Gold-catalyzed endo-selective cyclization of alkynylcyclobutanecarboxamides: synthesis of cyclobutane-fused dihydropyridones.

Cyclobutane-fused dihydropyridones can be efficiently synthesized by a completely endo-selective gold-catalyzed cyclization of alkynylcyclobutanes bearing an appended amide, which proceeds under mild conditions. The observed selectivity, which is reversed from that previously observed for the cyclization of related alcohols and acids, is supported by DFT calculations.

High dose craniospinal irradiation as independent risk factor of permanent alopecia in childhood medulloblastoma survivors: cohort study and literature review.

PURPOSE: Our aim was to determine the main risk factors related to the occurrence of permanent alopecia in childhood medulloblastoma (MB) survivors. METHODS: We retrospectively analyzed the clinical features of all consecutive MB survivors treated at our institute. We divided the patients into 3 groups depending on the craniospinal irradiation (CSI) dose received and defined permanent alopecia first in terms of the skin region affected (whole scalp and nape region), then on the basis of the toxicity degree (G). Any relationship between permanent alopecia and other characteristics was investigated by a univariate and multivariate analysis and Odds ratio (OR) with confidence interval (CI) was reported. RESULTS: We included 41 patients with a mean10-year follow-up. High dose CSI resulted as an independent factor leading to permanent hair loss in both groups: alopecia of the whole scalp (G1 p-value 0.030, G2 p-value 0.003) and of the nape region (G1 p-value 0.038, G2 p-value 0.006). The posterior cranial fossa (PCF) boost volume and dose were not significant factors at multivariate analysis neither in permanent hair loss of the whole scalp nor only in the nuchal region. CONCLUSION: In pediatric patients with MB, the development of permanent alopecia seems to depend only on the CSI dose ≥ 36 Gy. Acute damage to the hair follicle is dose dependent, but in terms of late side effects, constant and homogeneous daily irradiation of a large volume may have a stronger effect than a higher but focal dose of radiotherapy.

Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are frequent in Parkinson's disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD. METHODS: We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease for ICDs screening. Motor, nonmotor, and treatment-related features were evaluated according to the presence of ICDs. Twenty-one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs. RESULTS: Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical-genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms. CONCLUSIONS: Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient's genetic background to identify individuals at risk for ICDs.

Synthesis and Photophysical Behavior of a Highly Fluorescent Family of Unsymmetrical Organoboron Complexes Containing 5-(Pyridin-2-ylmethylene)imidazolidine-2,4-dione Moieties.

A new and highly fluorescent family of unsymmetrical organoboron complexes containing 5-(pyridin-2-ylmethylene)imidazolidine-2,4-dione moieties has been synthesized in three steps. These compounds show strong absorptions covering a wide range of the UV-vis spectrum and are strongly emissive (ϕf of up to 0.92 in CH3CN). Moreover, two fluorophores that include an alkyne or an azide group at the end of the alkyl chain and with potential utility in bioorthogonal chemistry have been developed. One of these, in which the glycol substituent provides an enhanced water solubility without compromising the fluorescence (ϕf = 0.85 in water), may be of particular importance.

Regiodivergent Electrophilic Cyclizations of Alkynylcyclobutanes for the Synthesis of Cyclobutane-Fused O-Heterocycles.

Cyclobutane-fused dihydropyrans and methylenetetrahydrofurans are highly interesting cores found in numerous natural products. Both these cores are selectively prepared from a common alkynylcyclobutane precursor bearing an appended hydroxyl group herein. Thus, cyclobutane-fused dihydropyrans can be obtained by a selective 6-endo-dig iodocyclization, whereas gold-catalyzed 5-exo-dig cycloisomerization provides a bicyclic core containing a methylenetetrahydrofuran moiety as major product. Several cyclobutane-fused O-heterocycles with diverse substituents are synthesized following the reported methodology.

Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis.

In the present study, we aimed to investigate the influence of clinical parameters and single-nucleotide polymorphisms of interleukin-6 receptor (rs12083537, rs2228145, rs4329505 and rs11265618) on response to tocilizumab, TCZ (European League Against Rheumatism (EULAR) response, remission, low disease activity (LDA) and improvement of DAS28). We performed a retrospective cohort study in patients with Rheumatoid Arthritis (RA) treated with TCZ for 12 months. Multivariable analysis showed that the only variable independently associated to satisfactory EULAR response (odds ratio (OR): 0.61; 95% of confidence interval (CI)95%: 0.42, 0.88; P=0.008), remission (OR: 0.51; CI95%: 0.35, 0.75; P=0.001), LDA (OR: 0.41; CI95%: 0.24, 0.72; P=0.002) and improvement in DAS28 (B=-0.32; CI95%): -0.47, -0.17; P=7.5 × 10-5) at 12 months was lower number of previous biological therapy (BT). High baseline DAS28 was also associated with a greater decrease in DAS28 at 12 months of treatment (B=0.99; CI95%: 0.79, 1.20; P=1.5 × 10-14). Those patients who were carriers of AA genotypes for rs12083537 (OR: 13.0; CI95%: 2.31, 72.91; P=0.004) and CC for rs11265618 (OR: 12.15; CI95%: 2.18, 67.81; P=0.004) had better LDA response at 12 months of treatment with TCZ. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates when a lower number of BT were previously administered. The AA genotype for rs12083537 and CC for rs11265618 polymorphisms for may act as predictors of good response LDA.

Pharmacogenetic biomarkers of response in Crohn's disease.

Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients.

Genomic approaches in the search for molecular biomarkers in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is recognised as a global public health problem, more prevalent in older persons and associated with multiple co-morbidities. Diabetes mellitus and hypertension are common aetiologies for CKD, but IgA glomerulonephritis, membranous glomerulonephritis, lupus nephritis and autosomal dominant polycystic kidney disease are also common causes of CKD. MAIN BODY: Conventional biomarkers for CKD involving the use of estimated glomerular filtration rate (eGFR) derived from four variables (serum creatinine, age, gender and ethnicity) are recommended by clinical guidelines for the evaluation, classification, and stratification of CKD. However, these clinical biomarkers present some limitations, especially for early stages of CKD, elderly individuals, extreme body mass index values (serum creatinine), or are influenced by inflammation, steroid treatment and thyroid dysfunction (serum cystatin C). There is therefore a need to identify additional non-invasive biomarkers that are useful in clinical practice to help improve CKD diagnosis, inform prognosis and guide therapeutic management. CONCLUSION: CKD is a multifactorial disease with associated genetic and environmental risk factors. Hence, many studies have employed genetic, epigenetic and transcriptomic approaches to identify biomarkers for kidney disease. In this review, we have summarised the most important studies in humans investigating genomic biomarkers for CKD in the last decade. Several genes, including UMOD, SHROOM3 and ELMO1 have been strongly associated with renal diseases, and some of their traits, such as eGFR and serum creatinine. The role of epigenetic and transcriptomic biomarkers in CKD and related diseases is still unclear. The combination of multiple biomarkers into classifiers, including genomic, and/or epigenomic, may give a more complete picture of kidney diseases.

Relationship between plasma bilirubin level and oxidative stress markers in HIV-infected patients on atazanavir- vs. efavirenz-based antiretroviral therapy.

OBJECTIVES: Chronic oxidative stress (OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UDP-glucuronosyl-transferase 1A1 (UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line antiretroviral therapy (ART). METHODS: A multicentre, prospective cohort study of HIV-infected patients who started first-line ART with either ATV/r or EFV was conducted. Lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO) and oxidized low-density lipoprotein (oxLDL) were measured for 145 patients in samples obtained at baseline and after at least 9 months of ART during which the initial regimen was maintained and the patient was virologically suppressed. The change in OS markers was modelled using multiple linear regressions adjusting for baseline values and confounders. RESULTS: After adjustment for baseline variables, patients on ATV/r had a significantly greater decrease in Lp-PLA2 [estimated difference -16.3; 95% confidence interval (CI) -31.4, -1.25; P = 0.03] and a significantly smaller increase in OxLDL (estimated difference -21.8; 95% CI -38.0, -5.6; P < 0.01) relative to those on EFV, whereas changes in MPO were not significantly different (estimated difference 1.2; 95% CI -14.3, 16.7; P = 0.88). Adjusted changes in bilirubin were significantly greater for the ATV/r group than for the EFV group (estimated difference 1.33 mg/dL; 95% CI 1.03, 1.52 mg/dL; P < 0.01). Changes in bilirubin and changes in OS markers were significantly correlated. CONCLUSIONS: When compared with EFV, ATV/r-based therapy was associated with lower levels of oxidative stress biomarkers, which was in part attributable to increased bilirubin levels.

Pineal germinoma in a child with interferon-γ receptor 1 deficiency. case report and literature review.

Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important.

Could 18F-FDG-PET/CT avoid unnecessary thyroidectomies in patients with cytological diagnosis of follicular neoplasm?

PURPOSE: Preoperative diagnosis of thyroid nodules with "follicular neoplasm" (FN) based on fine-needle aspiration cytology (FNAC) forces thyroidectomy to exclude malignancy. This study explores if (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) provides information enough to prevent unnecessary thyroidectomies in this clinical setting. METHODS: This is a prospective study involving 46 consecutive patients scheduled for thyroidectomy due to follicular neoplasm diagnosis in FNAC (36 follicular, 10 Hürthle cell neoplasms, Bethesda classification) since January 2009 until April 2012. All patients underwent preoperative (18)F-FDG-PET/CT. Abnormal (18)F-FDG thyroid uptake was assessed visually and by measuring the maximum standard uptake value (SUV max). Results were compared with definitive pathology reports. RESULTS: Thirteen out of 46 patients (28.3 %) were finally diagnosed with thyroid cancer. Focal uptake correlated with a greater risk of malignancy (p = 0.009). (18)F-FDG-PET/CT focal uptake showed sensitivity, specificity, positive and negative predictive values and overall accuracy of 92.3, 48.5, 41.4, 94.1 and 60.9 %, respectively. The optimal threshold SUV max to discriminate malignancy was 4.2 with an area under receiver-operating characteristic curve of 0.76 (95 % confidence interval, 0.60-0.90). Use of (18)F-FDG-PET/CT could reduce by 13-25 % the number of thyroidectomies performed for definitive benign nodules. However, it has demonstrated worse predictive ability in the subgroup of patients with diffuse uptake, oncocytic pattern in FNAC and lesions smaller than 2. CONCLUSIONS: (18)F-FDG-PET/CT can play a role in the management of thyroid nodules larger than 2 cm cytologically reported as follicular neoplasm without oncocytic differentiation, allowing the avoidance of a significant number of thyroidectomies for definitive benign lesions.

DNA barcoding of the genus Apaidia Hampson, 1900 for species delimitation from Western Mediterranean fauna (Lepidoptera, Erebidae).

The genus Apaidia Hampson, 1900 is a relict Western Mediterranean genus in the South-western part of Europe and the North-western areas of the Mediterranean Africa comprising so far three species, Apaidia rufeola (Rambur, 1832), Apaidia mesogona (Godart, [1824]) and Apaidia barbarica Legrand, 1939. According to the examined material, COI mitochondrial DNA sequences and adult morphology integration supports the existence of three main lineages of Apaidia with sequence divergence rates of approximately 4.5%, which are within the range reported for other well-defined insect species. In addition, we recovered three different BINS, suggesting the presence of different species with unique and specific identifier for A. mesogona (AEC6797), A. rufeola (AEI9539), and the Iberian-Balearic A. barbarica (AEI9540). This study contributes to a better understanding of the taxonomy of the genus Apaidia and challenges future revision of this genus in Northern Africa, as well as the presence of the Apaidia species in Western Mediterranean islands and populations located in Italy.

[Soft tissue infection associated with bacteremia caused by Shewanella putrefaciens]. / Dermohypodermite et bactériémie àShewanella putrefaciens.

Shewanella putrefaciens is rarely involved in human infectious disease. We report here a case of soft tissue infection with bacteremia on a patient with risk factors (liver cirrhosis, diabetes mellitus).

[Epidemiology of healthcare-associated infections due to MRSA in Brest University Hospital from 2004 to 2007. Impact of hydroalcoholic gel and antibiotics consumptions]. / Épidémiologie des infections nosocomiales à SARM au CHU de Brest du 1(er) janvier 2004 au 31 décembre 2007. Impact des consommations de produits hydroalcooliques et d'antibiotiques.

UNLABELLED: The fight against healthcare-associated infections is based on preventive measures of multidrug resistant bacteria diffusion. Hand hygiene is the simplest and the most effective preventive measure to reduce cross-transmission of infectious agents. Hydroalcoholic solutions for hand hygiene was recently introduced in the University Hospital of Brest (France). The aims of the study were: to describe the epidemiology of healthcare-associated infections due to methicillin-resistant Staphylococcus aureus (MRSA); to determine the annual consumptions of antistaphylococcal antibiotics; and to discuss the relation between consumption of antiseptic products or antibiotics and the epidemiology of MRSA. METHODS: A retrospective epidemiological and pharmaco-epidemiological study was realized from January 2004 to December 2007 in the University Hospital of Brest (France). It allowed to bring to light the cases of healthcare-associated infections due to MRSA and to quantify the consumptions of hang hygiene products and antistaphylococcal antibiotics. RESULTS: this retrospective study showed a decrease of healthcare-associated infections due to MRSA and an increase of the consumption of hydroalcoholic solutions. Antistaphylococcal resistance rates also decreased in a context of fall of the global antibiotics consumption in the hospital.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Understanding biological dynamics: following cells and molecules to track functions and mechanisms.

The dissection of the molecular circuitries at the base of cell life and the identification of their abnormal transformation during carcinogenesis rely on the characterization of biological phenotypes generated by targeted overexpression or deletion of gene products through genetic manipulation. Fluorescence microscopy provides a wide variety of tools to monitor cell life with minimal perturbations. The observation of living cells requires the selection of a correct balance between temporal, spatial and "statistical" resolution according to the process to be analyzed. In the following paper ad hoc developed optical tools for dynamical tracking from cellular to molecular resolution will be presented. Particular emphasis will be devoted to discuss how to exploit light-matter interaction to selectively target specific molecular species, understanding the relationships between their intracellular compartmentalization and function.

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma.

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity. A retrospective cohort study was conducted in 194 CRC patients. In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009). ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

Identification of a SUFU germline mutation in a family with Gorlin syndrome.

Gorlin syndrome (GS) is inherited in an autosomal dominant pattern with high-penetrance and is characterized by a range of developmental anomalies and increased risk of developing basal cell carcinoma and medulloblastoma. Between 50% and 85% of patients with GS harbor germ line mutations in the only susceptibility gene identified to date, PTCH1, a key component in the Sonic Hedgehog signaling pathway. Another component in this pathway, SUFU, is known to be involved in susceptibility to medulloblastoma but has never been reported in GS patients to date. We have identified the known c.1022 + 1G>A SUFU germ line splicing mutation in a family that was PTCH1-negative and who had signs and symptoms of GS, including medulloblastoma. This is the first report of a germ line SUFU mutation associated with GS.

Proteomic and metabolomic approaches in the search for biomarkers in chronic kidney disease.

Chronic kidney disease (CKD) is an aging-related disorder that represents a major global public health burden. Current biochemical biomarkers, such as serum creatinine and urinary albumin, have important limitations when used to identify the earliest indication of CKD or in tracking the progression to more advanced CKD. These issues underline the importance of finding and testing new molecular biomarkers that are capable of successfully meeting this clinical need. The measurement of changes in nature and/or levels of proteins and metabolites in biological samples from patients provide insights into pathophysiological processes. Proteomic and metabolomic techniques provide opportunities to record dynamic chemical signatures in patients over time. This review article presents an overview of the recent developments in the fields of metabolomics and proteomics in relation to CKD. Among the many different proteomic biomarkers proposed, there is particular interest in the CKD273 classifier, a urinary proteome biomarker reported to predict CKD progression and with implementation potential. Other individual non-invasive peptidomic biomarkers that are potentially relevant for CKD detection include type 1 collagen, uromodulin and mucin-1. Despite the limited sample sizes and variability of the metabolomics studies, some metabolites such as trimethylamine N-oxide, kynurenine and citrulline stand out as potential biomarkers in CKD.

Successful isolation and long-term establishment of a cell line with stem cell-like features from an anaplastic medulloblastoma.

AIMS: Herein we report on the successful isolation and establishment of a novel, long-term, primary, neurosphere-like cell line called 1603-MED from a 5-year-old boy affected by a highly aggressive anaplastic medulloblastoma. METHODS: Elaboration of the new protocol for neurosphere assay is extensively discussed, together with a complete immuno-histochemical and cytogenetic characterization of 1603-MED. RESULTS: Clinical course and histopathology are briefly discussed. The 1603-MED possesses a high capacity for proliferation, CD133 expression, self-renewal and differentiation, thus indicating that anaplastic medulloblastoma contains a subpopulation of cancer stem cells as observed in classic medulloblastoma. CONCLUSIONS: 1603-MED provides us with the first in vitro model of anaplastic medulloblastoma that may be suitable for studying both tumour progression and the genetic mechanisms related to therapy resistance, and may lead to the development and testing of chemosensitivity and new therapeutic targets.