Longitudinal metabolomics of human plasma reveal metabolic dynamics and predictive markers of antituberculosis drug-induced liver injury.

Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings.

Efficient estimation of Cox model with random change point.

In clinical studies, the risk of a disease may dramatically change when some biological indexes of the human body exceed some thresholds. Furthermore, the differences in individual characteristics of patients such as physical and psychological experience may lead to subject-specific thresholds or change points. Although a large literature has been established for regression analysis of failure time data with change points, most of the existing methods assume the same, fixed change point for all study subjects. In this paper, we consider the situation where there exists a subject-specific change point and two Cox type models are presented. The proposed models also offer a framework for subgroup analysis. For inference, a sieve maximum likelihood estimation procedure is proposed and the asymptotic properties of the resulting estimators are established. An extensive simulation study is conducted to assess the empirical performance of the proposed method and indicates that it works well in practical situations. Finally the proposed approach is applied to a set of breast cancer data.

Mechanical stimuli-mediated modulation of bone cell function-implications for bone remodeling and angiogenesis.

Bone remodeling, expressed as bone formation and turnover, is a complex and dynamic process closely related to its form and function. Different events, such as development, aging, and function, play a critical role in bone remodeling and metabolism. The ability of the bone to adapt to new loads and forces has been well known and has proven useful in orthopedics and insightful for research in bone and cell biology. Mechanical stimulation is one of the most important drivers of bone metabolism. Interestingly, different types of forces will have specific consequences in bone remodeling, and their beneficial effects can be traced using different biomarkers. In this narrative review, we summarize the major mediators and events in bone remodeling, focusing on the effects of mechanical stimulation on bone metabolism, cell populations, and ultimately, bone health.

Assessing the role of SH3RF1 and SH3RF2 polymorphisms in susceptibility to tuberculosis: A case-control study in the Han Chinese population.

BACKGROUND: Tuberculosis (TB) remains a major public health problem. SH3RF1 and SH3RF2 are candidate genes with multiple single-nucleotide polymorphisms (SNPs) that have the potential to participate in Mycobacterium infection via activation of the JNK signaling pathway. In this case-control study, we aimed to investigate the association of five SH3RF1 and SH3RF2 SNPs with susceptibility to TB in the Western Chinese population. METHODS: A total of 900 TB patients and 1534 healthy control subjects were enrolled in our study. All samples used were obtained from the Bio-Bank of resources of Tuberculosis Research in the Department of Laboratory Medicine, West China Hospital, Sichuan University, China. SNP genotyping was conducted using a commercial custom-by-design 2 × 48-Plex SNPscan Kit. RESULTS: The rs758037 variant of the SH3RF2 gene was found to be associated with decreased TB risk based on allelic effects (p = 0.00001, OR = 0.731, 95% CI = 0.641-0.833) and three genetic models (padd = 0.00001, pdom = 0.0003, prec = 0.0007) after the data were controlled for age and gender and underwent Bonferroni correction. The rs4913057 variant of the SH3RF2 gene was found to be associated with increased TB risk in a dominant model (p = 0.021, OR: 1.260, 95% CI: 1.065-1.490). No significant association was observed between other SNPs and TB risk. CONCLUSION: These findings indicate that polymorphisms in the SH3RF2 gene are involved in susceptibility to TB in the Western Chinese population.

Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines.

Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.

Long Noncoding RNA and Predictive Model To Improve Diagnosis of Clinically Diagnosed Pulmonary Tuberculosis.

Clinically diagnosed pulmonary tuberculosis (PTB) patients lack microbiological evidence of Mycobacterium tuberculosis, and misdiagnosis or delayed diagnosis often occurs as a consequence. We investigated the potential of long noncoding RNAs (lncRNAs) and corresponding predictive models to diagnose these patients. We enrolled 1,764 subjects, including clinically diagnosed PTB patients, microbiologically confirmed PTB cases, non-TB disease controls, and healthy controls, in three cohorts (screening, selection, and validation). Candidate lncRNAs differentially expressed in blood samples of the PTB and healthy control groups were identified by microarray and reverse transcription-quantitative PCR (qRT-PCR) in the screening cohort. Logistic regression models were developed using lncRNAs and/or electronic health records (EHRs) from clinically diagnosed PTB patients and non-TB disease controls in the selection cohort. These models were evaluated by area under the concentration-time curve (AUC) and decision curve analyses, and the optimal model was presented as a Web-based nomogram, which was evaluated in the validation cohort. Three differentially expressed lncRNAs (ENST00000497872, n333737, and n335265) were identified. The optimal model (i.e., nomogram) incorporated these three lncRNAs and six EHRs (age, hemoglobin, weight loss, low-grade fever, calcification detected by computed tomography [CT calcification], and interferon gamma release assay for tuberculosis [TB-IGRA]). The nomogram showed an AUC of 0.89, a sensitivity of 0.86, and a specificity of 0.82 in differentiating clinically diagnosed PTB cases from non-TB disease controls of the validation cohort, which demonstrated better discrimination and clinical net benefit than the EHR model. The nomogram also had a discriminative power (AUC, 0.90; sensitivity, 0.85; specificity, 0.81) in identifying microbiologically confirmed PTB patients. lncRNAs and the user-friendly nomogram could facilitate the early identification of PTB cases among suspected patients with negative M. tuberculosis microbiological evidence.

Testing for change-point in the covariate effects based on the Cox regression model.

Models with change-point in covariates have wide applications in cancer research with the response being the time to a certain event. A Cox model with change-point in covariate is considered at which the pattern of the change-point effects can be flexibly specified. To test for the existence of the change-point effects, three statistical tests, namely, the maximal score, maximal normalized score, and maximal Wald tests are proposed. The asymptotic properties of the test statistics are established. Monte Carlo approaches to simulate the critical values are suggested. A large-scale simulation study is carried out to study the finite sample performance of the proposed test statistics under the null hypothesis of no change-points and various alternative hypothesis settings. Each of the proposed methods provides a natural estimate for the location of the change-point, but it is found that the performance of the maximal score test can be sensitive to the true location of the change-point in some cases, while the performance of the maximal Wald test is very satisfactory in general even in cases with moderate sample size. For illustration, the proposed methods are applied to two medical datasets concerning patients with primary biliary cirrhosis and breast cancer, respectively.

A rare case report of laryngopharyngeal polyp formation following anterior cervical discectomy and fusion (ACDF).

BACKGROUND: Anterior Cervical Discectomy and Fusion (ACDF) has been regarded as the "gold standard" treatment of cervical spondylosis. Though it has good outcomes, many complications still exist, such as loss of fixation, degeneration of adjacent segments, dysphagia and pharyngeal perforation. In view of current literature, this study is the first to report a case of laryngopharyngeal polyp following ACDF. CASE PRESENTATION: A 63 year old male patient suffered from cervical spine hyperextension after trauma accompanied by numbness of the hands and decreased muscle strength in both upper limbs. Anterior cervical fusion surgery was performed in our hospital, after which the patient's upper limb numbness disappeared and muscle strength returned to normal. In the fifth month after surgery, the patient developed a sore throat and dysphagia. Symptoms gradually worsened, and the patient was hospitalized four times, subsequently undergoing tracheotomy, internal fixation removal, and polypectomy. The patient's pronunciation, breathing, and swallowing functions returned to normal, and the incision healed. After a one-year follow-up, the polyp did not recur. CONCLUSIONS: Laryngopharyngeal polyp formation following ACDF has yet to be reported in literature. By excluding esophageal fistula as soon as possible, removing internal fixation and polypectomy serves as the best treatment in relieving patient symptoms.

Genetic polymorphisms of long noncoding RNA RP11-37B2.1 associate with susceptibility of tuberculosis and adverse events of antituberculosis drugs in west China.

BACKGROUND: Little knowledge about the biological functions of RP11-37B2.1, a newly defined long noncoding RNA (lncRNA) molecule, is currently available. Previous studies have shown rs160441, located in the RP11-37B2.1 gene, is significantly associated with tuberculosis (TB) in a Ghanaian and the Gambian populations. METHODS: We investigated the influence of single-nucleotide polymorphisms (SNPs) within lncRNA RP11-37B2.1 on the risk of TB and the possible correlation with adverse drug reactions (ADRs) from TB treatment in a Western Chinese population. Four SNPs within lncRNA RP11-37B2.1 were genotyped in 554 TB cases and 561 healthy subjects using the improved multiplex ligation detection reaction method, and the patients were followed up monthly to monitor the development of ADRs. RESULTS: No significant association between the SNPs of lncRNA RP11-37B2.1 and TB susceptibility was observed (all P > 0.05). Surprisingly, significant association was observed between two SNPs (rs218916 and rs160441) and thrombocytopenia development during anti-TB therapy under the dominant model (P = 0.003 and 0.014, respectively). CONCLUSIONS: Our findings firstly exhibit that rs218916 and rs160441 within lncRNA RP11-37B2.1 significantly associate with the occurrence of thrombocytopenia and suggest RP11-37B2.1 genetic variants are potential biosignatures for thrombocytopenia during anti-TB treatment.

Mesenchymal stem cell sheets: a new cell-based strategy for bone repair and regeneration.

Mesenchymal stem cells (MSCs), a class of adult stem cells, are considered a promising source for bone regeneration. Although combining MSCs with biomaterial scaffolds offers an interesting clinical strategy for bone tissue engineering, the presence of the scaffolds could induce an undesirable effect on cell-cell interactions. Moreover, before the application of scaffold materials in bone tissue reconstruction, cells must be manipulated with proteolytic enzymes, such as trypsin or dispase that degrade extracellular matrix (ECM) molecules and cell surface proteins, which can result in the cell damage and loss of cellular activity. Therefore, the development of alternative strategies for bone regeneration is required to solve these problems. Recently, a novel tissue engineering technology named 'cell sheet' has been efficaciously utilized in the regeneration of bone, corneal, cardiac, tracheal and periodontal ligament-like tissues. The cell sheet is a layer of cells, which contains intact ECM and cell surface proteins such as growth factor receptors, ion channels and cell-to-cell junction proteins. MSC sheets can be easily fabricated by layering the recovered cell sheets without any scaffolds or complicated manipulation. This review summarizes the current state of the literature regarding the use of MSCs to produce cell sheets and assesses their applicability in bone tissue regeneration and repair.

The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529.

mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation. Significantly, RES-529 induced reactive oxygen species (ROS) production and mitochondrial depolarization in U2OS cells as well. RES-529-induced anti-OS cell activity was more potent than other known Akt-mTOR inhibitors. In vivo, RES-529 intraperitoneal injection significantly inhibited U2OS xenograft tumor growth in severe combined immunodeficiency (SCID) mice. mTORC1/2 activation in RES-529-treated tumor tissues was largely inhibited. Collectively, the mTOR inhibitor RES-529 efficiently inhibits human OS cell growth in vitro and in vivo.

Long non-coding RNA THOR promotes human osteosarcoma cell growth in vitro and in vivo.

Long non-coding RNA (LncRNA) dysregulation is associated with human osteosarcoma (OS) cell progression. Recent studies have characterized a novel but ultra-conserved LncRNA THOR ("Lnc-THOR") as a cancer-specific LncRNA, mediating cell growth. In the current study, we show that Lnc-THOR is expressed in established and primary human OS cells. It is also detected in human OS tissues, but not in the surrounding normal bone tissues. siRNA-induced knockdown or CRSIPR/Cas9-mediated knockout Lnc-THOR significantly inhibited human OS cell survival and proliferation. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) target mRNAs, including IGF2, GLI1 and CD44, were downregulated in Lnc-THOR-silenced OS cells as well. Conversely, forced over-expression of Lnc-THOR enhanced IGF2BP1 target mRNA expression, promoting OS cell survival and proliferation. In vivo, xenograft tumors of Lnc-THOR-knockout U2OS cells grew significantly slower than the control U2OS tumors. Together, these results show that Lnc-THOR expression is essential for human OS cell growth. Lnc-THOR could be a novel therapeutic target and/or diagnosis marker for human OS.

Integrated powered density: Screening ultrahigh dimensional covariates with survival outcomes.

Modern biomedical studies have yielded abundant survival data with high-throughput predictors. Variable screening is a crucial first step in analyzing such data, for the purpose of identifying predictive biomarkers, understanding biological mechanisms, and making accurate predictions. To nonparametrically quantify the relevance of each candidate variable to the survival outcome, we propose integrated powered density (IPOD), which compares the differences in the covariate-stratified distribution functions. The proposed new class of statistics, with a flexible weighting scheme, is general and includes the Kolmogorov statistic as a special case. Moreover, the method does not rely on rigid regression model assumptions and can be easily implemented. We show that our method possesses sure screening properties, and confirm the utility of the proposal with extensive simulation studies. We apply the method to analyze a multiple myeloma study on detecting gene signatures for cancer patients' survival.

Novel mutations in the lipase H gene lead to secretion defects of LIPH in Chinese patients with autosomal recessive woolly hair/hypotrichosis (ARWH/HT).

Autosomal recessive woolly hair/hypotrichosis (ARWH/HT: OMIM #278150/604379) is a rare hereditary hair disease characterized by tightly curled hair at birth which can lead to sparse hair later in life. The mutations in both LIPH and LPAR6/P2RY5 are responsible for autosomal recessive woolly hair with or without hypotrichosis (ARWH/HT). To conduct clinical and genetic investigations in four patients from three unrelated Chinese Han families with ARWH/HT, we performed mutation screening of LIPH and LPAR6/P2RY5 gene and identified four mutations in LIPH: c.454G>A, c.614A>G, c.736T>A, c.742C>A. c.736T>A and c.742C>A mutations were reported in previous studies, and c.454G>A, c.614A>G were identified for the first time. We carried out functional studies of the two mutants with c.454G>A (p.Gly152Arg, G152R) or c.614A>G (p.His205Arg, H205R). Interestingly, both of them lead to secretion defects of LIPH, which are involved in the pathogenesis of ARWH/HT.

Mycobacterium tuberculosis PE25/PPE41 protein complex induces activation and maturation of dendritic cells and drives Th2-biased immune responses.

Mycobacterium tuberculosis evades innate host immune responses by parasitizing macrophages and causes significant morbidity and mortality around the world. A mycobacterial antigen that can activate dendritic cells (DCs) and elicit effective host innate immune responses will be vital to the development of an effective TB vaccine. The M. tuberculosis genes PE25/PPE41 encode proteins which have been associated with evasion of the host immune response. We constructed a PE25/PPE41 complex gene via splicing by overlapping extension and expressed it successfully in E. coli. We investigated whether this protein complex could interact with DCs to induce effective host immune responses. The PE25/PPE41 protein complex induced maturation of isolated mouse DCs in vitro, increasing expression of cell surface markers (CD80, CD86 and MHC-II), thereby promoting Th2 polarization via secretion of pro-inflammatory cytokines IL-4 and IL-10. In addition, PE25/PPE41 protein complex-activated DCs induced proliferation of mouse CD4(+) and CD8(+) T cells, and a strong humoral response in immunized mice. The sera of five TB patients were also highly reactive to this antigen. These findings suggest that interaction of the PE25/PPE41 protein complex with DCs may be of great immunological significance.

Diagnostic accuracy of pleural fluid tumor necrosis factor-α in tuberculous pleurisy: A meta-analysis.

BACKGROUND: Pleurisy is a common extra pulmonary complication of tuberculosis, but current methods for diagnosing it are fairly crude. Here we product a meta-analysis for the available evidence on the ability of tumor necrosis factor-α (TNF-α) in pleural fluid to serve as a diagnostic marker of tuberculous pleurisy (TP). MATERIALS AND METHODS: We searched the PubMed, EMBASE, and Google Scholar databases systematically for studies measuring sensitivity, specificity and other measures of diagnostic accuracy of pleural fluid TNF-α in the diagnosis of TP were meta-analyzed by Stata, version 12 and meta-disc. RESULTS: A total of six publications reporting seven case-control studies were identified. Pooled results indicated that pleural fluid TNF-α showed a diagnostic sensitivity of 0.89 (95% confidence interval [95% CI] 0.83-0.93; range, 0.42-1.0) and a diagnostic specificity of 0.82 (95% CI: 0.78-0.86; range, 0.58-0.98). The pooled positive likelihood ratio was 4.78 (95% CI: 3.32-6.89); the negative likelihood ratio, 0.16 (95% CI: 0.1-0.27); the diagnostic odds ratio, 32.43 (95% CI: 14.48-72.6); and the area under the curve was 0.8556 (standard error of mean 0.0559). CONCLUSION: Pleural fluid TNF-α levels shows relatively high sensitivity but insufficient specificity for diagnosing TP. Pleural fluid TNF-α measurement may be useful in combination with clinical manifestations and conventional tests such as microbiological examination or pleural biopsy.

Simultaneous heart valve replacement surgery and abdominal subtotal hysterectomy: case report.

A middle-aged woman with rheumatic heart disease, mitral valve prolapse and incompletely closed mitral valve medium, patent foramen ovale, merge multiple uterine fibroids, and moderate blood loss anemia underwent mitral valve replacement surgery with total abdominal hysterectomy under general anesthesia and cardiopulmonary bypass condition. The surgery was successful, and postoperative bleeding, blood clots, heart failure, and other related complications did not occur. Heart valve replacement surgery with the surgical treatment of uterine fibroids effectively improves the safety of surgical treatment for patients as well as reduces the patient's medical expenses and risk of secondary surgery and trauma.

Proportional hazards model with varying coefficients for length-biased data.

Length-biased data arise in many important applications including epidemiological cohort studies, cancer prevention trials and studies of labor economics. Such data are also often subject to right censoring due to loss of follow-up or the end of study. In this paper, we consider a proportional hazards model with varying coefficients for right-censored and length-biased data, which is used to study the interact effect nonlinearly of covariates with an exposure variable. A local estimating equation method is proposed for the unknown coefficients and the intercept function in the model. The asymptotic properties of the proposed estimators are established by using the martingale theory and kernel smoothing techniques. Our simulation studies demonstrate that the proposed estimators have an excellent finite-sample performance. The Channing House data is analyzed to demonstrate the applications of the proposed method.

Regression analysis of longitudinal data with random change point.

A great deal of literature has been established for regression analysis of longitudinal data and in particular, many methods have been proposed for the situation where there exist some change points. However, most of these methods only apply to continuous response and focus on the situations where the change point only occurs on the response or the trend of the individual trajectory. In this article, we propose a new joint modeling approach that allows not only the change point to vary for different subjects or be subject-specific but also the effect heterogeneity of the covariates before and after the change point. The method combines a generalized linear mixed effect model with a random change point for the longitudinal response and a log-linear regression model for the random change point. For inference, a maximum likelihood estimation procedure is developed and the asymptotic properties of the resulting estimators, which differ from the standard asymptotic results, are established. A simulation study is conducted and suggests that the proposed method works well for practical situations. An application to a set of real data on COVID-19 is provided.

Inference for restricted mean survival time as a function of restriction time under length-biased sampling.

The restricted mean survival time (RMST) is often of direct interest in clinical studies involving censored survival outcomes. It describes the area under the survival curve from time zero to a specified time point. When data are subject to length-biased sampling, as is frequently encountered in observational cohort studies, existing methods cannot estimate the RMST for various restriction times through a single model. In this article, we model the RMST as a continuous function of the restriction time under the setting of length-biased sampling. Two approaches based on estimating equations are proposed to estimate the time-varying effects of covariates. Finally, we establish the asymptotic properties for the proposed estimators. Simulation studies are performed to demonstrate the finite sample performance. Two real-data examples are analyzed by our procedures.