Single-cell RNA sequencing in tuberculosis: Application and future perspectives.

ABSTRACT: Tuberculosis (TB) has one of the highest mortality rates among infectious diseases worldwide. The immune response in the host after infection is proposed to contribute significantly to the progression of TB, but the specific mechanisms involved remain to be elucidated. Single-cell RNA sequencing (scRNA-seq) provides unbiased transcriptome sequencing of large quantities of individual cells, thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research. Here, we first briefly introduce the concept of scRNA-seq, followed by a summarization on the application of scRNA-seq to TB. Furthermore, we underscore the potential of scRNA-seq for clinical biomarker exploration, host-directed therapy, and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.

Adenocarcinoma of sigmoid colon with metastasis to an ovarian mature teratoma: A case report.

BACKGROUND: Colorectal cancer ranks third in global cancer-related mortality, often due to metastases to liver and lungs. Ovarian metastases are less common, accounting for 3.6% to 7.4% of cases. In contrast, mature ovarian teratomas are frequently benign. Tumor-to-tumor metastasis is a rare phenomenon, with a limited number of documented cases. Three cases of mature ovarian teratomas metastasizing from different cancers have been reported. This report focuses on a case of tumor-to-tumor metastasis from sigmoid colon adenocarcinoma to a mature ovarian teratoma. CASE SUMMARY: A 41-year-old Taiwanese woman with no known systemic diseases presented with lower back pain, which led to imaging revealing malignant lesions in the spine, pelvis, liver, and multiple lung metastases. She was diagnosed with sigmoid colon adenocarcinoma with metastases to the liver, lung, bone, and a left ovarian teratoma. Treatment involved radiotherapy and chemotherapy, resulting in regression of the primary tumor and stable lung and liver lesions. Due to abdominal symptoms, she underwent exploratory surgery, unveiling a mature teratoma in the left ovary with signs of metastatic adenocarcinoma. CONCLUSION: Consider resecting mature ovarian teratomas with concurrent colorectal adenocarcinoma to prevent tumor-to-tumor metastasis.

Solid-Phase Microextraction/Gas Chromatography-Time-of-Flight Mass Spectrometry Approach Combined with Network Pharmacology Analysis to Evaluate the Quality of Agarwood from Different Regions against Anxiety Disorder.

Agarwood (Aquilaria malaccensis Lam.) is a resinous material from different geographical locations. The current evaluation of agarwood quality is usually based on its physical properties and chemical compounds, yet only a few studies have linked agarwood quality with its anxiolytic effect, as indicated by characteristic compounds. In this study, using solid-phase microextraction/gas chromatography-time-of-flight mass spectrometry (SPME/GC-TOFMS) and multivariate analysis, we found 116 significantly different compounds in agarwood samples from four locations in Southeast Asia with regard to their quality. Brunei and Nha Trang agarwood had abundant sesquiterpenoids, exhibiting notable pharmacological efficacy in relieving anxiety. Malaysian and Irian agarwood had abundant alcohols and aldehydes, qualifying them as high-quality spices. Compound-target-disease network and pathway enrichment analysis were further employed to predict 79 gene targets and 20 pathways associated with the anxiolytic effects based on the 62 sesquiterpenoids. The correlated relationships among the sesquiterpenoids and targets suggest that agarwood treats anxiety via multiple compounds acting on multiple targets. Varying levels of sesquiterpenes across agarwood groups might lead to differences in the anxiolytic effects via signaling pathways, such as neurotransmitter- and hormone-regulated pathways. Our study originally evaluates agarwood quality and its anxiolytic effect by linking the characteristic compounds to potential gene targets and pathways.

Associated factors and hemodynamic characteristics of resistant hypertension in the elderly.

The purpose of this study was to explore the associated factors and hemodynamic characteristics of resistant hypertension (RHTN) in the elderly. A total of 283 patients aged ≥60 years with hypertension were evaluated by the CNAP™ monitor. Among them, 240 patients were non-RHTN (controlled hypertension with use of three or fewer antihypertensive medications) and 43 patients were RHTN (uncontrolled hypertension despite the concurrent use of ≥3 antihypertensive drugs at optimized doses, including a diuretic, or achieving target blood pressure with the use of ≥4 antihypertensive medications). RHTN was associated with higher body mass index (BMI), longer hypertension duration, and coronary heart disease (p = .004, p < .001, and p = .042, respectively). The mean number of antihypertensive medications was greater in patients with RHTN (p < .001). Hemodynamic analysis revealed higher cardiac output in the RHTN group than in the non-RHTN group, while no difference was observed in systemic vascular resistance. Screening for secondary etiology showed that, among the 43 patients with RHTN, 8 (18.6%) had chronic kidney disease, 8 (18.6%) had obstructive sleep apnea, 4 (9.3%) had primary aldosteronism, 2 (4.7%) had renovascular disease. No significant differences were observed in the cardiac output and systemic vascular resistance values between different causes of RHTN. These findings suggest that higher body mass index, longer hypertension duration, and coronary heart disease emerged as the associated factors of RHTN in the elderly. RHTN is characterized by higher cardiac output. Screening for the possible secondary etiology of RHTN in the elderly patients is necessary and important.

Rationale and Design of LAPIS: A Multicenter Prospective Cohort Study to Investigate the Efficacy and Safety of Low-Dose Aspirin in Elderly Chinese Patients.

Purpose: Although aspirin can effectively reduce the occurrence of atherothrombosis, it is significantly associated with increased bleeding, with elderly individuals being at increased risk of cardiovascular diseases(CVDs) and hemorrhage. While the adverse effects of aspirin can be reduced by using the lowest effective dose, its optimal dose remains undetermined in the elderly Chinese population with both higher cardiovascular and bleeding risks. This study aims to assess the current status of aspirin therapy in real-world clinical settings as well as investigate the efficacy and safety of different doses of aspirin intake (≤ 50 mg/d and > 50 mg/d) for CVD prevention and management in elderly Chinese individuals. Patients and Methods: The Low-dose Aspirin for Primary and Secondary Prevention of Cardiovascular Disease in the Elderly Study (LAPIS) is a multicenter, prospective, observational cohort study. At least 10,000 people aged ≥ 60 years who require long-term aspirin therapy will be recruited. The effectiveness outcome is a composite of major cardiovascular events(MACEs), including nonfatal myocardial infarction, unstable angina, arteriosclerotic disease requiring surgery or intervention, nonfatal stroke, transient ischemic attack, or cardiovascular death (excluding intracranial hemorrhage). The safety outcome is a composite of the first occurrence of fatal bleeding, major bleeding and minor bleeding. Information on the incidence of aspirin-associated gastrointestinal adverse events will also be collected for safety analyses. Outcome measurements will be performed at intervals of 30 days, 3 months, 6 months and then every 6 months for the next 3 years. Conclusion: The results of the LAPIS study will ascertain the efficacy and safety of different doses of aspirin for the prevention and management of CVD, thereby providing evidence to determine the optimal evidence-based dose of aspirin therapy in Chinese elderly individuals. Trial Registration: ChiCTR1900021980 (chictr.org.cn). Registered on March 19, 2019.

Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on low-grade appendiceal mucinous neoplasm: A single tertiary hospital experience.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a rare disease, which prognostic factors were difficult to evaluate. Inflammation markers, like neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were used as prognosticators for various cancers. This study aimed to investigate the prognostic value of pretreatment NLR and PLR on LAMN. METHODS: From January 2000 to September 2018, there were 57 patients diagnosed with LAMN in Taipei Veterans General Hospital. Patients diagnosed with mucinous cystadenoma, mucinous tumor with uncertain malignant potential before 2010 were also included based on previous classification. Clinical and pathological data were collected. Patients were separated into high-NLR (NLR-H) and low-NLR (NLR-L) groups according to cutoff value of 3. Similarly, they were separated into high-PLR (PLR-H), and low-PLR (PLR-L) groups with cutoff value of 300. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. RESULTS: Among all patients, the median follow-up time was 42 months. Age, gender, clinical manifestations, type of surgery, and T stage were similar in different NLR and PLR groups. Both NLR-H and PLR-H groups had higher rate of M1 stage of diseases (22.7% vs 9.4%, p = 0.04; 57.1% vs 8.8%, p < 0.01, respectively). PLR-H group had more presence of pseudomyxoma peritonei (PMP) (57.1% vs 15.2%, p = 0.03). In univariate analysis, factors such as age, gender, tumor perforation, and operation did not have impact on OS nor RFS. On the other hand, M1b stage is the only significantly poor prognostic factor on RFS (hazard ratio, 57.96, 95% CI, 5.16-651.23, p < 0.01). CONCLUSION: Both NLR-H and PLR-H had more M1 stage of diseases, but they were not correlated to OS nor RFS. PLR-H group had higher rate of presence PMP. Nevertheless, patients with LAMN and cellular PMP (M1b stage) had a higher rate of recurrence, and other factors showed no statistical difference in OS nor RFS.

Synergistic effect of Abraxane that combines human IL15 fused with an albumin-binding domain on murine models of pancreatic ductal adenocarcinoma.

Nab-paclitaxel (Abraxane), which is a nanoparticle form of albumin-bound paclitaxel, is one of the standard chemotherapies for pancreatic ductal adenocarcinoma (PDAC). This study determined the effect of Abraxane in combination with a fusion protein, hIL15-ABD, on subcutaneous Panc02 and orthotopic KPC C57BL/6 murine PDAC models. Abraxane combined with hIL15-ABD best suppressed tumour growth and produced a 40%-60% reduction in the tumour size for Panc02 and KPC, compared to the vehicle group. In the combination group, the active form of interferon-γ (IFN-γ)-secreting CD8+ T cells and CD11b+ CD86+ M1 macrophages in tumour infiltrating lymphocytes (TILs) were increased. In the tumour drainage lymph nodes (TDLNs) of the combination group, there was a 18% reduction in CD8+ IFN-γ+ T cells and a 0.47% reduction in CD4+ CD25+ FOXP3+ regulatory T cells, as opposed to 5.0% and 5.1% reductions, respectively, for the control group. Superior suppression of CD11b+ GR-1+ myeloid-derived suppressor cells (MDSCs) and the induction of M1 macrophages in the spleen and bone marrow of mice were found in the combination group. Abraxane and hIL15-ABD effectively suppressed NF-κB-mediated immune suppressive markers, including indoleamine 2,3-dioxygenase (IDO), Foxp3 and VEGF. In conclusion, Abraxane combined with hIL15-ABD stimulates the anticancer activity of effector cells, inhibits immunosuppressive cells within the tumour microenvironment (TME) of PDAC, and produces a greater inhibitory effect than individual monotherapies.

Ginsenoside Rb1 prevents lipopolysaccharide-induced depressive-like behavior by inhibiting inflammation and neural dysfunction and F2 elicits a novel antidepressant-like effect: A metabolite-based network pharmacology study.

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory responses are associated wieh the pathophysiology of depression. Ginsenoside Rb1 (Rb1) exerts antidepressant effect, but the relationship between its activity and inflammation remains unclear. AIM OF THE STUDY: In this study, the antidepressant-like effect and underlying mechanisms of Rb1 were been investigated. MATERIALS AND METHODS: The neuroinflammatory mouse model of lipopolysaccharide (LPS)-induced acute depression-like behavior was employed to detect the action of Rb1. An integrative strategy combining the identification of prototype (Rb1) and its metabolites in vivo with network pharmacology analysis was used to explore therapeutic mechanisms of these ingredients. The putative targets and signalings were experimentally validated. The antidepressant-like effect of F2, the metabolite of Rb1, was firstly evaluated. RESULTS: Rb1 significantly ameliorated LPS-induced depressive-like behavior. Rb1 and its metabolites (Rd, F2, compound K, Rh2, Rg3, PPD) were identified and then a disease-component-target network was established. Experimental validation showed that Rb1 inhibited peripheral and hippocampal inflammation via MAPK/NF-κB signaling. In inflammatory-mediated depression state, Rb1 improved impaired glucocorticoid receptor, suppressed indoleamine 2,3-dioxygenase activity, increased 5-HT level and 5-HT1A receptor expression. Additionally, F2 was firstly discovered to exert antidepressant-like effect, and it existed higher activity than Rb1 against depression. CONCLUSION: The study highlighted the potential of Rb1 and F2 as healthy supplement or agent for inflammation-induced depression.

High concordance of mutation patterns in 10 common mutated genes between tumor tissue and cell-free DNA in metastatic colorectal cancer.

The concordance of mutation patterns between cell-free DNA (cfDNA) and tumor DNA varies in colorectal cancers (CRCs). Next-generation sequencing (NGS) by targeted sequencing can detect novel genes. We aimed to use NGS to test the concordance between cfDNA and tumor DNA in metastatic CRCs. A total of 95 paired tumor and peripheral blood samples from metastatic CRC patients were included. The tumor DNA and cfDNA were analyzed with a 10-gene NGS panel (Illumina HiSeq2500 system). The median number of mutations in tumor samples was 3 (range 0-7). The most commonly mutated gene was TP53 (63.2%), followed by APC (49.5%), KRAS (35.8%) and FAT4 (15.8%). The concordance of mutation patterns in these 10 genes was as high as 91% between cfDNA and tumor samples in these metastatic CRC patients. A sensitivity of 88.2% and specificity of 100% was found when using KRAS mutation status of cfDNA to predict KRAS mutation in tumor tissue. For tumor DNA with TP53, KRAS, or APC mutations, right-sided CRCs were more likely to develop peritoneal metastases, while for tumor DNA with TP53 mutations, left-sided tumors were more likely to have lung metastases. For cfDNA with TP53 or KRAS mutations, right-sided CRCs were more likely to have peritoneal metastases. Due to the high concordance of mutation patterns between cfDNA and tumor samples, monitoring the mutation pattern of cfDNA may be applicable in the treatment of metastatic CRC.

Clinicopathological and molecular features between synchronous and metachronous metastases in colorectal cancer.

The molecular difference between synchronous and metachronous metastases in colorectal cancer (CRC) remains unclear. Between 2000 and 2010, a total of 492 CRC patients were enrolled, including 280 with synchronous metastasis and 212 with metachronous metastasis. Clinicopathological and molecular features were compared between the two groups. Patients with synchronous metastasis were more likely to have right-sided CRC, poorly differentiated tumors, lymphovascular invasion, advanced pathological tumor (T) and node (N) categories, and liver metastases than those with metachronous metastasis. For right-sided CRC, patients with synchronous metastasis had more lymphovascular invasion and liver metastases than those with metachronous metastasis. For left-sided CRC, patients with synchronous metastasis were more likely to have poorly differentiated tumors, lymphovascular invasion, advanced pathological T and N categories, and liver metastases than those with metachronous metastasis. Regarding the genetic mutations, patients with metachronous metastasis had more mutations in TP53, NRAS, and HRAS and fewer mutations in APC than those with synchronous metastasis; for right-sided CRC, synchronous metastasis was associated with more APC mutations than metachronous metastasis, while for left-sided CRC, metachronous metastasis was associated with more TP53 and NRAS mutations than synchronous metastasis. The 5-year overall survival (OS) rates were significantly higher in metachronous metastasis patients than in synchronous metastasis patients, especially those with left-sided CRC. Multivariate analysis showed that age, sex, lymphovascular invasion, pathological N category, metachronous metastasis, and BRAF and NRAS mutations were independent prognostic factors affecting OS. CRC patients with synchronous metastasis had a worse OS than those with metachronous metastasis and exhibited distinct genetic mutations.

Phytochemical Analysis Using UPLC-MSn Combined with Network Pharmacology Approaches to Explore the Biomarkers for the Quality Control of the Anticancer Tannin Fraction of Phyllanthus emblica L. Habitat in Nepal.

Phyllanthus emblica L. is widely used in traditional Tibetan medicine for its therapeutic effects on treating liver, kidney, and bladder problems. We have reported that the tannin fraction has a good anti-hepatocellular carcinoma effect, but its active ingredients are not clear. This study was to find the active ingredients of the tannin fraction using UPLC-MSn and network pharmacology. First of all, the UPLC-MSn method was employed to obtain high-resolution mass spectra of different components, and 110 compounds were obtained. Then a network pharmacology method was used to find biomarkers for quality control. Network pharmacology results showed that gallic acid, punicalagin A, punicalagin B, methyl gallate, geraniin, corilagin, chebulinic acid, chebulagic acid, and ellagic acid should be the biomarkers of the tannin fraction. Furthermore, 9 components were detected in the serum, which also proved that they could be biomarkers, because we generally believe that the ingredients which are absorbed into the blood are effective. In the end, a simple method for simultaneously determining the contents of the 9 compounds was constructed by HPLC-DAD. This research established a new method to find biomarkers of traditional Chinese medicine. This is of great significance to improving the quality standards of Tibetan medicine.

Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer.

BACKGROUND: Few reports have investigated genetic alterations between patients with early and late recurrence following curative surgery for colorectal cancer (CRC). METHODS: A total of 1227 stage I-III CRC patients who underwent curative resection were included retrospectively. Among them, 236 patients had tumor recurrence: 139 had early (<2 years after surgery) and 97 had late (≥2 years after surgery) recurrence. Clinicopathological features and genetic alterations were compared between the two groups. RESULTS: Compared to those with late recurrence, patients with early recurrence were more likely to have advanced pathological node (N) categories; tumor, node, metastasis (TNM) stages; adjuvant chemotherapy treatment; liver metastases; APC mutations; and worse five-year overall survival rates. Patients with right-sided colon cancer were more likely to develop early recurrence than were those with left-sided colon cancer or rectal cancer. Regarding rectal cancer, patients with early recurrence were more likely to be at advanced pathological N categories and TNM stages than those with late recurrence. Multivariate analysis revealed old age, early recurrence, multiple-site recurrence, and BRAF and NRAS mutations to be independent prognostic factors. CONCLUSION: CRC patients with early recurrence have a worse OS rate and more APC mutations than those with late recurrence.

Tannins in Terminalia bellirica inhibit hepatocellular carcinoma growth by regulating EGFR-signaling and tumor immunity.

The fruits of Terminalia bellirica (Gaertn.) Roxb. (TB) are used as a multi-use therapeutic herbal product in the Tibetan medicinal system and are prescribed as a general health tonic in the traditional Ayurvedic medicinal system. It has been demonstrated that these fruits have a variety of pharmacological activities, including anti-tumor, anti-oxidative, anti-inflammatory, hepatoprotective and immunoregulatory effects, etc. However, the therapeutic effects of tannins in TB on HCC and the underlying mechanisms remain uncharacterized. In the current study, we aimed to identify the anti-tumor effect of tannins in TB by employing a H22 xenograft mouse model and by performing cell-based in vitro studies with the assistance of the network pharmacology analysis. The crude extract of TB was purified to yield total tannin fraction (TB-TF), and our results found that TB-TF significantly inhibited the tumor growth of H22 xenografts in mice by inducing apoptosis and reducing angiogenesis. A total of 90 compounds were then identified in TB-TF by UPLC-MS/MS, and 27 were found in serum after oral administration of TB-TF in mice. The network pharmacology analysis based on these absorbed components was performed and, along with experimental evidence, it revealed that the ERBB, PI3K-Akt, and MAPK signaling pathways may be involved in the anti-tumor effect of TB-TF on HCC. Furthermore, we suggested that TB-TF effectively modulated the immunosuppressive tumor microenvironment in H22 xenograft mice. In summary, our study demonstrated that TB-TF could be developed as a functional food, which is not only a promising anti-cancer reagent but also a potential candidate with bright prospects for the emerging trends of immunotherapy for HCC.

Clinicopathological and Molecular Features of Colorectal Cancer Patients With Mucinous and Non-Mucinous Adenocarcinoma.

BACKGROUND: The prognosis of mucinous adenocarcinoma (MAC) and non-mucinous adenocarcinoma (NMAC) in colorectal cancer (CRC) is controversial, and the molecular differences between them are unclear. METHODS: Between 2000 and 2010, a total of 1,483 CRC patients were included. Among them, 73 patients (4.9%) were diagnosed with MAC. The clinicopathological features and genetic alterations were compared between MAC and NMAC. RESULTS: After propensity score matching to balance age and sex between MAC and NMAC patients, 292 CRC patients (73 MAC and 219 NMAC) were enrolled in the analysis at a 1:3 ratio. In right-sided colon cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, and advanced T category and tumor, node, metastasis (TNM) stage, chemotherapy, and a similar 5-year overall survival (OS) rate compared with patients with NMAC. In left-sided colon cancer and rectal cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, lymphovascular invasion, advanced T and N categories and TNM stages, chemotherapy, and a worse 5-year OS rate than patients with NMAC. Regarding genetic alterations, for NMAC, right-sided colon cancer had more BRAF mutations than left-sided colon cancer and rectal cancer. For MAC, right-sided colon cancer was associated with more microsatellite instability-high tumors and more AKT1 mutations than left-sided colon cancer and rectal cancer. CONCLUSION: The genetic alterations are distinct between MAC and NMAC in CRC. Tumor location may have an impact on genetic alterations and patient prognosis in MAC and NMAC.

Ginsenosides Improve Nonalcoholic Fatty Liver Disease via Integrated Regulation of Gut Microbiota, Inflammation and Energy Homeostasis.

Ginseng, the root and rhizome of Panax ginseng C. A. Mey., is a famous herbal medicine, and its major ginsenosides exert beneficial effects on nonalcoholic fatty liver disease (NAFLD). Due to the multicomponent and multitarget features of ginsenosides, their detailed mechanisms remain unclear. This study aimed to explore the role of ginsenosides on NAFLD and the potential mechanisms mediated by the gut microbiota and related molecular processes. C57BL/6J mice were fed a high-fat diet (HFD) supplemented or not supplemented with ginsenoside extract (GE) for 12 weeks. A strategy that integrates bacterial gene sequencing, serum pharmacochemistry and network pharmacology was applied. The results showed that GE significantly alleviated HFD-induced NAFLD symptoms in a dose-dependent manner. Furthermore, GE treatment modulated the HFD-induced imbalance in the gut microbiota and alleviated dysbiosis-mediated gut leakage and metabolic endotoxemia. Additionally, 20 components were identified in the mouse plasma after the oral administration of GE, and they interacted with 82 NAFLD-related targets. A network analysis revealed that anti-inflammatory effects and regulation of the metabolic balance might be responsible for the effects of GE on NAFLD. A validation experiment was then conducted, and the results suggested that GE suppressed NF-κB/IκB signaling activation and decreased the release and mRNA levels of proinflammatory factors (TNF-α, IL-1ß and IL-6). Additionally, GE promoted hepatic lipolytic genes (CPT-1a), inhibited lipogenic genes (SREBP-1c, FAS, ACC-1) and improved leptin resistance. These findings imply that the benefits of GE are involved in modulating the gut microbiota, enhancing the gut barrier function, restoring the energy balance, and alleviating metabolic inflammation. Moreover, GE might serve as a potential agent for the prevention of NAFLD through the integration of prebiotic, anti-inflammatory and energy-regulatory effects.

Association between renal function and platelet reactivity during aspirin therapy in elderly patients with atherosclerotic cardiovascular disease.

BACKGROUND: Aspirin is the key treatment in the secondary prevention of atherosclerotic cardiovascular disease. High on-treatment platelet reactivity (HTPR) to aspirin has been reported to partially account for the enhanced risk of thrombotic events. In particular, HTPR has been described more frequently among elderly patients. The aim of this study was to identify the clinical and biological factors associated with HTPR in a real-life elderly population. METHODS: In this retrospective study, elderly patients with atherosclerotic cardiovascular disease on regular aspirin treatment were enrolled. Cardiovascular risk factors, routine biological parameters, comorbidities, and concomitant medications were recorded. The upper quartile of the platelet aggregation rate, determined by light transmission aggregometry with arachidonic acid, was defined as the HTPR group. RESULTS: A total of 304 patients were included (mean age 77 ± 8 years, 76% men). Patients in the HTPR group were older than the patients in the non-HTPR group (mean age: 79 ± 7 vs. 76 ± 8 years, p = 0.008). Patients with moderately decreased estimated glomerular filtration rate (eGFR) had a higher frequency of HTPR than patients with slightly decreased eGFR or normal eGFR (35.8, 22.5, 12.2%, respectively, p < 0.05). In multivariate analysis, an independent risk factor for HTPR was the eGFR (OR: 0.984, 95% CI: 0.980-0.988, p < 0.001). CONCLUSIONS: Advanced age and decreased eGFR are correlated with poor pharmacodynamic response to aspirin.

Clinicopathological and Molecular Profiles of Sporadic Microsatellite Unstable Colorectal Cancer with or without the CpG Island Methylator Phenotype (CIMP).

BACKGROUND: The 5'-C-phosphate-G-3' island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. METHODS: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. The mutation spectra of 22 common CRC-associated genes were analyzed by NGS. RESULTS: Of the 92 sporadic MSI-high tumors, 23 (25%) were considered CIMP-high (expressed more than 5 of 8 markers). CIMP-high tumors showed proximal colon preponderance and female predominance. The mutation profiles of CIMP-high tumors were significantly different from those of CIMP-low or CIMP-0 tumors (i.e., higher frequencies of BRAF, POLD1, MSH3, and SMAD4 mutations but lower frequencies of APC, TP53, and KRAS mutations). Multivariate analysis demonstrated that tumor, node, metastasis (TNM) stage was the independent prognostic factor affecting overall survival (OS). Among the MSI-high cases, the CIMP status did not impact the outcome of patients with MSI-high tumors. CONCLUSIONS: Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

Outcomes of primary membranous nephropathy based on serum anti-phospholipase A2 receptor antibodies and glomerular phospholipase A2 receptor antigen status: a retrospective cohort study.

INTRODUCTION: Primary membranous nephropathy (PMN) is associated with the anti-phospholipase A2 receptor (anti-PLA2R) antibody in 70% of cases. Some anti-PLA2R-negative patients have the PLA2R antigen in renal tissue. This study examined the prognosis of patients with PMN according to their serum anti-PLA2R antibody (SAb) and glomerular PLA2R antigen (GAg) status. METHODS: Patients diagnosed with PMN were included retrospectively. Patients were grouped according to their PLA2R status into the SAb-/GAg-, SAb-/GAg+, and SAb+/GAg + groups. Baseline data, renal biopsy results, treatment, and clinical data were compared among the groups. Cox univariable and multivariable analyses examined the factors related to complete remission (CR). RESULTS: A total of 114 patients were enrolled; 10 (9%) in the SAb-/GAg-, 23 (20%) in the SAb-/GAg+, and 81 (71%) in the SAb+/GAg+ groups. Cumulative CR rate showed a significant difference between the SAb-/GAg - and SAb+/GAg+ groups (log-rank p = 0.003). The multivariable Cox proportional hazard analysis showed that age (HR = 0.968; 95%CI = 0.946-0.990; p = 0.005), SAb+/GAg+ versus SAb-/GAg- (HR = 0.387; 95%CI = 0.190-0.788; p = 0.009), SAb-/GAg+ versus SAb-/GAg- (HR = 0.398; 95%CI = 0.169, 0.939; p = 0.035), total renal chronicity score ≥2 (HR = 0.461, 95%CI: 0.277-0.766, p = 0.003), and IgA deposition (HR = 2.596; 95%CI = 1.227-5.492; p = 0.013) were all independently related (p < 0.05) to CR. CONCLUSIONS: The SAb and GAg status was an indicator of PMN prognosis. The patients with SAb-/GAg - had an increased likelihood of achieving CR than those with SAb-/GAg+ and SAb+/GAg+.

Infection-related hospitalization after intensive immunosuppressive therapy among lupus nephritis and ANCA glomerulonephritis patients.

Introduction: This study aimed to investigate the clinical characteristics, risk factors, and outcomes of infection-related hospitalization (IRH) in patients with lupus nephritis (LN) and ANCA glomerulonephritis after intensive immunosuppressive therapy.Methods: Patients diagnosed with LN or ANCA glomerulonephritis who received intensive immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from 2005 to 2014 were enrolled. Demographics, laboratory parameters, immunosuppressive agents, and IRH details were collected. Multivariable Cox regression was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were reported.Results: Totally, 872 patients with 806 LN and 66 ANCA glomerulonephritis were enrolled, and 304 (34.9%) patients with 433 episodes of IRH were recorded. ANCA glomerulonephritis patients were more vulnerable to IRH than LN patients (53.0% vs. 33.4%, p = .001). Multivariable Cox regression analysis showed that ANCA glomerulonephritis (HR = 1.62, 95% CI: 1.06-2.49, p = .027), diabetes (HR = 1.82, 95% CI: 1.03-3.22, p = .039) and a higher initial dose of prednisone (HR = 1.01, 95% CI: 1.00-1.02, p = .013) were associated with a higher likelihood of IRH. Higher albumin (HR = 0.96, 95% CI: 0.94-0.98, p < .001), globulin (HR = 0.98, 95% CI: 0.96-0.99, p = .008), and eGFR (HR = 0.99, 95% CI: 0.99-1.00, p < .001), were associated with a lower likelihood of IRH. The rates of transfer to ICU and mortality for ANCA glomerulonephritis patients were higher than those for LN patients (22.9% vs. 1.9%, p < .001, and 20.0% vs. 0.7%, p < .001, respectively).Conclusions: ANCA glomerulonephritis patients had a higher risk of IRH and poorer outcome once infected after intensive immunosuppressive therapy than LN patients. More strict control for infection risks is required for ANCA glomerulonephritis patients who undergo intensive immunosuppressive therapy.