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Aims Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Methods and results Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues. Conclusion Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2.

A mesoporous UiO-66-NH2 aerogel is prepared via a straightforward sol-gel method without using any binders or mechanical pressures, in which the amine groups are directly introduced into the matrix by using 2-aminoterephthalic acid. The novel UiO-66-NH2 aerogel also exhibits high specific surface area and mesopore-dominated structure, implying its highly potential use in CO2 adsorption. For ulteriorly investigating the effect of amine loading on the CO2 adsorption ability, a series of UiO-66-NH2 aerogel with different amino content is fabricated by changing the ligand/metal molar ratio. When the molar ratio is 1.45, the CO2 adsorption capacity reaches the optimum value of 2.13 mmol·g–1 at 25 °C and 0.1 MPa, which is 12.2% higher than that of pure UiO-66 aerogel. Additionally, UiO-66-NH2-1.45 aerogel also has noticeable CO2 selectivity against N2 and CH4 as well as good regeneration stability. Such results imply that it has good application prospect in the field of CO2 adsorption, and also contains the potential to be applied in catalysis, separation and other fields.

We describe the Cr-catalyzed enantioconvergent synthesis of chiral 2,3-allenones from aldehydes and propargyl bromides, which features an unprecedented cascade of Cr-catalyzed asymmetric reductive radical–polar crossover and Oppenauer oxidation.

ZnO–nano-ZnO@porous carbon (ZnO–nZnO@PC) was in situ fabricated through the Ostwald ripening mechanism and facile pyrolysis process, which demonstrated the performance of piezo-photocatalytic degradation efficiency of 99.4%.

Due to advances in medical treatments, a substantial proportion of heart failure (HF) patients with reduced left ventricular ejection fraction (EF, HFrEF) have experienced partial or complete recovery of EF, termed HFrecEF, and markedly improved clinical outcomes. In the present study, we sought to investigate the relationship between glycemic control and the incidence of HFrecEF in hospitalized HFrEF patients with type 2 diabetes mellitus (T2DM).A total of 463 hospitalized T2DM patients with HFrEF were consecutively enrolled. Follow-up echocardiogram was performed after around 12 months. Patients who had an absolute EF improvement ≥10% and a second EF 40% were classified into HFrecEF, and those who did not meet these criteria were defined as persistent HFrEF.During the 12-month follow-up, 44.5% of T2DM patients developed HFrecEF. Patients with HFrecEF had significantly lower HbA1c level than those with persistent HFrEF (6.5% [IQR 5.8% ∼ 7.2%] vs. 6.7% [IQR 6.1% ∼ 7.8%], P = 0.003), especially in HF of an ischemic etiology. HbA1c levels were inversely correlated with changes in EF during follow-up. After multivariate adjustment, every 1% increase in HbA1c conferred a 17.4% (OR: 0.826 [95% CI 0.701-0.968]) lower likelihood of HFrecEF. Compared to patients with good glycemic control (HbA1c ≤ 6.2%), those with poor glycemic control (HbA1c 7.1%) had a 52.0% (OR: 0.480 [95% CI 0.281-0.811] decreased likelihood of HFrecEF.This study demonstrates that uncontrolled HbA1c level is associated with compromised development of HFrecEF in T2DM patients with HF, especially in those with an ischemic etiology.

Anastomotic leak is still a severe complication in esophageal surgery due to high mortality. This article reviews the updates on the treatment of anastomotic leak after esophagectomy in order to provide reference for clinical treatment and research. The relevant studies published in the Chinese Zhiwang, Wanfang, and MEDLINE databases to December 21, 2021 were retrieved, and esophageal carcinoma, esophagectomy, anastomotic leakage, and fistula selected as the keywords. A total of 78 studies were finally included. The treatments include traditional surgical drainage, new reverse drainage trans-fistula, stent plugging, endoscopic clamping, biological protein glue injection plugging, endoluminal vacuum therapy (EVT), and reoperation, etc. Early diagnosis, accurate classification and optimal treatment can promote the rapid healing of anastomotic leaks. EVT may be the most valuable approach, simultaneously with good commercial prospects. Reoperation should be considered in patients with complex fistula in which conservative treatment is insufficient or has failed.

Understanding the genetic mechanisms of phenotypic variation in hybrids between domestic animals and their wild relatives may aid germplasm innovation. Here, we report the high-quality genome assemblies of a male Pamir argali (O. ammon polii, 2n = 56), a female Tibetan sheep (O. aries, 2n = 54), and a male hybrid of Pamir argali and domestic sheep, and the high-throughput sequencing of 425 ovine animals, including the hybrids of argali and domestic sheep. We detected genomic synteny between Chromosome 2 of sheep and two acrocentric chromosomes of argali. We revealed consistent satellite repeats around the chromosome breakpoints, which could have resulted in chromosome fusion. We observed many more hybrids with karyotype 2n = 54 than with 2n = 55, which could be explained by the selfish centromeres, the possible decreased rate of normal/balanced sperm, and the increased incidence of early pregnancy loss in the aneuploid ewes or rams. We identified genes and variants associated with important morphological and production traits (e.g., body weight, cannon circumference, hip height, and tail length) that show significant variations. We revealed a strong selective signature at the mutation (c.334C > A, p.G112W) in TBXT and confirmed its association with tail length among sheep populations of wide geographic and genetic origins. We produced an intercross population of 110 F2 offspring with varied number of vertebrae and validated the causal mutation by whole-genome association analysis. We verified its function using CRISPR-Cas9 genome editing. Our results provide insights into chromosomal speciation and phenotypic evolution and a foundation of genetic variants for the breeding of sheep and other animals.

Background Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past. Methods Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals. Results We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient. Conclusions Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.

We propose a new method to identify rapid X-ray transients observed with focusing telescopes. They could be statistically significant if three or more photons are detected with Chandra in a single CCD frame within a point-spread-function region out of quiescent background. In the Chandra archive, 11 such events are discovered from regions without point-like sources, after discrimination of cosmic rays and background flares and control of false positives. Among them, two are spatially coincident with extended objects in the Milky Way, one with the Small Magellanic Cloud, and another one with M31; the rest have no or a dim optical counterpart ($\gtrsim 20$ mag), and are not clustered on the Galactic plane. Possible physical origins of the rapid transients are discussed, including short gamma-ray bursts (GRBs), short-lived hypermassive neutron stars produced by merger of neutron stars, accreting compact objects in the quiescent state, magnetars, and stellar flares. According to the short GRB event rate density, we expect to have detected $2.3_{-0.6}^{+0.7}$ such events in the Chandra archive. This method would also allow us to reveal quiescent black holes with only a few photons., Comment: accepted for publication in Monthly Notices of the Royal Astronomical Society

Goats with diverse economic phenotypic traits play an important role in animal husbandry. However, the genetic mechanisms underlying complex phenotypic traits are unclear in goats. Genomic studies of variations provided a lens to identify functional genes. In this study, we focused on the worldwide goat breeds with outstanding traits and used whole-genome resequencing data in 361 samples from 68 breeds to detect genomic selection sweep regions. We identified 210–531 genomic regions with six phenotypic traits, respectively. Further gene annotation analysis revealed 332, 203, 164, 300, 205, and 145 candidate genes corresponding with dairy, wool, high prolificacy, poll, big ear, and white coat color traits. Some of these genes have been reported previously (e.g., KIT, KITLG, NBEA, RELL1, AHCY, and EDNRA), while we also discovered novel genes, such as STIM1, NRXN1, LEP, that may be associated with agronomic traits like poll and big ear morphology. Our study found a set of new genetic markers for genetic improvement in goats and provided novel insights into the genetic mechanisms of complex traits.

Supplementary Figure from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Supplementary Data from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Purpose:In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non–small cell lung cancer (NSCLC).Patients and Methods:In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety.Results:The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0–69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0–9.6 months), and median OS was 12.5 months (95% CI, 8.2–16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%−40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression.Conclusions:Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

Supplementary figures

Purpose: Metastatic colorectal cancer patients with low epidermal growth factor receptor (EGFR) gene copy number are unlikely to respond to anti-EGFR monoclonal antibody (mAb) treatment. The objective of this study was to investigate EGFR fluorescence in situ hybridization (FISH) patterns of chromosome 7 disomy with efficacy of cetuximab therapy in metastatic colorectal cancer patients.Experimental Design: We detected the EGFR FISH patterns and KRAS status in 74 tumors from cetuximab-treated metastatic colorectal cancer patients and analyzed with response rate (RR) and progression-free survival (PFS).Results: One of the 16 (6.25%) patients with chromosome 7 homogeneous disomy (defined as FISH negative) had objective response to cetuximab. A total of 53(76.8%) patients with chromosome 7 pattern of variable ratios of disomy versus polysomy (defined as FISH positive) had a significantly higher RR (37.7% versus 6.25%; P = 0.01), a trend towards longer PFS (4.5 versus 2.9 months; P = 0.07). Among 54 KRAS wild-type patients, EGFR FISH-positive patients had significantly higher RR (51.3% versus 9%; P = 0.01) and longer PFS (5.0 versus 2.3 months; P = 0.02) than EGFR FISH-negative patients. However, among 20 KRAS mutant-type patients, there was no difference in RR (0% versus 0%) and PFS (2.5 versus 3.8 months; P = 0.51) between EGFR FISH-positive and -negative patients.Conclusion: Our results show firstly that patients with EGFR FISH pattern of chromosome 7 disomy have a very low chance to benefit from cetuximab-based therapy. EGFR FISH pattern of chromosome 7 disomy may be as a negative predicative factor for cetuximab response in KRAS wild-type metastatic colorectal cancer patients. Clin Cancer Res; 17(2); 382–90. ©2011 AACR.

Supplementary tables

Supplementary Table S1.

Mutations in the well-known Myostatin (MSTN) produce a “double-muscle” phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of theMSTNoften produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, aMSTNDel273Cmutation withFGF5knockout sheep, in which theMSTNandFGF5dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon ofMSTN, resulting in cysteine-depleted at amino acid position 273, and theFGF5double allele mutation led to inactivation ofFGF5gene. TheMSTNDel273Cmutation withFGF5knockout sheep highlights a dominant “double-muscle” phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, theMSTNDel273Cmutation withFGF5knockout mediated the activation ofFOSL1via the MEK-ERK-FOSL1 axis. The activatedFOSL1promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the transcription of MyoD1, and resulting in smaller myotubes.

Backgrounds: Apolipoprotein (apo) B and apo A1 are major protein component of low-density lipoprotein and high-density lipoprotein particles, which are closely linked to lipid metabolism, atherosclerosis, and endothelial function. We sought to investigate whether circulating apoB/A1 ratio could serve as a potential metabolic risk factor for the progression of chronic heart failure (HF). Methods Serum levels of apo B and apo A1 were measured in 1299 consecutive patients with clinical symptoms of chronic HF. Left ventricular ejection fraction (EF) and E/e’ were determined by two-dimensional echocardiography and Doppler flow imaging using standard biplane technique. The relationship of apo B/A1 ratio to classification and etiology of HF was examined. Results Overall, apoB/A1 ratio was gradually decreased from HF with reduced EF (HFrEF), HF with mid-range reduced EF (HFmrEF), to HF with preserved EF (HFpEF), and correlated negatively with left ventricular EF (r=-0.162, p

Atherosclerosis is a chronic inflammatory disease. The triggering receptor expressed on myeloid cells-1 (TREM-1) plays a crucial role in inflammatory diseases; recently, it was identified as a major upstream proatherogenic receptor, but its mechanism is still unclear. In this study, we explore the role of TREM-1 on dendritic cells maturation and inflammatory responses induced by ox-LDL and its possible mechanism. Human dendritic cells were differentiated from blood monocytes and treated with ox-LDL. Naive autologous T cells were cocultured with pretreated DCs or treated directly. The expression of TREM-1 and inflammatory factors were evaluated by real-time PCR, western blot, and ELISA methods. And the expression of immune factors to evaluate the DCs maturation and T-cell activation were determined by the FACS. Our study showed that ox-LDL induced TREM-1 expression, DC maturation, and T-cell activation. T cells exposed to ox-LDL-treated DCs produced interferon-γ and interleukin-17 (IL-17). Blocking TREM-1 suppressed the DC maturation, showing lower expression of CD1a, CD40, CD86, CD83, and HLA-DR, and limited their production of tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1), meanwhile increased transforming growth factor-β(TGF-β) and IL-10 production. Ox-LDL induced miR-155, miR-27, Let-7c, and miR-185 expression; however, TREM-1 inhibiting decreased miRNA-155 expression. Furthermore, silencing miRNA-155 restores SOCS1 repression induced by ox-LDL. Experiments with T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results. Our results uncover a new link between ox-LDL and TREM-1 and may provide insight into this interaction in the context of atherosclerosis.

Intestinal microflora plays a critical role in the process of nutrient digestion and immunomodulation. Normal gut microbiota is responsible for resistance to colonization by exogenous pathogenic microorganisms. Pathogen invasion alters the intestinal microbiota composition and causes intestinal disorder in domestic animals. Moreover, stress, infection, or dysbiosis during the feeding period also results in an imbalanced gut microbiota, which also leads to postweaning diarrhea of piglets and necrotic enteritis of chickens. It has been demonstrated that B. licheniformis and B. subtilis has antimicrobial activity against pathogens through the production of antibacterial cyclic lipopeptide surfactin. Therefore, in the present review a series research works on the Bacillus based-fermented products efficacy and validation by alleviating the diarrhea incidence, enteritis, coccidiosis, modified gut microbiota, and decrease postpartum dysgalactia syndrome in pigs and chickens.

We explored the influence of hospitality employees' workplace spirituality on person–organization (P–O) fit and workplace deviance, and P–O fit as a mediator of the link between workplace spirituality and workplace deviance. Data were collected from 275 employees across 20 tourist hotels in Taiwan. To avoid common method variance, participants completed the survey at two time points. They first responded to items related to workplace spirituality, then 4 weeks later, they responded to the workplace deviance and P–O fit measures. Results show that workplace spirituality negatively affected interpersonal and organizational workplace deviance, and P–O fit mediated the relationship between workplace spirituality and interpersonal deviance. However, the mediating effect of P–O fit in the link between workplace spirituality and organizational deviance was not significant. These results provide a reference for practice and researchers.

BACKGROUND: Recent evidence suggests that IL-33, a novel member of the IL-1β family, is involved in organ fibrosis. However, the roles of IL-33 and its receptor ST2 in epidural fibrosis post spine operation remain elusive. METHODS: A mouse model of epidural fibrosis was established after laminectomy. IL-33 in the wound tissues post laminectomy was measured with Western blotting, ELISA and immunoflurosence imaging. The fibroblast cell line NIH-3T3 and primary fibroblasts were treated with IL-33 and the mechanisms of maturation of fibroblasts into myofibroblasts were analyzed. To explore roles of IL-33 and its receptor ST2 in vivo, IL-33 knockout (KO) and ST2 KO mice were employed to construct the model of laminectomy. The epidural fibrosis was evaluated using H&E and Masson staining, western-blotting, ELISA and immunohistochemistry. RESULTS: As demonstrated in western blotting and ELISA, IL-33 was increased in epidural wound tissues post laminectomy. The immunoflurosence imaging revealed that endothelial cells (CD31(+)) and fibroblasts (α-SAM(+)) were major producers of IL-33 in the epidural wound tissues. In vitro, IL-33 promoted fibroblast maturation, which was blocked by ST2 neutralization antibody, suggesting that IL-33-promoted-fibroblasts maturation was ST2 dependent. Further, IL-33/ST2 activated MAPK p38 and TGF-β pathways. Either p38 inhibitor or TGF-β inhibitor decreased fibronectin and α-SAM production from IL-33-treated fibroblasts, suggesting that p38 and TGF-β were involved with IL-33/ST2 signal pathways in the fibroblasts maturation. In vivo, IL-33 KO or ST2 KO decreased fibronectin, α-SMA and collagen deposition in the wound tissues of mice that underwent spine surgery. In addition, TGF-β1 was decreased in IL-33 KO or ST2 KO epidural wound tissues. CONCLUSION: In summary, IL-33/ST2 promoted fibroblast differentiation into myofibroblasts via MAPK p38 and TGF-β in a mouse model of epidural fibrosis after laminectomy.

To describe the prevalence and risk factors for refractive errors in a northeastern Chinese population with type 2 diabetes.Subjects (age ≥30 years) from a community-based study, the Fushun Diabetic Retinopathy Cohort Study, were enrolled. All subjects underwent comprehensive ocular examinations, including autorefraction. Myopia, high myopia, and hyperopia were defined as a spherical equivalent (SE) of the right eye-0.5 diopter (D),-5.0D, and0.5D, respectively. Astigmatism was defined as cylinder-0.5D in a minus cylinder prescription. Anisometropia was defined as a difference of SE1.0D between two eyes.A total of 1929 participants (790 males, 41.0%) were enrolled. The age and gender standardized prevalence of myopia, high myopia, hyperopia, astigmatism, and anisometropia were 43.1% (95% confidence interval [CI]: 40.9%-45.3%), 8.5% (95% CI: 7.3%-9.8%), 21.5% (95% CI: 19.7%-23.4%), 61.0% (95% CI: 58.9%-63.2%), and 17.2% (95% CI: 15.5%-18.9%), respectively. Advancing age was associated with a higher frequency of hyperopia, astigmatism, and anisometropia, as opposed to a lower frequency of myopia. Female (adjusted odds ratio [aOR], 1.27; 95% CI, 1.02-1.57) participants, higher intraocular pressure (aOR, 1.03; 95% CI, 1.00-1.07), and lenticular opacity (aOR, 1.53; 95% CI, 1.20-1.94) were also found to be associated with myopia. Long duration of diabetes (15 years) was found to be a significant factor for astigmatism (aOR, 1.62; 95% CI, 1.15-2.27) and anisometropia (aOR, 1.87; 95% CI, 1.29-2.71).Nearly two-thirds of participants with type 2 diabetes had a refractive error. Age is a common factor with different types of refractive errors.

In this paper, the congestion control for named data networking (NDN) is studied. A novel dynamic content store-based congestion control strategy is proposed on account of the characteristic of in-network cache in NDN. A queuing network model is constructed to judge whether congestion occurs. If the network has the tendency of congestion or the congestion happened, the buffer of the output queue is dynamically expanded by borrowing NDN content store (CS), and the forwarding rates of data packets and corresponding interest packets are reduced so as to prevent or alleviate network congestion. In order to reflect fairness, the CS to be borrowed by the data output queue in the port is calculated in terms of the data output queue length and its weight. The simulation results based on ndnSIM show that the given scheme improves the bottleneck link utilization and maintains a low packet loss rate and average flow completion time.

Acute stress disorder (ASD) is a kind of mental disease caused by trauma, which will bring heavy burdens to patients themselves, their family, their work and their lives. Once a person who has suffered a trauma develops post-traumatic stress disorder (PTSD), the quality of life of patients will be overall impaired. It is found that the occurrence of stress disorder is related to the overactivation of hypothalamus pituitary adrenal axis (HPA axis). The most commonly used medications for ASD are recommended medications for PTSD, including serotonin reuptake inhibitors (SRIs), second-generation antipsychotics, benzodiazepines, beta blockers, and others. The purpose of this article is to systematically organize and review the possible mechanisms of stress disorder and drugs for treatment of ASD.

A facile strategy toward the synthesis of theranostic curcumin–tryptanthrin–Zn(ii) complexes for cancer-specific therapy is demonstrated.

In this study, cell and animal experiments proved that C-phycocyanin can inhibit the necroptotic signaling pathway by down-regulating RIPK1, RIPK3, and p-MLKL expression.

IntroductionGastric cancer (GC) complicated by bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) represents poor prognosis and most of these patients would die in a few months. Active treatment strategies such as chemotherapy are effective in restoring coagulation function and prolonging patients’ survival time. Immunotherapy including programmed death protein 1 (PD-1) or programmed death protein ligand 1 (PD-L1) inhibitors has emerged as a first-line treatment of gastric cancer. However, the efficacy of PD-1 inhibitor-based treatment strategies in these patients remains unknown.Case descriptionHerein, we presented two cases of advanced gastric cancer (AGC) complicated by BMM and DIC, in which two patients received chemotherapy and PD-1 inhibitor as the first-line treatment. Both of them achieved a partial response after treatment, and the coagulation function was restored. The patient who discontinued the PD-1 inhibitor after 6 months experienced DIC relapse, whereas the other patient who maintained the PD-1 inhibitor treatment cycle remained responsive after 10 months.ConclusionsWe speculate that PD-1 inhibitor-based treatment strategies are effective and safe in prolonging survival against gastric cancer with BMM and DIC, and the coagulation function is well controlled by the treatment with a combination of immunotherapy and chemotherapy.

The fat tail of sheep is an important organ that has evolved to adapt to extreme environments. However, the genetic mechanisms underlying the fat tail phenotype remain poorly understood. Here, we characterize transcriptome and lipidome profiles and morphological changes in 250 adipose tissues from two thin-tailed and three fat-tailed sheep populations in summer and winter. We implement whole-genome selective sweep tests to identify genetic variants related to fat-tails. We identify a set of functional genes that show differential expression in the tail fat of fat-tailed and thin-tailed sheep in summer and winter. These genes are significantly enriched in pathways, such as lipid metabolism, extracellular matrix (ECM) remodeling, molecular transport, and inflammatory response. In contrast to thin-tailed sheep, tail fat from fat-tailed sheep show slighter changes in adipocyte size, ECM remodeling, and lipid metabolism, and had less inflammation in response to seasonal changes, indicating improved homeostasis. Whole-genome selective sweep tests identify genes involved in preadipocyte commitment (e.g., BMP2, PDGFD) and terminal adipogenic differentiation (e.g., VEGFA), which could contribute to enhanced adipocyte hyperplasia. Altogether, we establish a model of regulatory networks regulating adipose homeostasis in sheep tails. These findings improve our understanding of how adipose homeostasis is maintained, in response to extreme environments in animals.

ObjectiveThe burden of both general and drug-resistant tuberculosis in rural areas is higher than that in urban areas in China. To characterize the genetic structure and transmission risk of Mycobacterium tuberculosis in rural China, we used whole genome sequencing to analyze clinical strains collected from patients in two counties of Yichang for three consecutive years.MethodsFrom 2018 to 2020, sputum samples were collected for cultures from patients with suspected tuberculosis in Yidu and Zigui county, and DNA was extracted from the positive strains for genome sequencing. The online SAM-TB platform was used to identify the genotypes and drug resistance-related mutations of each strain, establish a phylogenetic tree, and calculated the genetic distances between pairwise strains. Twelve single nucleotide polymorphisms (SNPs) were used as thresholds to identify transmission clusters. The risk of related factors was estimated by univariable and multivariable logistic regression.ResultsA total of 161 out of the collected 231 positive strains were enrolled for analysis, excluding non-tuberculous mycobacterium and duplicate strains from the same patient. These strains belonged to Lineage 2 (92, 57.1%) and Lineage 4 (69, 42.9%), respectively. A total of 49 (30.4%) strains were detected with known drug resistance-related mutations, including 6 (3.7%) multidrug-resistant-TB (MDR-TB) strains and 11 (6.8%) RIF-resistant INH-susceptible TB (Rr-TB) strains. Six of the MDR/Rr-TB (35.3%) were also resistant to fluoroquinolones, which made them pre-extensively drug-resistant TB (pre-XDR-TB). There were another seven strains with mono-resistance to fluoroquinolones and one strain with resistance to both INH and fluoroquinolones, making the overall rate of fluoroquinolones resistance 8.7% (14/161). A total of 50 strains (31.1%) were identified as transmission clusters. Patients under 45 years old (adjusted odds ratio 3.46 [95% confidential intervals 1.28–9.35]), treatment-naive patients (6.14 [1.39–27.07]) and patients infected by lineage 4 strains (2.22 [1.00–4.91]) had a higher risk of transmission.ConclusionThe drug resistance of tuberculosis in rural China, especially to the second-line drug fluoroquinolones, is relatively serious. The standardized treatment for patients and the clinical use of fluoroquinolones warrant attention. At the same time, the recent transmission risk of tuberculosis is high, and rapid diagnosis and treatment management at the primary care needs to be strengthened.