Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis

A recent Genome-wide Association Study (GWAS) identified association with variants in X-linked CLDN2 and MORC4 and PRSS1-PRSS2 loci with Chronic Pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at s \sqrt{\mathrm{s}} = 13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at s √ s = 13 TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb−1. Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12±0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations

Search for electroweak production of charginos and neutralinos in proton-proton collisions at s \sqrt{s} = 13 TeV

A direct search for electroweak production of charginos and neutralinos is presented. Events with three or four leptons, with up to two hadronically decaying τ leptons, or two same-sign light leptons are analyzed. The data sample consists of 137 fb−1 of proton-proton collisions with a center of mass energy of 13 TeV, recorded with the CMS detector at the LHC. The results are interpreted in terms of several simplified models. These represent a broad range of production and decay scenarios for charginos and neutralinos. A parametric neural network is used to target several of the models with large backgrounds. In addition, results using orthogonal search regions are provided for all the models, simplifying alternative theoretical interpretations of the results. Depending on the model hypotheses, charginos and neutralinos with masses up to values between 300 and 1450 GeV are excluded at 95% confidence level

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe

Pyridoxine to protect from oxaliplatin-induced neurotoxicity without compromising antitumour effect

Purpose: Oxaliplatin (OHP) in combination with 5-Xuorouracil/leucovorin (FOLFOX) is clinically used as frontline therapy in patients with advanced colorectal carcinoma (CRC), with response rates ranging from 46 to 71%. This combination is now considered a standard treatment for metastatic CRC and also in the post-operative adjuvant setting. Reversible, cumulative, peripheral sensory neuropathy is the principal dose-limiting toxicity of OHP therapy. Pyridoxine (vitamin B6) has been shown to reduce cisplatin and Xuoropyrimidine-related neurotoxicity but its administration with OHP has not yet been studied. Low doses of pyridoxine are free of side effects; it can be given orally. If pyridoxine administration with oxaliplatin has no adverse effect on OHP cytotoxicity effects, it will be a simple and cost-effective way to minimise OHP-induced neurotoxicity. Methods: In vitro simultaneous combination of OHP and pyridoxine was studied in 6 CRC cell lines (HT29, Widr, SW480, HCT116, H630 and SW1116), in an ovarian cancer cell line (A2780) and its cisplatin-resistant subline (ADDP) and in an oestrogen-dependent breast cancer cell line (MCF-7). Three fixed concentrations of pyridoxine: 1, 10 and 25 μM were combined with varying concentrations of OHP, and the growth inhibitory effects were evaluated using the MTT cell growth assay. Results: Oxaliplatin induced consistent cytotoxicity in all cell lines with GI₅₀ values between 0.23 and 7.6 μM. Addition of pyridoxine at concentrations of 1–25 μM does not affect OHP cytotoxicity. Conclusions: Administration of pyridoxine, at concentrations extending across possible therapeutic plasma levels in humans, does not antagonise OHP antitumour effects in a range of relevant tumour cell lines. This study provides a foundation for clinical studies to test whether pyridoxine can minimise OHP-related neurotoxicity, and clinicians can be confident that pyridoxine is very unlikely to reverse the antitumour effects of OHP, as seems to be the case with Ca/Mg infusions. This could prove to be a cost-effective way to minimise OHP-related neurotoxicity, allowing more effective less toxic treatment and better outcomes in patients

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites,o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA)provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites,DDE and DDA.The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77–88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ226nm. Inter and intraday validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2μg/ml for mitotane and DDE, and 0.5μg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1–18 times higher than the parent compound

First-in-human phase I study of infusional and bolus schedules of Deflexifol, a novel 5-fluorouracil and leucovorin formulation, after failure of standard treatment

Background: 5‐Fluorouracil (5‐FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all‐in‐one, pH neutral stable solution of 5‐FU plus LV with β‐cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first‐in‐human phase I trial. Methods: Patients with advanced solid malignancy received Deflexifol as weekly bolus (375–575 mg/m²) or two‐weekly 46 h infusion (1200–3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. Results: Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose‐limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m2 (maximum tolerated dose 525 mg/m²), whereas none were reported for the infusional schedule. The recommended phase II infusional dose was declared as 3,000 mg/m², >25% that of 5‐FU used in standard‐of‐care regimens. Pharmacokinetic analyses showed evidence of inter‐patient variability, with no evidence of saturation in clearance, and a trend to linear increase in AUC with dose. Disease control rate was 64% despite most patients having failed previous 5‐FU regimens. Conclusion: Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5‐FU and LV. A phase II study evaluating Deflexifol is planned

Security in Decentralised Computing, IoT and Industrial IoT

Internet-of-Things (IoT) is applied in many contexts, Industrial IoT (IIoT) is one such example. This chapter explores the security issues and challenges in IIoT. Cloud Computing is significantly influencing the architectural and implementation factors for IoT. Due to the nature of Cloud and IoT architectures and infrastructures, it is important to consider distributed and Decentralised Computing. With the focus on security aspects and concerns in IIoT, this chapter presents a discussion on Decentralised Computing and security concerns of Decentralised Computing from a Cloud Computing and IoT perspective. The chapter introduces the concept and definitions of Cloud Computing, Decentralised Computing, and IoT. It also addresses how Decentralised Computing is an approach to implement Cloud Architecture and IoT infrastructure, and how Cloud and IoT security concerns affect the deployment of a decentralised architecture. The above security and implementation aspects of Decentralised Computing, Cloud Computing and IoT are mapped into the context of IIoT