Synthesis and Physical Properties of the Misfit Layered Compound (EuS)1.13(NbSe2)2.

A new misfit layered compound with the stoichiometry (EuS)1+δ(NbSe2)2 (δ ≈ 0.13) has been successfully synthesized. High-resolution transmission electron microscopy and powder X-ray diffraction confirm the misfit structure with (EuS)-(EuS) spacing of 18.30(1) Å. Magnetization, electrical resistivity, heat capacity, and thermal transport measurements show that the material is a heavily doped semiconductor or poor metal with a low thermal conductivity of ∼1 W/m K and an antiferromagnetic ordering transition at TN = 4.7 K. In contrast to the parent materials, the misfit is neither ferromagnetic nor superconducting down to T = 0.4 K. We find evidence of a field-driven transition to a ferromagnetic state due to reorientation of ferromagnetic EuS layers at µoH = 0.5 T at T = 2 K.

Quasi-2D-Ising-type magnetic critical behavior in trigonal Cr1.27Te2.

Single crystal Cr1.27Te2 samples were synthesized by using the chemical vapor transport method. Single crystal x-ray diffraction studies show a trigonal crystal structure with a P3̄m1 symmetry space group. We then systematically investigate magnetic properties and critical behaviors of single crystal Cr1.27Te2 around its paramagnetic-to-ferromagnetic phase transition. The Arrott plot indicates a second-order magnetic phase transition. We estimate critical exponents ß = 0.2631 ± 0.002, γ = 1.2314 ± 0.007, and TC = 168.48 ± 0.031 K by using the Kouvel-Fisher method. We also estimate other critical exponents δ = 5.31 ± 0.004 by analyzing the critical isotherm at TC = 168.5 K. We further verify the accuracy of our estimated critical exponents by the scaling analysis. Further analysis suggests that Cr1.27Te2 can be best described as a quasi-2D Ising magnetic system.

Fe Site Order and Magnetic Properties of Fe1/4NbS2.

Transition-metal dichalcogenides (TMDs) have long been attractive to researchers for their diverse properties and high degree of tunability. Most recently, interest in magnetically intercalated TMDs has resurged due to their potential applications in spintronic devices. While certain compositions featuring the absence of inversion symmetry such as Fe1/3NbS2 and Cr1/3NbS2 have garnered the most attention, the diverse compositional space afforded through the host matrix composition as well as intercalant identity and concentration is large and remains relatively underexplored. Here, we report the magnetic ground state of Fe1/4NbS2 that was determined from low-temperature neutron powder diffraction as an A-type antiferromagnet. Despite the presence of overall inversion symmetry, the pristine compound manifests spin polarization induced by the antiferromagnetic order at generic k points, based on density functional theory band-structure calculations. Furthermore, by combining synchrotron diffraction, pair distribution function, and magnetic susceptibility measurements, we find that the magnetic properties of Fe1/4NbS2 are sensitive to the Fe site order, which can be tuned via electrochemical lithiation and thermal history.

The effects of glucagon-like peptide (GLP)-1 receptor agonists on weight and glycaemic control in Prader-Willi syndrome: A systematic review.

OBJECTIVE: The mainstay management of hyperphagia and obesity in Prader-Willi syndrome (PWS) relies on dietary restrictions, strict supervision and behavioural modifications, which can be stressful for the patient and caregiver. There is no established pharmacological strategy to manage this aspect of PWS. Theoretically, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RA) used in patients with obesity and type 2 diabetes mellitus (T2DM) may be efficacious in weight and glycaemic control of PWS patients. We conducted a systematic review of the literature to summarize the evidence on the use of GLP1-RA in PWS patients. DESIGN: Primary studies were searched in major databases using key concepts 'Prader-Willi syndrome' and 'GLP1 receptor agonist' and outcomes, 'weight control OR glycaemic control OR appetite regulation'. RESULTS: Ten studies included, summarizing GLP1-RA use in 23 PWS patients (age, 13-37 years), who had used either exenatide (n = 14) or liraglutide (n = 9) over a duration of 14 weeks to 4 years. Sixteen (70%) of these patients had T2DM. Ten patients experienced improvement in body mass index, ranging from 1.5 to 16.0 kg/m2 , while improvement in HbA1c was seen in 19 of 23 cases, ranging between 0.3% and 7.5%. All five studies reporting appetite or satiety showed improvement in satiety levels. There were no reported serious side effects. CONCLUSIONS: GLP1-RA appears safe in PWS patients and may have potential benefits for weight, glycaemic and appetite control. Nonetheless, we also highlight a significant gap in the literature on the lack of well-designed studies in this area, which limits the recommendation of GLP1-RA use in PWS patients at present.

Patient Acceptability of a Novel Technological Solution (Ambient Intelligent Geriatric Management System) to Prevent Falls in Geriatric and General Medicine Wards: A Mixed-Methods Study.

INTRODUCTION: As effective interventions to prevent inpatient falls are lacking, a novel technological intervention was trialed. The Ambient Intelligent Geriatric Management (AmbIGeM) system used wearable sensors that detected and alerted staff of patient movements requiring supervision. While the system did not reduce falls rate, it is important to evaluate the acceptability, usability, and safety of the AmbIGeM system, from the perspectives of patients and informal carers. METHODS: We conducted a mixed-methods study using semistructured interviews, a pre-survey and post-survey. The AmbIGeM clinical trial was conducted in two geriatric evaluation and management units and a general medical ward, in two Australian hospitals, and a subset of participants were recruited. Within 3 days of being admitted to the study wards and enrolling in the trial, 31 participants completed the pre-survey. Prior to discharge (post-intervention), 30 participants completed the post-survey and 27 participants were interviewed. Interview data were thematically analyzed and survey data were descriptively analyzed. RESULTS: Survey and interview participants had an average age of 83 (SD 9) years, 65% were female, and 41% were admitted with a fall. Participants considered the AmbIGeM system a good idea. Most but not all thought the singlet and sensor component as acceptable and comfortable, with no privacy concerns. Participants felt reassured with extra monitoring, although sometimes misunderstood the purpose of AmbIGeM as detecting patient falls. Participants' acceptability was strongly positive, with median 8+ (0-10 scale) on pre- and post-surveys. DISCUSSION/CONCLUSION: Patients' acceptability is important to optimize outcomes. Overall older patients considered the AmbIGeM system as acceptable, usable, and improving safety. The findings will be important to guide refinement of this and other similar technology developments.

Evaluation of pregnancy outcomes in women with GCK-MODY.

AIMS: To determine the fetal and maternal outcomes in pregnant women with Glucokinase-Maturity onset diabetes of the young (GCK-MODY). METHODS: We studied the obstetric and perinatal outcomes in 99 pregnancies of 34 women with GCK-MODY. The mutation status of the offspring was known in 29 and presumed in 33. Clinical outcomes were determined and compared between affected (n = 39) and unaffected (n = 23) offspring. RESULTS: 59% of pregnancies were treated with diet alone and 41% received insulin. Birthweight, percentage of large for gestational age (LGA) and caesarean section (CS) in GCK-unaffected offspring was significantly higher than in GCK-affected offspring (4.0 ± 0.7 vs. 3.4 ± 0.4 kg, p = 0.001), 15 (65%) vs. 5(13%) (p = 0.00006) and 17 (74%) vs. 11 (28%) (p = 0.001), respectively. We observed an earlier gestational age at delivery on insulin in unaffected offspring (38.3 ± 1.0 vs. 39.5 ± 1.5 weeks, p = 0.03) with no significant change in LGA (9 (82%) vs. 6 (50%); p = 0.12), and a higher rate of CS (8 [73%] vs. 3 [11%]; p < 0.001), and no change in small for gestational age (0 [0%] vs. 4 [14%]; p = 0.30) in affected offspring. CONCLUSION: Insulin therapy in unaffected offspring did not reduce LGA and was associated with earlier gestational age at delivery. Insulin treatment in GCK-affected offspring was associated with an increased incidence of CS, but did not adversely affect fetal outcome. Fetal genotype determines birthweight rather than treatment. Pre-pregnancy diagnosis of GCK-MODY, use of continuous glucose monitoring and non-invasive fetal genotyping may enable further investigation of targeted therapy in this condition.

Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation.

BACKGROUND: Mutations in GATA6 are the most frequent cause of pancreatic agenesis. Most cases present with neonatal diabetes mellitus. CASE PRESENTATION: The case was a female born after an uncomplicated pregnancy and delivery in a non-consanguineous family (3.59 kg, 70th percentile). Severe cardiac malformations were diagnosed at two and a half months old. No hyperglycaemic episodes were recorded in the neonatal period. Diabetes was diagnosed at 21 years due to the detection of incidental glycosuria. She had a low but detectable C-peptide level at diagnosis. Anti-GAD and Islet-cell antibodies were negative and she failed oral hypoglycaemic therapy and was started on insulin. Abdominal MRI revealed the absence of most of the neck, body, and tail of pancreas with normal pancreas elastase levels. Criteria for type 1 or type 2 diabetes were not fulfilled, therefore a next generation sequencing (NGS) panel was performed. A novel heterozygous pathogenic GATA6 mutation (p.Tyr235Ter) was identified. The GATA6 variant was not detected in her parents, implying that the mutation had arisen de novo in the proband. CONCLUSION: Rarely GATA6 mutations can cause adult onset diabetes. This report highlights the importance of screening the GATA6 gene in patients with adult-onset diabetes, congenital cardiac defects and pancreatic agenesis with no first-degree family history of diabetes. It also emphasizes the importance of genetic counselling in these patients as future offspring will be at risk of inheriting the variant and developing GATA6 anomalies.

Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling.

OBJECTIVES: Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc. METHODS: The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-ß-receptor I. RESULTS: Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis. CONCLUSIONS: These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.

Endoscopic Evaluation in Children With End-Stage Liver Disease-Associated Portal Hypertension Awaiting Liver Transplant.

OBJECTIVES: Routine oesophago-gastro-duodenoscopy (OGD) pre-liver transplantation (LT) for evaluation and management of gastrointestinal (GI) pathology, in particular GI varices secondary to portal hypertension, is common practice in adult LT programmes. There is no universal consensus for this practice in children. We report our endoscopic experience in children with end-stage liver disease (ESLD) pre-LT. METHODS: Retrospective audit of LT database and review of OGD findings of patients who had undergone endoscopy preceding LT. RESULTS: Of 69 patients with ESLD, 50 (72.4%) had pre-LT OGD, 37 of which were done electively, whereas the remaining 13 were event driven. Forty-eight (96%) patients who underwent OGD had abnormalities, in which 38 (76%) patients had varices and 23 (46%) had portal hypertensive gastropathy. Eleven (22%) patients required therapeutic intervention at initial OGD either with endoscopic variceal band ligation or endoscopic sclerotherapy. Compared with the group who underwent elective OGDs, the group who had event-driven OGDs had a significantly higher requirement for endoscopic intervention (P < 0.0001), occurrence of rebleeding (P < 0.029) and requirement for repeat OGDs (P = 0.014). There was no significant difference in terms of patient (P = 0.2746) or graft survival (P = 0.3192) between the 2 groups. CONCLUSIONS: The role of pre-LT OGDs in patients with ESLD associated with portal hypertension is possibly limited to control of bleeding during episodes of GI bleed, where the aim would be to stabilize the patient until eventual LT. Multicentre prospective studies are required to provide more evidence on the use of routine endoscopy for pre-LT assessment in children.

Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma.

A growing number of agents targeting ligand-induced Wnt/ß-catenin signaling are being developed for cancer therapy. However, clinical development of these molecules is challenging because of the lack of a genetic strategy to identify human tumors dependent on ligand-induced Wnt/ß-catenin signaling. Ubiquitin E3 ligase ring finger 43 (RNF43) has been suggested as a negative regulator of Wnt signaling, and mutations of RNF43 have been identified in various tumors, including cystic pancreatic tumors. However, loss of function study of RNF43 in cell culture has not been conducted, and the functional significance of RNF43 mutations in cancer is unknown. Here, we show that RNF43 inhibits Wnt/ß-catenin signaling by reducing the membrane level of Frizzled in pancreatic cancer cells, serving as a negative feedback mechanism. Inhibition of endogenous Wnt/ß-catenin signaling increased the cell surface level of Frizzled. A panel of 39 pancreatic cancer cell lines was tested for Wnt dependency using LGK974, a selective Porcupine inhibitor being examined in a phase 1 clinical trial. Strikingly, all LGK974-sensitive lines carried inactivating mutations of RNF43. Inhibition of Wnt secretion, depletion of ß-catenin, or expression of wild-type RNF43 blocked proliferation of RNF43 mutant but not RNF43-wild-type pancreatic cancer cells. LGK974 inhibited proliferation and induced differentiation of RNF43-mutant pancreatic adenocarcinoma xenograft models. Our data suggest that mutational inactivation of RNF43 in pancreatic adenocarcinoma confers Wnt dependency, and the presence of RNF43 mutations could be used as a predictive biomarker for patient selection supporting the clinical development of Wnt inhibitors in subtypes of cancer.

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening.

BACKGROUND: MYC family members are among the most frequently deregulated oncogenes in human cancers, yet direct therapeutic targeting of MYC in cancer has been challenging thus far. Synthetic lethality provides an opportunity for therapeutic intervention of MYC-driven cancers. METHODS: A pooled kinase shRNA library screen was performed and next-generation deep sequencing efforts identified that PRKDC was synthetically lethal in cells overexpressing MYC. Genes and proteins of interest were knocked down or inhibited using RNAi technology and small molecule inhibitors, respectively. Quantitative RT-PCR using TaqMan probes examined mRNA expression levels and cell viability was assessed using CellTiter-Glo (Promega). Western blotting was performed to monitor different protein levels in the presence or absence of RNAi or compound treatment. Statistical significance of differences among data sets were determined using unpaired t test (Mann-Whitney test) or ANOVA. RESULTS: Inhibition of PRKDC using RNAi (RNA interference) or small molecular inhibitors preferentially killed MYC-overexpressing human lung fibroblasts. Moreover, inducible PRKDC knockdown decreased cell viability selectively in high MYC-expressing human small cell lung cancer cell lines. At the molecular level, we found that inhibition of PRKDC downregulated MYC mRNA and protein expression in multiple cancer cell lines. In addition, we confirmed that overexpression of MYC family proteins induced DNA double-strand breaks; our results also revealed that PRKDC inhibition in these cells led to an increase in DNA damage levels. CONCLUSIONS: Our data suggest that the synthetic lethality between PRKDC and MYC may in part be due to PRKDC dependent modulation of MYC expression, as well as MYC-induced DNA damage where PRKDC plays a key role in DNA damage repair.