Mycobacterium tuberculosis sepsis with multiple intermuscular abscesses and respiratory failure as the main manifestations: a case report.

BACKGROUND: Tuberculous sepsis is uncommon in individuals without human immunodeficiency virus (HIV) infection, and some patients may not exhibit clinical signs and symptoms of suspected sepsis upon admission, leading to delayed diagnosis and treatment. CASE PRESENTATION: This report present the case of a 60-year-old female patient who presented with erythema, edema, and pain in her right upper limb accompanied by fever and chills. Further evaluation revealed multiple intermuscular abscesses caused by suspected gram-positive bacteria. Despite receiving anti-infection treatment, the patient rapidly progressed to septic shock and respiratory failure. Metagenomic next-generation sequencing (mNGS) analysis of blood samples detected Mycobacterium tuberculosis complex groups (11 reads). Additionally, mNGS analysis of fluid obtained from puncture of the abscess in the right upper extremity also suggested Mycobacterium tuberculosis complex groups (221 981 reads). Consequently, the patient was diagnosed with tuberculous sepsis resulting from hematogenous dissemination of Mycobacterium tuberculosis. Following the administration of anti-tuberculosis treatment, a gradual recovery was observed during the subsequent follow-up period. CONCLUSION: It is noteworthy that atypical hematogenous disseminated tuberculosis can be prone to misdiagnosis or oversight, potentially leading to septic shock. This case illustrates the importance of early diagnosis and treatment of tuberculosis sepsis. Advanced diagnostic techniques such as mNGS can aid clinicians in the early identification of pathogens for definitive diagnosis.

Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure.

OBJECTIVE: Acute-on-chronic liver failure (ACLF) is an extreme condition after severe acute exacerbation of chronic hepatitis B; however, the underlying genetic factors involved in its onset and progression are currently unclear. DESIGN: We carried out a genome-wide association study among 399 HBV-related ACLFs (cases) and 401 asymptomatic HBV carriers (AsCs, as controls) without antiviral treatment. The initial findings were replicated in four independent case-control sets (a total of 901 ACLFs and 1686 AsCs). The roles of risk variants on clinical traits of ACLF were also analysed. RESULTS: Among 1300 ACLFs and 2087 AsCs, we identified rs3129859 at human leucocyte antigen (HLA) class II region (chromosome 6p21.32) associated with HBV-related ACLF (combined P dominant =2.64×10-20, OR=1.83). Analysis identified HLA-DRB1*12:02 as the top susceptible HLA allele associated with ACLF (p=3.94×10-6, OR=2.05). The association of rs3129859 was robust in ACLF subgroups (ACLFs with liver cirrhosis, p=1.36×10-16; ACLFs without liver cirrhosis, p=1.52×10-7), and patients at low-replicative phase (p=6.36×10-11, OR=2.29) or HBV e antigen-negative chronic hepatitis B phase (p=1.51×10-14, OR=1.86). Clinical traits analysis in patients with ACLF showed that the risky rs3129859*C allele was also associated with prolonged prothrombin time, faster progression to ascites development and higher 28-day mortality. CONCLUSIONS: Our genome-wide association study identified HLA-DR as the major locus for susceptibility to HBV-related ACLF. Our findings highlight the importance of HLA class II restricted CD4+ T-cell pathway on the immunopathogenesis of HBV-related ACLF.

Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

Sustainable wheat gluten foams with self-expansion and water/blood-triggered shape recovery.

A cheap and easily obtainable wheat gluten (WG) was used to fabricate bio-foams via a simple method of stirring, heating, and lyophilization. The foam possesses a 3D layered porous structure with interconnected channels, and the biofoam has excellent mechanical properties through glycerol plasticization and glutaraldehyde (GA) cross-linking. The water absorption and volume expansion rate can reach 793.67 ∼ 918.45% and 201.47 ∼ 239.53% respectively. In dry state, the foams had good compression resilience, and can basically recover its original shape after withstanding 60% compression strain for about 7 h. In wet state, they can withstand 10 cycles of compression test, and had good compressive resilience and durability; they also had fast liquid-triggered shape recovery performance, of which the foams can reabsorb liquid, expand, and recover its original shape within 40 seconds after withstanding 80% compression strain. In addition, The hemolysis rates of red blood cells treated with 1, 3, and 5 mg/mL of 14WG-20g-5GA foam suspension were 0.53 ± 0.12%, 2.12 ± 0.34%, and 3.97 ± 0.21%, respectively, all of which were below the permissible range for biological materials (<5%). The above-mentioned advantages made the sustainable foams be potentially useful for medical dressings, especially for the treatment of non-compressible haemorrhaging, which offered a new field of application for WG protein and its added value was also increased obviously.

Numerical diagnoses of superinfection in chronic hepatitis B viral dynamics.

OBJECTIVES: Fluctuation profile has been observed in chronic hepatitis B patients who are untreated or interrupt therapy. A mathematical model and its parameters could be used to diagnose the assumption of superinfection of hepatocytes and to understand the causes for the spontaneous fluctuation pattern of HBV DNA loads in chronically infected patients. METHODS: We propose a new conceptual model in terms of chemical kinetics, which is based on the assumption that hepatocytes can be superinfected with hepatitis B virus (HBV). Minimizing the sum of squares of the deviations, we fitted the model to the HBV DNA trajectories from clinical data and obtained the model parameters. RESULTS: The model with the fitted parameters can capture the tendency of HBV DNA trajectories. The mean value of the fitted number of virions that enter a single hepatocyte at the beginning stage of an invasion is 2.10 ± 0.18. The dynamics patterns may correlate with the clinical phenotypes of patients and the value of clinical parameters, such as α-fetoprotein, hepatitis B e-antigen, hepatitis B e-antibody, total bilirubin and alanine transaminase. CONCLUSIONS: The superinfection scenario is possible in HBV infection and it may induce HBV DNA fluctuation in the host.

Association between NER pathway gene polymorphisms and neuroblastoma risk in an eastern Chinese population.

Neuroblastoma is a common childhood malignancy. Nucleotide excision repair (NER) polymorphisms have been shown to influence cancer susceptibility by modifying DNA repair efficiency. To investigate the association of NER gene polymorphisms with neuroblastoma risk, we constructed a three-center case-control study. A total of 19 candidate single-nucleotide polymorphisms (SNPs) in NER genes were analyzed. Odds ratios (ORs) and 95% confidential intervals (CIs) were calculated to evaluate the associations. We identified five independent SNPs that were significantly associated with neuroblastoma risk, including XPA rs1800975 (dominant model: adjusted OR = 0.73, 95% CI = 0.55-0.98, p = 0.033), XPA rs3176752 (recessive model: adjusted OR = 2.78, 95% CI = 1.12-6.91, p = 0.028), XPD rs3810366 (dominant: adjusted OR = 1.44, 95% CI = 1.05-1.97, p = 0.022; recessive: adjusted OR = 1.58, 95% CI = 1.18-2.11, p = 0.002), XPD rs238406 (dominant: adjusted OR = 0.64, 95% CI = 0.48-0.84, p = 0.002; recessive: adjusted OR = 0.67, 95% CI = 0.48-0.94, p = 0.021), and XPG rs2094258 (recessive: adjusted OR = 1.44, 95% CI = 1.03-2.04, p = 0.036). Stratified analysis was carried out. Furthermore, these findings were strengthened by false-positive report probability (FPRP) analysis and expression quantitative trait loci (eQTL) analysis. In conclusion, our study indicates that five SNPs in NER genes are correlated with neuroblastoma susceptibility in the eastern Chinese population, providing novel insight into the genetic underpinnings of neuroblastoma. However, further large-scale studies are required to verify these findings.

SIX1/EYA1 are novel liver damage biomarkers in chronic hepatitis B and other liver diseases.

BACKGROUND: This study aimed to investigate the clinicopathological significance of sine oculis homeobox homolog 1 (SIX1) and eyes absent 1 (EYA1) in patients with chronic hepatitis B (CHB) and other liver diseases. METHODS: SIX1 and EYA1 levels were detected in human serum and liver tissues by enzyme linked immunosorbent assay (ELISA) and immunofluorescent staining method, respectively. RESULTS: The serum SIX1 and EYA1 levels in 313 CHB patients were 7.24±0.11 and 25.21±0.51 ng/mL, respectively, and these values were significantly higher than those in 33 healthy controls (2.84±0.15 and 13.11±1.01 ng/mL, respectively; P<0.05). Serum SIX1 and EYA1 levels were also markedly increased in patients with numerous other liver diseases, including liver fibrosis, hepatocellular carcinoma, fatty liver disease, alcoholic liver disease, fulminant hepatic failure, autoimmune liver disease, and hepatitis C, compared to the healthy controls (P<0.05). Dynamic observation of these proteins over time in 35 selected CHB patients revealed that SIX1 and EYA1 serum levels increased over an interval. Immunofluorescent staining revealed that both SIX1 and EYA1 were only expressed in hepatic stellate cells (HSCs), and their increased expression was evident in CHB liver tissue. CONCLUSIONS: SIX1 and EYA1 are novel biomarkers of liver damage in patients of CHB and other liver diseases, with potential clinical utility.

[Evolution of hepatitis B virus quasispecies during lamivudine-entecavir sequential therapy].

OBJECTIVES: To study the evolution of HBV quasispecies under the pressures of lamivudine (LAM) - entecavir (ETV) sequential therapy and its clinical significance. METHODS: Consecutive serum samples from 2 patients underwent LAM-ETV sequential therapy were extensively studied for HBV quasispecies composition and evolution, using PCR-cloning-sequencing method. Maximum likelihood trees were built to analyze the genetic relationship between representative sequences. Correlation between HBV quasispecies evolution and serological/virological data was analyzed to determined the clinical significance of the evolution of HBV quasispecies during prolonged nucleotide analog therapy. RESULTS: Virological breakthrough was observed in both patients. Patient I acquired sustained virological response after switching to ETV rescue therapy, whereas Patient II suffered from virological breakthrough after 72 weeks of ETV therapy. Each virological breakthrough was accompanied with the replacement of previous drug susceptible dominant quasispecies with a drug resistant variant, indicating a close correlation between quasispecies composition and drug susceptibility. The rtL180M+S202G+M204V triple mutant, which was most likely a descendant of the LAM resistant rtL180M+M204V variant, was closely correlated with ETV resistant in Patient II. CONCLUSION: Quasispecies composition of HBV is closely correlated with nucleotide analog susceptibility. ETV resistant variant can emerge from a LAM resistant viral population. Dynamic monitoring of HBV quasispecies composition is of great importance during nucleotide analog therapy.

Antiviral therapy for hepatitis B virus associated hepatic failure.

BACKGROUND: Chronic hepatitis B virus (HBV) infection remains a major global health issue, and the prognosis of patients with HBV-associated fulminant hepatic failure is extremely poor. The application of antiviral therapies has led to significant improvements in patient outcomes. This article aimed to review the current strategies in antiviral treatment of HBV-associated fulminant hepatic failure. DATA SOURCES: Literature search was conducted using PubMed on the related subjects. Part of the data was from the most recent work of the authors' laboratory. RESULTS: Hepatitis B immunoglobulin in prevention of recurrent HBV infection after orthotopic liver transplantation (OLT) has been proven effective. However, its cost is high, and significant side effects have been found to induce viral mutations. Lamivudine has a potent suppression for HBV replication and an excellent safety profile in decompensated cirrhotic patients, but its major drawback is the high rate of drug-resistance. Adefovir is effective for lamivudine-resistance strains in the post-OLT situation, and its drug-resistance rate is relatively low. Combination therapies such as hepatitis B immunoglobulin combined with lamivudine and lamivudine combined with adefovir have been widely adopted for prophylaxis against HBV recurrence of infection after OLT. Entecavir, telbivudine, tenofovir and other newer agents have been widely used in antiviral therapy. CONCLUSIONS: The prognosis of HBV-associated fulminant hepatic failure is being transformed by developments in antiviral therapy. However, it should be noticed that HBV is controlled but never eliminated, and drug-resistance still remains a major issue. Hopefully, newer strategies may help to solve these problems.

[Analysis of the correlation between the pre-S1 antigen, pre-S2 antigen and DNA of hepatitis B virus in the serum of chronic hepatitis B patients undergoing nucleoside analogue therapy.].

OBJECTIVE: To investigate the dynamic correlation between pre-S1 antigen, pre-S2 antigen and HBV DNA in the serum of chronic hepatitis B (CHB) patients undergoing nucleoside analogue therapy. METHODS: 12 CHB patients with transient virological response after lamivudine treatment, and 20 patients treated with adefovir for 5 years were recruited in this study. Serum samples were collected at four time points when HBV DNA fluctuated sharply during lamivudine treatment, and at 0, 8, 12, 28, 52, 104, 156, 208, 260 weeks following adefovir treatment. HBV DNA was quantified by real-time PCR, pre-S1 and pre-S2 antigens were detected by ELISA. RESULTS: The titers of pre-S1 and pre-S2 antigens were not correlated with the HBV DNA level in the serum of lamivudine treated patients. Only in one case of the adfovir treated patients, the decrease of pre-S1 and pre-S2 antigens was in parallel with the decrease of HBV DNA. Linear regression analysis indicated that neither pre-S1 antigen nor pre-S2 antigen was correlated with HBV DNA in the serum of lamivudine or adfovir treated patients (P more than 0.05). CONCLUSION: Our results indicate that the titers of pre-S1 and pre-S2 antigens are not correlated with the serum HBV DNA in CHB patients undergoing nucleoside analogue therapy. Neither pre-S1 nor pre-S2 is a good predictor for the outcome of nucleoside analogue treatment.

Association of miR-146a, miR-149 and miR-196a2 polymorphisms with neuroblastoma risk in Eastern Chinese population: a three-center case-control study.

Neuroblastoma is one of the most common malignancy in childhood, which originates from the developing sympathetic nervous system. Single nucleotide polymorphisms (SNPs) in primary miRNA (pri-miRNA) have shown to associate with cancer susceptibility, including neuroblastoma. Three precursor miRNA (pre-miRNA) SNPs (pre-miR-146a rs2910164, pre-miR-149 rs2292832 and pre-miR-196a2 rs11614913) were found to contribute to pathogenesis of various diseases. Here, to evaluate the association among these three pre-miRNA SNPs and neuroblastoma susceptibility in Eastern Chinese children, we carried out a three-center case-control study involving 312 neuroblastoma cases and 762 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of these three polymorphisms with neuroblastoma risk. However, no significant association was observed among these three SNPs and neuroblastoma susceptibility, in either overall or subgroups analysis by tumor sites, gender and age. Further larger studies consisting of diverse ethnic populations are required to clarify the associations among these three pre-miRNAs polymorphisms and neuroblastoma risk.

LMO1 Gene Polymorphisms Reduce Neuroblastoma Risk in Eastern Chinese Children: A Three-Center Case-Control Study.

Background: Neuroblastoma, a neuroendocrine tumor, stems from the developing sympathetic nervous system. Previous genome-wide association studies (GWASs) have discovered a number of neuroblastoma susceptibility genes in Caucasians including LIM domain only 1 (LMO1). Objective: We conducted a three-center case-control study including 313 cases and 716 controls with the purpose to evaluate the association between five GWAS-identified LMO1 variants (rs110419 A>G, rs4758051 G>A, rs10840002 A>G, rs204938 A>G, and rs2168101 G>T) and neuroblastoma susceptibility in eastern Chinese children. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. False positive report possibility (FPRP) analysis was performed to check whether significant results were noteworthy. Results: Significant associations with neuroblastoma risk were found for four (rs110419, rs4758051, rs10840002, and rs2168101) out of the five polymorphisms. Combined analysis demonstrated that carriers of 4-5 protective genotypes had a significantly decreased risk of neuroblastoma in comparison those with 0-3 protective genotypes (adjusted OR = 0.51, 95% CI = 0.39-0.68, P < 0.0001). Haplotype analysis of the five SNPs yield four significant haplotypes associated with neuroblastoma susceptibility. Conclusion: In conclusion, we confirmed LMO1 polymorphisms may reduce neuroblastoma risk in eastern Chinese populations.

Utilization of a Wheat55K SNP Array for Mapping of Major QTL for Temporal Expression of the Tiller Number.

Maximum tiller number and productive tiller number are important traits for wheat grain yield, but research involving the temporal expression of tiller number at different quantitative trait loci (QTL) levels is limited. In the present study, a population set of 371 recombined inbred lines derived from a cross between Chuan-Nong18 and T1208 was used to construct a high-density genetic map using a Wheat55K SNP Array and to perform dynamic QTL analysis of the tiller number at four growth stages. A high-density genetic map containing 11,583 SNP markers and 59 SSR markers that spanned 4,513.95 cM and was distributed across 21 wheat chromosomes was constructed. A total of 28 single environmental QTL were identified in the recombined inbred lines population, and among these, seven QTL were stable and used for multi-environmental and dynamic analysis. These QTL were mapped to chromosomes 2D, 4A, 4D, 5A, 5D, and 7D, respectively. Each QTL explained 1.63-21.22% of the observed phenotypic variation, with an additive effect from -20.51 to 11.59. Dynamic analysis showed that cqTN-2D.2 can be detected at four growth stages of tillering, explaining 4.92-17.16% of the observed phenotypic variations and spanning 13.71 Mb (AX-109283238-AX-110544009: 82189047-95895626) according to the physical location of the flanking markers. The effects of the stable QTL were validated in the recombined inbred lines population, and the beneficial alleles could be utilized in future marker-assisted selection. Several candidate genes for MTN and PTN were predicted. The results provide a better understanding of the QTL selectively expressing the control of tiller number and will facilitate future map-based cloning. 9.17% SNP markers showed best hits to the Chinese Spring contigs. It was indicated that Wheat55K Array was efficient and valid to construct a high-density wheat genetic map.

Molecular mapping and genetic analysis of a QTL controlling spike formation rate and tiller number in wheat.

Spike formation rate (SR), which is based on maximum tiller number per unit area and spike number per unit area, is an important yield-related trait in wheat. Increasing the spike formation rate reduces growth competition and wastage of photosynthate from ineffective tillers. Unfortunately, research studies involving quantitative trait locus (QTL) mapping for wheat spike formation rate are limited. In the present study, a set of 371 recombinant inbreed line (RIL) population, which were derived from 1BL/LRS wheat-rye translocation lines CN18 and T1208, was analysed by simple sequence repeat (SSR) markers. Genetic analysis showed that a stable and major QTL (QSR.sicau-4D) for spike formation rate was localized to chromosome 4D and explained 18.24% and 24.48% of the observed phenotypic variance in 2015 and 2016, respectively. This QTL was closely linked to SSR marker Xcfd23, and the genetic distance between the flank markers was 3.28cM. Furthermore, QSR.sicau-4D might be a novel pleiotropic QTL, which also controlled maximum tiller number per unit area (QMTN.sicau-4D) and tiller number during pre-winter per unit area (QTNW.sicau-4D). The marker Xcfd23 associated with SR may be utilized in marker-assisted selection in wheat breeding.

Evolutionary pattern of full hepatitis B virus genome during sequential nucleos(t)ide analog therapy.

The evolutionary and mutational pattern of full hepatitis B virus (HBV) quasispecies during sequential nucleos(t)ide analog (NUC) therapy remains unclear. In this study, full-length HBV clones were generated from serial serum samples of five chronic hepatitis B patients who received sequential NUC therapies (treated patients) and two untreated patients with acute flares. The evolutionary and mutational patterns of full HBV quasispecies were studied. In the three treated patients who received lamivudine as initial antiviral therapy, nucleotide polymorphism and nonsynonymous divergence all decreased at lamivudine breakthrough but increased after rescue therapies. Conversely, two other treated patients showed a distinct change in divergence during adefovir-telbivudine sequential therapies. Untreated subjects exhibited increased polymorphism and divergence in the preC/C region at ALT flare. Four of the treated patients presented amino acid changes in the "a" determinant during NUC therapy. All of the treated subjects showed amino acid changes within the known T-cell or B-cell epitopes in the surface or core antigen, most of which were accompanied by mutations in reverse transcriptase (RT) region. Co-variations in the core promoter, the preC region and in the known epitopes of the preS gene accompanied by RT mutations, were common. In untreated patients, most of these co-variations located in the preC/C gene. In conclusion, the distribution of genetic variability of HBV shows remarkably different patterns between the treated and untreated subjects and the quasispecies divergence of different regions of HBV may vary remarkably even within a single host.