Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas.

BACKGROUND: Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. PATIENTS AND METHODS: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). RESULTS: A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. CONCLUSIONS: In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

[The in vivo imaging of zebrafish for chemical vascular toxicity assessment].

Objective: To evaluate the vascular toxicity of chemicals by a real-time observation approach using the transgenic zebrafish. Methods: The spatiotemporal vascular alterations of transgenic zebrafish after chemical exposure were assessed by laser confocal microscopy and high-content screening analysis, respectively. Results: The method using Laser Confocal Microscopy (LCM) is easier to operate and yields high-resolution images, while it is lower throughput and inefficient. In contrast, high-content analysis (HCA) analysis obtains high-quality data of vascular toxicity manifesting whole blood vasculature, whereas it requires delicate operation procedures and advanced experimental conditions. Conclusion: Two kinds of zebrafish imaging methods each have advantages and disadvantages. LCM is suitable for the evaluation of a small number of chemicals. HCA, a cutting-edge technology, has great potential for chemical safety assessment allowing high throughput vascular toxicity tests of a good number of chemicals at a time.

[Non-surgical local treatment for pulmonary aspergilloma].

Pulmonary aspergilloma (PA) is usually secondary to pulmonary cavities. The main purpose of PA treatment is to prevent life-threatening hemoptysis. Many patients cannot tolerate surgical resection, which is considered the preferred treatment. Oral or intravenous antifungal therapy is less effective because PA usually does not invade the blood vessels of the pulmonary cavity. In this case, arterial embolization, local injection with drugs, and radiation therapy can be considered. This article will summarized various non-surgical local treatments for PA (hemoptysis) to refer clinical decision-making.

Controlled expression of lysis gene E by a mutant of the promoter pL of the thermo-inducible λcI857-pL system.

AIMS: To identify a lambda promoter pL mutant that could extend the thermal stability of the thermo-inducible λcI857-pR/pL system and to evaluate the effects of the modified system for the controlled expression of lysis gene E during the production of bacterial ghosts (BGs). METHODS AND RESULTS: The promoter pL mutant was identified by random mutagenesis and site-directed mutagenesis. The results showed that a T â†’ 35C mutation in the pL promoter was responsible for the phenotype alteration. Under the same induction conditions, the lysis rates of the modified lytic system on Escherichia coli and Salmonella enteritidis were significantly lower than that of the control, while the lysis rates of Escherichia coli with the thermo-inducible lytic system were significantly higher than that of S. enteritidis with the corresponding plasmid (P < 0·05). CONCLUSIONS: Increasing the heat stability of the thermo-inducible lytic systems decreased lysis efficiency during the production of BGs. There exist differences in the lysis efficiency of thermo-inducible lytic systems between different bacterial strains. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings enrich current knowledge about modifications to thermo-inducible systems and provide a reference for the application of these modified systems for the production of BGs and controlled gene expression in bacteria.

Coverage and effectiveness of hypertension screening in different altitudes of Tibet autonomous region.

BACKGROUND: Tibet is an autonomous region in China located around an average altitude of 4500 m above sea level. Since 2012 the local government of Tibet has been providing free physical examinations, including screening for hypertension. However, the coverage and effectiveness of this free program have not been uncovered. This study aims to assess the coverage and effectiveness of hypertension screening and management program in 3 altitude levels of Tibet, and also the determinants of the success of the screening program. METHODS: A stratified cluster survey was conducted among 1636 residents aged 18 years or over in three different altitude areas in Tibet. We adjusted for age and sex based on national census data and used weighted logistic regression models to find factors associated with hypertension screening. RESULTS: The coverage of the hypertension screening program evaluated by participation rate in the previous screening was 94.9%, while 24.7% (95% CI: 22.1-27.3%) of them were diagnosed with hypertension. Females and alcohol drinkers were more likely to be screened. Among those diagnosed with hypertension, 28.7% had it under control. High altitude areas had a high proportion of controlled hypertension. The overall rate of controlled hypertension in high, moderate and low altitude areas was 35.1% (95% CI: 24.8-45.3%), 32.7% (95% CI: 22.2-43.2%) and 23.7% (95% CI: 14.7-32.6%), respectively. Younger aged persons were more likely to have better control of their hypertension. CONCLUSIONS: The coverage of hypertension screening in Tibet was high, especially in the low altitude areas. However, the effectiveness of hypertension control was low, indicating a need to implement the treatment adherence routines into the current screening interventions.

Do marginal abatement costs matter for improving air quality? Evidence from China's major cities.

This paper performs a two-stage analysis to investigate the trade-off between economic growth and pollution abatement. We first estimate the marginal abatement costs (MACs) of CO2, SO2, NOx, and particulate matter (PM) for 30 major Chinese cities from 2006 to 2015 via the shadow price approach under the directional distance function framework. The results show that the optimal directional vector is (11, -1, -1, -1, -1), which may indicate that increasing economic output is much more important than reducing the above undesirable outputs in these cities. Then, having examined the relationship between MACs and air quality by panel regression and dose-response analyses, we found ranges of positive and statistically significant treatment effects for the MACs of SO2 and PM on their respective concentrations. The overall results suggest that government officials in these cities may give precedence to economic growth over environmental protection.

Alteration of liver-infiltrated and peripheral blood double-negative T-cells in primary biliary cholangitis.

BACKGROUND & AIMS: Double-negative (DN) T-cell is a unique regulatory T-cell, which is essential for maintaining immune system homoeostasis. However, the role of DN T-cells in the pathogenesis of primary biliary cholangitis (PBC) is still unknown. METHODS: We investigated the number and function of DN T-cells in peripheral blood and liver biopsy specimens of PBC patients. RESULTS: The number and frequency of DN T-cells significantly decreased in peripheral blood and liver tissue of PBC patients. Furthermore, the frequency of DN T-cells in PBC was negatively correlated with disease severity and positively correlated with ursodeoxycholic acid response. In vitro assays showed that perforin expression and the suppressive capability of DN T-cells on the proliferation of CD4+ and CD8+ T-cells were impaired in PBC. Finally, lithocholic acid, the most hydrophobic acid, could downregulate the proliferation and perforin expression of DN T-cells. CONCLUSIONS: Decreased quantity and function of DN T-cells in PBC may result in the loss of immune regulations on effector CD4+ and cytotoxic CD8+ T-cells, and thereby may break the immune tolerance and promote the pathogenesis of PBC.

The maximum predicted content of cation vacancies in inorganic and organic-inorganic perovskites: the role of the tolerance factor.

The maximum content of cation vacancies in perovskites determines the maximum adjustment to the physical properties. By using the classical criterion of the tolerance factor, we put forward a new method to obtain the maximum content of cation vacancies in perovskites. The effective ionic radius was calculated using the weighted average method, and the limit of tolerance factors was used to determine the maximum value of the cation vacancies. The calculated results of the La1-xMnO3 and La0.75Sr0.25Mn1-yO3 materials coincide with experimental results. For application, [(A1)1-x(A2)x]1-z1(B1B2)X3 or [(A1)1-x(A2)x](B1B2)1-z2X3 (X = O, F, Cl, Br, I) inorganic and hybrid organic-inorganic perovskite materials with vacancies at the A or B sites were predicted successfully, which provides a new method to improve the physical properties of perovskite materials.

Generation of RUNX3 knockout pigs using CRISPR/Cas9-mediated gene targeting.

Pigs are an attractive animal model to study the progression of cancer because of their anatomical and physiological similarities to human. However, the use of pig models for cancer research has been limited by availability of genetically engineered pigs which can recapitulate human cancer progression. Utilizing genome editing technologies such as CRISPR/Cas9 system allows us to generate genetically engineered pigs at a higher efficiency. In this study, specific CRISPR/Cas9 systems were used to target RUNX3, a known tumour suppressor gene, to generate a pig model that can induce gastric cancer in human. First, RUNX3 knockout cell lines carrying genetic modification (monoallelic or biallelic) of RUNX3 were generated by introducing engineered CRISPR/Cas9 system specific to RUNX3 into foetal fibroblast cells. Then, the genetically modified foetal fibroblast cells were used as donor cells for somatic cell nuclear transfer, followed by embryo transfer. We successfully obtained four live RUNX3 knockout piglets from two surrogates. The piglets showed the lack of RUNX3 protein in their internal organ system. Our results demonstrate that the CRISPR/Cas9 system is effective in inducing mutations on a specific locus of genome and the RUNX3 knockout pigs can be useful resources for human cancer research and to develop novel cancer therapies.

Proteomic analysis identifies differentially expressed proteins participating in forming Type III brush hair in Yangtze River Delta white goat.

The Yangtze River Delta white goat is a goat breed that can produce high quality brush hair (Type III hair) around the world. This study aimed to compare Type III hair and non-Type III hair goat skin tissues using differentially expressed proteins based on 2-dimensional gel electrophoresis technology. The differentially expressed protein spots were analyzed using the PDquest 8.0 software. Ten protein spots were detected as positive for mass spectrometric analysis based on a threshold of 2-fold change. Through matching based on Ultraflex III TOF/TOF and MASCOT database, four differentially expressed proteins were identified. Fibrinogen beta chain isoform 1 and ATP synthase beta subunit were upregulated in Type III hair, while succinyl-CoA:3-ketoacid-coenzyme A transferase 1-mitochondrial-like and actin-cytoplasmic 1 were upregulated in non-Type III hair. The 4 proteins play important roles in different aspects of hair follicle development. These findings could pave a good foundation for explaining the mechanism of forming Type III hair.

Strain dynamics of ultrathin VO2 film grown on TiO2 (001) and the associated phase transition modulation.

Tuning the metal insulator transition (MIT) behavior of VO2 film through the interfacial strain is effective for practical applications. However, the mechanism for strain-modulated MIT is still under debate. Here we directly record the strain dynamics of ultrathin VO2 film on TiO2 substrate and reveal the intrinsic modulation process by means of synchrotron radiation and first-principles calculations. It is observed that the MIT process of the obtained VO2 films can be modulated continuously via the interfacial strain. The relationship between the phase transition temperature and the strain evolution is established from the initial film growth. From the interfacial strain dynamics and theoretical calculations, we claim that the electronic orbital occupancy is strongly affected by the interfacial strain, which changes also the electron-electron correlation and controls the phase transition temperature. These findings open the possibility of an active tuning of phase transition for the thin VO2 film through the interfacial lattice engineering.

Altered patterning of neural activity in a tauopathy mouse model.

Alzheimer's disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales-spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animal's location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions.

Theta oscillons in behaving rats.

Recently discovered constituents of the brain waves-the oscillons-provide high-resolution representation of the extracellular field dynamics. Here we study the most robust, highest-amplitude oscillons that manifest in actively behaving rats and generally correspond to the traditional θ-waves. We show that the resemblances between θ-oscillons and the conventional θ-waves apply to the ballpark characteristics-mean frequencies, amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms' structure, origins and functions. We demonstrate that oscillons are frequency-modulated waves, with speed-controlled parameters, embedded into a noise background. We also use a basic model of neuronal synchronization to contextualize and to interpret the observed phenomena. In particular, we argue that the synchronicity level in physiological networks is fairly weak and modulated by the animal's locomotion.

Theta oscillons in behaving rats.

Recently discovered constituents of the brain waves-the oscillons-provide high-resolution representation of the extracellular field dynamics. Here we study the most robust, highest-amplitude oscillons that manifest in actively behaving rats and generally correspond to the traditional θ-waves. We show that the resemblances between θ-oscillons and the conventional θ-waves apply to the ballpark characteristics-mean frequencies, amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms' structure, origins and functions. We demonstrate that oscillons are frequency-modulated waves, with speed-controlled parameters, embedded into a noise background. We also use a basic model of neuronal synchronization to contextualize and to interpret the observed phenomena. In particular, we argue that the synchronicity level in physiological networks is fairly weak and modulated by the animal's locomotion.

Preliminary clinical observations on autologous cultured skin fibroblasts transplantation in the treatment of keloids: a case report.

BACKGROUND: Keloids are benign skin lesions that gradually invade the surrounding normal tissue, and no treatment has proven curative. In our previous clinical practice of autologous cultured fibroblast transplantation, we found that fibroblast injection might have some effect on treating keloids, and we attempted to treat keloids by using fibroblast transplantation after obtaining the patient's approval. CASE REPORT: 1 patient was treated from March 2017 to June 2018. Autologous skin fibroblasts were separated from postauricular skin biopsy or resected keloid. They were cultured and expanded with exclusive methods. Cells (3×107/ml) within four or five passages were injected intradermally at the keloid at one-month intervals, 15 times in the patient. Shrink of the keloid on the patient was observed. The keloid became softer, flatter, and lighter in color after treatment. The elasticity of the keloid was also increased. The treatment effect was associated with the number of treatment sessions. CONCLUSIONS: This is the first report in which autologous fibroblast transplantation was used to treat keloids. Despite being only a single case experience, it suggests that keloid formation is a complex process in which still unknown factors may play a role.

Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials.

BACKGROUND: Suvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies. PATIENTS AND METHODS: The phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3 + 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials. RESULTS: All patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months). CONCLUSIONS: Suvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer.

Rotenone-induced death of RGC-5 cells is caspase independent, involves the JNK and p38 pathways and is attenuated by specific green tea flavonoids.

The aim of the present studies was to characterise cell death following inhibition of mitochondrial complex I with rotenone in a transformed cell line (RGC-5 cells) and to examine the neuroprotective properties of the flavonoids genistein, epigallocatechin gallate (EGCG), epicatechin (EC) and baicalin. Rotenone-induced cell death of RGC-5 cells results in a generation of reactive oxygen species, a breakdown of DNA, the translocation of membrane phosphatidylserine, an up-regulation of haemoxygenase-1 and is unaffected by necrostatin-1 (inhibitor of necroptosis), z-VAD-fmk (pan caspase inhibitor) or NU1025 (PARP inhibitor) but attenuated with SP600125 (JNK inhibitor). Rotenone-induced toxicity of RGC-5 cells also caused an activation of mitogen-activated kinases indicated by an up-regulation and translocation into mitochondria of p-c-Jun, pJNK and pp38. Exposure of RGC-5 cells to rotenone does not affect apoptosis inducing factor or significantly stimulate caspase-3 activity. EGCG and EC both significantly blunt rotenone toxicity of RGC-5 cells at concentrations of 50 µM while genistein and baicalin were without effect. Significantly, genistein is approximately 20 times less efficacious than EGCG (IC(50) 2.5 µM) and EC (IC(50) 1.5 µM) at inhibiting sodium nitroprusside-induced lipid peroxidation. These studies show that rotenone toxicity of RGC-5 cells is neither necroptosis nor caspase-dependent apoptosis but involves the activation of mitogen-activated kinases and is inhibited by a JNK inhibitor, EGCG and EC. Genistein attenuates lipid peroxidation less efficaciously than EC and EGCG and does not affect rotenone toxicity of RGC-5 cells.

Association of SCD1 and DGAT1 SNPs with the intramuscular fat traits in Chinese Simmental cattle and their distribution in eight Chinese cattle breeds.

Intramuscular fat (IMF) is a key parameter for evaluation of nutritional quality of beef, with its endogenous synthesis regulated by stearoyl CoA desaturase (SCD1) and diacylglycerol-acyl transferase 1 (DGAT1) genes in cattle. The object of this research was to evaluate the effect of SCD1 and DGAT1 polymorphisms on IMF trait in beef cattle and to estimate the frequency distribution of SNPs in the two genes in Chinese cattle populations. The SCD1 and DGAT1 polymorphisms were detected by PCR-single strand conformation polymorphism (PCR-SSCP) method in Chinese Simmental cattle and their associations with IMF traits were analyzed using the general linear model (GLM). The frequency distribution of SNPs in SCD1 and DGAT1 genes were detected by PCR-SSCP method and analyzed in seven other cattle populations. The results showed significant associations of SNPs SCD1-878, SCD1-762, and DGAT1 10433 and 10434 with IMF (%) and shearing force values (SFV; kg) in Chinese Simmental cattle. A haplotype combining SCD1-878C, SCD1-762T, and DGAT1 10433 and 10434-GC had the highest IMF, marbling score and shearing force. The polymorphic investigation indicated that the frequency of SCD1-878C or SCD1-762T was significantly higher in Chinese southern cattle (Leiqiong, Yunnan High pump, BMY or Minnan Cattle) than in Chinese northern cattle (Chinese Simmental, Luxi Cattle, Bohai Black or Chinese Holstein), while the frequency of DGAT1 10433 and 10434-GC in Chinese indigenous breed (Leiqiong, Yunnan High pump, BMY, Luxi Cattle, Bohai Black, or Minnan Cattle) was significantly lower than breeds with imported blood (Chinese Simmental or Chinese Holstein). These findings demonstrated that both the SCD1 and DGAT1 SNPs were prospect genetic markers for IMF traits, and the SCD1 SNPs could be used as a genetic marker for southern or northern blood in Chinese cattle.