Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK ...inhibitor, in adults and children who had tumors with these fusions.
We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.
A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval CI, 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.
Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
A facile synthesis of pristine and g-C3N4 loaded CdWO4 (Cadmium Tungstate) were reported and analyzed the effect of pollutants removal in wastewater. The samples were characterized and the morphology ...of the pristine sample showed the nanostructures with high cluster of layer formed. While adding PEG (Polyethylene glycol), the surface has exhibited less agglomeration and in g-C3N4 added sample the agglomeration was intensely reduced and nanostructures have been clearly found. Photocatalytic performance on cationic dye was investigated under visible light. The efficiency calculated for g–C3N4– CdWO4 sample was 85% for MB. The C/C0 plot gives better degradation. The kinetic study revealed pseudo first order reaction. The g–C3N4–CdWO4 sample exhibited higher “k” value which proved best efficiency on removing the pollutant. g–C3N4–CdWO4 sample will make better reduction on toxic pollutants and be a good candidate in futuristic applications. By carbon based derivates inclusion with photo active materials, the morphology and surface area was greatly improved and it enhances activity of host material and it will be the promising material for industrial applications.
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•Pristine and g-C3N4 loaded CdWO4 were synthesized.•PEG and g-C3N4 explored more less agglomeration.•Calculated efficiency for g–C3N4–CdWO4 was 85% for MB.•g–C3N4–CdWO4 exhibited higher “k” value and proved best pollutant removing efficiency.•g–C3N4–CdWO4 revealed better reduction on toxic pollutants.
Pristine and Ce doped TiO2 nanoparticles were fabricated for toxic pollutants removal from wastewater. Pristine, 2% Ce and 4% Ce doped TiO2 photocatalysts were produced via hydrothermal route. 4% Ce ...doped TiO2 exhibited 2.41 eV bandgap which is smaller than pure TiO2. The morphology was also investigated and it was established that doping of Ce ions enhanced the surface roughness and reduced the particle size. The surface area was characterized through BET analysis and 4% Ce–TiO2 possess higher surface with large pore diameter which helped the photocatalytic activity. The prepared photocatalysts were investigated on reduction of pollutants from wastewater under visible light. Higher efficiency was obtained for 4% Ce–TiO2 photocatalyst for both model pollutants. The “k” value possessed was also higher for the doped TiO2 catalyst. These analysis reports the optimum level of ceria doping to enhance morphology, surface area and it increased activity than bare TiO2. 4% Ce–TiO2 will be the potential candidate for efficient wastewater management. The 4% Ce doped TiO2 photocatalyst provided 77% and 88% on reducing MB and RhB dyes. The dopant has developed higher surface area, morphology and good recombination rate which reduced the toxic pollutants and changed the wastewater to reuse.
•4% Ce–TiO2 possess higher surface with large pore diameter.•4% Ce–TiO2 explored higher efficiency for both model pollutants.•The “k” value possessed was also higher for the doped TiO2 catalyst.•4% Ce–TiO2 will be the potential candidate for efficient wastewater management.
Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase ...1b study.
We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival.
The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo control group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively.
In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, ...represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
Due to over depletion of fossil fuels, researchers started to find hydrogen energy to compete with the energy demands. Bi2WO6 and Ni (5% and 10%) doped Bi2WO6 were prepared via hydrothermal route. ...Structural confirmation of undoped and doped Bi2WO6 nanostructures was estimated by using standard characterization studies. The nanoflake and nanoneedle like morphology of undoped and Ni doped Bi2WO6 was confirmed in nanoscale range. The highest OER activity was achieved for 10% Ni doped Bi2WO6 nanostructure electrode with the excellent current density of 272 mA/g with overpotential of 242 mV in the fabricated three electrode half cell set up. The higher electron transport offered by Ni ions to Bi2WO6 host has been reported with the electrochemical mechanism. Hence, the unusual robust electrodes for electrochemical potential applications by tuning its property via suitable foreign ion dopant could be the great beginning of this recent year research. In such a way, this work would be the better way of swapping of nobel metal catalysts for electrochemical OER activity.
•Bare and Ni doped Bi2WO6 morphological evolution has been explored.•10% Ni doped Bi2WO6 revealed excellent OER activity of 272 mA/g at 10 mV/s.•Appreciably low overpotential of 242 mV has been achieved for 10% Ni doped Bi2WO6.•Explored higher electron transport offered by Ni ions to Bi2WO6 host.•Outstanding stability over 24 h with high conductivity was achieved.
Background Chronic psychological stress (CPS) is associated with increased intestinal epithelial permeability and visceral hyperalgesia. It is unknown whether corticosterone (CORT) plays a role in ...mediating alterations of epithelial permeability in response to CPS.
Methods Male rats were subjected to 1‐h water avoidance (WA) stress or subcutaneous CORT injection daily for 10 consecutive days in the presence or absence of corticoid receptor antagonist RU‐486. The visceromotor response (VMR) to colorectal distension (CRD) was measured. The in situ single‐pass intestinal perfusion was used to measure intestinal permeability in jejunum and colon simultaneously.
Key Results We observed significant decreases in the levels of glucocorticoid receptor (GR) and tight junction proteins in the colon, but not the jejunum in stressed rats. These changes were largely reproduced by serial CORT injections in control rats and were significantly reversed by RU‐486. Stressed and CORT‐injected rats demonstrated a threefold increase in permeability for PEG‐400 (MW) in colon, but not jejunum and significant increase in VMR to CRD, which was significantly reversed by RU‐486. In addition, no differences in permeability to PEG‐4000 and PEG‐35 000 were detected between control and WA groups.
Conclusions & Inferences Our findings indicate that CPS was associated with region‐specific decrease in epithelial tight junction protein levels in the colon, increased colon epithelial permeability to low molecular weight macromolecules which were largely reproduced by CORT treatment in control rats and prevented by RU‐486. These observations implicate a novel, region‐specific role for CORT as a mediator of CPS‐induced increased permeability to macromolecules across the colon epithelium.
Context. Over the past five decades, radio astronomy has shown that molecular complexity is a natural outcome of interstellar chemistry, in particular in star forming regions. However, the pathways ...that lead to the formation of complex molecules are not completely understood and the depth of chemical complexity has not been entirely revealed. In addition, the sulfur chemistry in the dense interstellar medium is not well understood. Aims. We want to know the relative abundances of alkanethiols and alkanols in the Galactic center source Sagittarius B2(N2), the northern hot molecular core in Sgr B2(N), whose relatively small line widths are favorable for studying the molecular complexity in space. Methods. We investigated spectroscopic parameter sets that were able to reproduce published laboratory rotational spectra of ethanethiol and studied effects that modify intensities in the predicted rotational spectrum of ethanol. We used the Atacama Large Millimeter Array (ALMA) in its Cycles 0 and 1 for a spectral line survey of Sagittarius B2(N) between 84 and 114.4 GHz. These data were analyzed by assuming local thermodynamic equilibrium (LTE) for each molecule. Our observations are supplemented by astrochemical modeling; a new network is used that includes reaction pathways for alkanethiols for the first time. Results. We detected methanol and ethanol in their parent 12C species and their isotopologs with one 12C atom substituted by 13C; the latter were detected for the first time unambiguously in the case of ethanol. The 12C/13C ratio is ~25 for both molecules. In addition, we identified CH318 OH with a 16O/18O ratio of ~180 and a 13CH3OH/CH318 OH ratio of ~7.3. Upper limits were derived for the next larger alkanols normal- and iso-propanol. We observed methanethiol, CH3SH, also known as methyl mercaptan, including torsionally excited transitions for the first time. We also identified transitions of ethanethiol (or ethyl mercaptan), though not enough to claim a secure detection in this source. The ratios CH3SH to C2H5SH and C2H5OH to C2H5SH are ≳21 and ≳125, respectively. In the process of our study, we noted severe discrepancies in the intensities of observed and predicted ethanol transitions and propose a change in the relative signs of the dipole moment components. In addition, we determined alternative sets of spectroscopic parameters for ethanethiol. The astrochemical models indicate that substantial quantities of both CH3SH and C2H5SH may be produced on the surfaces of dust grains, to be later released into the gas phase. The modeled ratio CH3SH/C2H5SH = 3.1 is lower than the observed value of ≳21; the model value appears to be affected most by the underprediction of CH3SH relative to CH3OH and C2H5OH, as judged by a very high CH3OH/CH3SH ratio. Conclusions. The column density ratios involving methanol, ethanol, and methanethiol in Sgr B2(N2) are similar to values reported for Orion KL, but those involving ethanethiol are significantly different and suggest that the detection of ethanethiol reported toward Orion KL is uncertain. Our chemical model presently does not permit the prediction of sufficiently accurate column densities of alkanethiols or their ratios among alkanethiols and alkanols. Therefore, additional observational results are required to establish the level of C2H5SH in the dense and warm interstellar medium with certainty.
Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of ...glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 SD years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 IQR: 1-9 years; mean HbA1c 7.4% ± 1.7%; mean body mass index BMI 25.3 ± 4.0 kg/m.sup.2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c greater than or equal to8.5% while on greater than or equal to2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval CI 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio HR: 1.07 95% CI 1.03-1.12 per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 95% CI 1.06-1.46 per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta SE = 0.312 0.057 per SD; P = 5.84 x 10.sup.-8) but not glycemic progression (HR: 1.01 95% CI 0.96-1.05 per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.
Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in ...diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.
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