Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia.

G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response. We hypothesized that this polymorphism may be associated with response to antipsychotics in a population of 145 chronic schizophrenic patients deriving from two study-samples and being mainly treated with clozapine for up to 6 months. Overall, the C/C genotype was significantly associated with relative clinical improvement as measured by Brief Psychiatric Rating Scale (BPRS) change scores after 6 and 12 weeks (p<0.01 and p=0.03, respectively), with estimated effect sizes ranging from 4.8 to 7%. Our results further suggest that this effect is only attributable to Caucasians when compared to African-Americans. Moreover, our findings point to the role of intracellular mechanisms in antipsychotic response.     

Dedifferentiated chordoma of the thoracic spine with rhabdomyosarcomatous differentiation. Report of a case and review of the literature

A case of spinal thoracic chordoma involving the T9 vertebra in a 70-year-old male patient, destroying the vertebral body and invading the vertebral canal with compression of the spinal cord, is presented. The patient was referred to our neurosurgical unit with a history of an irradiated metastatic adenocarcinoma to the thoracic vertebra, a diagnosis that was rendered 3 years earlier at another hospital on presentation. This misdiagnosis was likely due to the absolute rarity of thoracic vertebral chordomas (2%-3% of all chordomas), the higher frequency of metastatic deposits to the vertebrae from visceral cancers in the elderly, the limited amount of biopsy material available for histologic examination, and the epithelial phenotype of the tumor (keratin/EMA positive). The patient underwent second palliative surgery with subtotal piecemeal removal of the tumor bringing relief of the neurologic symptoms. The bulk of the tumor was represented by a high-grade pleomorphic sarcoma with adjacent areas of atypical chordoma. Small foci of conventional chordoma were also found. The previous histologic slides were also reviewed, which were consistent with the areas of atypical chordoma. Small targeted tissue fragments from areas of (atypical) chordoma and from sarcomatous areas were recovered for electron microscopy. The fine features of chordoma and focal rhabdomyoblastic differentiation were found with the latter retrospectively supported by immunohistochemical detection of striated muscle markers. A final diagnosis of dedifferentiated chordoma with rhabdomyoblastic differentiation was finally established. Rhabdomyoblastic metaplasia is a novelty in dedifferentiated chordoma. The patient died after 5 months. Autopsy was not requested.     

Measurement of local strains induced into the femur by trochanteric Gamma nail implants with one or two distal screws

This study aims to evaluate experimentally the behaviour after fracture consolidation of two intramedullary Gamma nail implants, having one (G1) or two (G2) distal screws, respectively. Nails have been implanted into standardized synthetic femora, instrumented with strain gauges. Strains measurements, supported by finite element numerical modelling, showed that the G2 implant, although ensuring higher flexional and torsional stiffness, can lead to localized contacts that occur between the tip of the nail and the femoral endosteum. This might be one of the reasons of the complications associated with pain in the mid-portion of the thigh after implantation which has been reported in several clinical studies when Gamma nails with two distal screws are used.     

A two-signal model for T cell trafficking

T-cell-receptor triggering and the delivery of co-stimulation are essential events leading to T cell expansion, differentiation and effector function. The influence that such signals exert on T cell migration during and following priming has been highlighted by recent reports. Moreover, induction of peripheral tolerance might act in part by affecting T cell migration. Here, we propose that the integration of co-stimulatory signals, which regulate the ability of primed T cells to access nonlymphoid tissue, and cognate recognition of the endothelium, which determines the selective recruitment of specific T cells, contribute to the anatomy of T cell-mediated immunity and tolerance. The implications for therapeutic strategies manipulating these signals are discussed.     

ENPP1 gene, insulin resistance and related clinical outcomes

PURPOSE OF REVIEW: Insulin resistance plays a significant role in both morbidity and mortality of the general population. Understanding the molecular mechanisms of insulin resistance would help the identification of at-risk individuals in the presymptomatic stage, and the discovery of novel and more effective treatments. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin receptor signalling and has recently emerged as a key player in the development of insulin resistance. This review will summarize data available on the relationship between ENPP1 and insulin resistance. RECENT FINDINGS: Overexpression of ENPP1 in insulin target tissues is an early, intrinsic defect observed in human insulin resistance. A missense ENPP1 single nucleotide polymorphism, K121Q, has been recently described with the Q121 variant being a stronger inhibitor than K121 of insulin receptor function. In addition, the Q121 variant has been repeatedly associated with insulin resistance and related abnormalities including body weight changes, type 2 diabetes and macrovascular complications, thus suggesting a pleiotropic role of the ENPP1 gene on several metabolic abnormalities. SUMMARY: A deep understanding of ENPP1 mode of action and the mechanisms regulating its expression and function are likely to provide new tools for early identification and treatments of patients at risk for the devastating clinical outcomes related to insulin resistance.     

Potential role of serum mesothelin in predicting survival of patients with malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66–1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.     

Advanced head and neck cancer in older adults: Results of a short course accelerated radiotherapy trial

ObjectivesTo assess the feasibility and safety of a repeated SHort course Accelerated RadiatiON therapy (SHARON) regimen in the palliative setting of Head and Neck (H&N) cancer in older adults.Material and MethodsPatients with histological confirmed H&N cancers, age ≥ 80 years, expected survival >3 months, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 were enrolled. Patients were treated in cohorts of six patients: a total dose of 20 Gy was delivered in 2 consecutive days with a twice-daily fractionation (5 Gy per fraction) and at least 8-h interval. If no Grade 3 toxicity was registered, a second enrollment started with another cohort of six patients to whom were administered two cycles (total dose of 40 Gy). The primary endpoint was to evaluate the feasibility of the two cycles of treatment. Secondary endpoints were evaluation of symptoms control rate, symptoms-free survival (SFS), and Quality of Life (QoL) scores.ResultsSeventeen consecutive patients (median age: 85 years) were treated. Nine patients were treated with one cycle and 8 patients with two cycles. No G3 toxicity was reported in either cohort. With a median follow-up time of 4 months, 3-month SFS in the first and second cohorts was 83.3%, and 87.5%, respectively. The overall palliative response rate was 88%. Among 13 patients reporting pain, 8 (61.5%) showed an improvement or resolution of their pain.ConclusionRepeated short course accelerated radiotherapy in a palliative setting of H&N cancers is safe and well-tolerated in older adults.