted in a 40-fold population decline. The overall genomic impact of this decline included the complete loss of variation in the mitochondrial genome and along long stretches of the nuclear genome. Several private and deleterious amino acid changes were fixed by random drift; predicted effects include energy deficit, muscle weakness, anomalies in cranial and skeletal development, and reduced aggressiveness. Despite this extreme loss of diversity, Apennine bear genomes show nonrandom peaks of high variation, possibly maintained by balancing selection, at genomic regions significantly enriched for genes associated with immune and olfactory systems. Challenging the paradigm of increased extinction risk in small populations, we suggest that random fixation of deleterious alleles (i) can be an important driver of divergence in isolation, (ii) can be tolerated when balancing selection prevents random loss of variation at important genes, and (iii) is followed by or results directly in favorable behavioral changes

Advanced lung cancer inflammation index and its prognostic value in HPV-negative head and neck squamous cell carcinoma: a multicentre study

Purpose: The aim of this study is to evaluate the prognostic value of pre-treatment advanced lung cancer inflammation index (ALI) in patients with HPV-negative HNSCC undergoing up-front surgical treatment. Methods: The present multi-centre, retrospective study was performed in a consecutive cohort of patients who underwent upfront surgery with or without adjuvant (chemo)-radiotherapy for head and neck squamous cell carcinoma (HNSCC). Patients were stratified by ALI, and survival outcomes were compared between groups. In addition, the prognostic value of ALI was compared with two other indices, the prognostic nutritional index (PNI) and systemic inflammatory index (SIM). Results: Two hundred twenty-three patients met the inclusion criteria (151 male and 72 female). Overall and progression-free survival were significantly predicted by ALI &lt; 20.4 (HR 3.23, CI 1.51–6.90 for PFS and HR 3.41, CI 1.47–7.91 for OS). Similarly, PNI &lt; 40.5 (HR = 2.43, 95% CI: 1.31–4.51 for PFS and HR = 2.40, 95% CI: 1.19–4.82 for OS) and SIM &gt; 2.5 (HR = 2.51, 95% CI: 1.23–5.10 for PFS and HR = 2.60, 95% CI: 1.19–5.67 for OS) were found to be significant predictors. Among the three indices, ALI &lt; 20.4 identified the patients with the worst 5-year outcomes. Moreover, patients with a combination of low PNI and low ALI resulted to be a better predictor of progression (HR = 5.26, 95% CI: 2.01–13.73) and death (HR = 5.68, 95% CI: 1.92–16.79) than low ALI and low PNI considered alone. Conclusions: Our results support the use of pre-treatment ALI, an easily measurable inflammatory/nutritional index, in daily clinical practice to improve prognostic stratification in surgically treated HPV-negative HNSCC

Ceramic Femoral Components in Total Knee Arthroplasty - Two Year Follow-Up Results of an International Prospective Multi-Centre Study

BACKGROUND: Total knee arthroplasty can be considered as a reliable surgical procedure with a good long-term clinical result. However, implant failure due to particle induced aseptic loosening as well as the aspect of hypersensitivity to metal ions still remains an emerging issue. METHODS: The purpose of this prospective international multi-centre study was to evaluate the clinical and radiological outcomes and the reliability of the unconstrained Multigen Plus Total Knee System with a new BIOLOX® delta ceramic femoral component. Cemented total knee arthroplasty was performed on 108 patients (110 knees) at seven hospitals in three countries. Clinical and radiological evaluations were performed preoperatively, and after 3, 12 and 24 months postoperatively using the HSS-, WOMAC-, SF-36-score and standardised X-rays. RESULTS: The mean preoperative HSS-Score amounted to 55.5 ± 11.5 points and improved significantly in all postoperative evaluations (85.7 ± 11.7 points at 24 months). Furthermore, improvements in WOMAC- and SF-36-score were evaluated as significant at all points of evaluation. Radiolucent lines around the femoral ceramic component at 24 months were found in four cases. Progression of radiolucent lines was not seen and no implant loosening was observed. During the 24 month follow-up eight patients underwent subsequent surgery due to reasons unrelated to the implant material. CONCLUSIONS: The observed clinical and radiological results are encouraging for a long-term survival of the ceramic femoral component. Therefore, ceramic implants could be a promising solution not only for patients with allergies against metallic implant materials, but also for the osteoarthritic knee joint. Long-term follow-up is necessary to draw conclusions regarding the superiority of the ceramic knee implants concerning in vivo wear and long-term survivorship

Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma

BackgroundRefractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease.Patients and MethodsBetween 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters.ResultsAll patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (&lt;3 disease sites), and plasma EBV-DNA &lt;1000 copies/mL had a better outcome.ConclusionsAutologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial

Can Clinical and Surgical Parameters Be Combined to Predict How Long It Will Take a Tibia Fracture to Heal? A Prospective Multicentre Observational Study: The FRACTING Study

Background. Healing of tibia fractures occurs over a wide time range of months, with a number of risk factors contributing to prolonged healing. In this prospective, multicentre, observational study, we investigated the capability of FRACTING (tibia FRACTure prediction healING days) score, calculated soon after tibia fracture treatment, to predict healing time. Methods. The study included 363 patients. Information on patient health, fracture morphology, and surgical treatment adopted were combined to calculate the FRACTING score. Fractures were considered healed when the patient was able to fully weight-bear without pain. Results. 319 fractures (88%) healed within 12 months from treatment. Forty-four fractures healed after 12 months or underwent a second surgery. FRACTING score positively correlated with days to healing: r = 0.63 (p &lt; 0.0001). Average score value was 7.3 \ub1 2.5; ROC analysis showed strong reliability of the score in separating patients healing before versus after 6 months: AUC = 0.823. Conclusions. This study shows that the FRACTING score can be employed both to predict months needed for fracture healing and to identify immediately after treatment patients at risk of prolonged healing. In patients with high score values, new pharmacological and nonpharmacological treatments to enhance osteogenesis could be tested selectively, which may finally result in reduced disability time and health cost savings