Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial.

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858R/T790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.

Privacy-Preserving Decision-Tree Evaluation with Low Complexity for Communication.

Due to the rapid development of machine-learning technology, companies can build complex models to provide prediction or classification services for customers without resources. A large number of related solutions exist to protect the privacy of models and user data. However, these efforts require costly communication and are not resistant to quantum attacks. To solve this problem, we designed a new secure integer-comparison protocol based on fully homomorphic encryption and proposed a client-server classification protocol for decision-tree evaluation based on the secure integer-comparison protocol. Compared to existing work, our classification protocol has a relatively low communication cost and requires only one round of communication with the user to complete the classification task. Moreover, the protocol was built on a fully homomorphic-scheme-based lattice that is resistant to quantum attacks, as opposed to conventional schemes. Finally, we conducted an experimental analysis comparing our protocol with the traditional approach on three datasets. The experimental results showed that the communication cost of our scheme was 20% of the cost of the traditional scheme.

A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.

HER2 Splice Site Mutation c.1899-1G>A as the Potential Acquired Resistance to Trastuzumab in a Patient with HER2-Positive Gastric Adenocarcinoma.

The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. KEY POINTS: The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.

Metastatic Low-Grade Sarcoma with CARS-ALK Fusion Dramatically Responded to Multiple ALK Tyrosine Kinase Inhibitors: A Case Report with Comprehensive Genomic Analysis.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. KEY POINTS: To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion-positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.

Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis.

BACKGROUND AND AIM: Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. METHODS: A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. RESULTS: The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls (P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase (r = -0.40, P = 0.01), alkaline phosphatase (r = -0.36, P = 0.02), gamma glutamyl transpeptidase (r = -0.53, P < 0.01), tumor necrosis factor (TNF)-α (r = -0.332, P = 0.03), interleukin (IL)-1ß (r = -0.386, P = 0.01), and IL-8 (r = -0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment (P < 0.01). The production of TNF-α, IL-1ß, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-κB pathways through increasing phosphorylation and degradation of IκB in peripheral blood monocytes from PBC patients. CONCLUSION: The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC.

Human Epididymis Protein 4: A Novel Biomarker for Lupus Nephritis and Chronic Kidney Disease in Systemic Lupus Erythematosus.

BACKGROUND: Human epididymis protein 4 (HE4) is an available tumor biomarker for detecting ovarian cancer. However, it is unknown if serum HE4 could be a novel biomarker for diagnosis of lupus nephritis (LN) and chronic kidney disease (CKD) in patients with systemic lupus erythematosus (SLE). METHODS: This study enrolled 209 SLE patients, 75 patients with renal dysfunction without SLE and 32 healthy subjects. HE4 concentrations were analyzed by ELISA (enzyme-linked immunosorbent assay; Fujirebio Diagnostics, Sweden). The receiver operating characteristic (ROC) curves were constructed to assess diagnostic accuracy of HE4 for LN or CKD in SLE. RESULTS: Serum HE4 level was significantly higher in SLE patients than that in healthy controls (P < 0.001), especially for those with LN or CKD. It was also higher in patients with renal dysfunction without SLE than healthy controls (P < 0.001), while there was no significant difference between these patients and those with SLE with CKD (P = 0.73). Multivariate analysis showed significant association between increased HE4 and LN or CKD after controlling for confounders. ROC curves showed the cutoff values were 150.1 pM (sensitivity, 76.8%; specificity, 91.1%) for the diagnosis of LN in SLE and 233.9 pM (sensitivity, 92.9%; specificity, 93.5%) for CKD in SLE. CONCLUSIONS: Increased serum HE4 level is closely associated with the development of LN or CKD in SLE patients. Furthermore, it can be used as a novel and useful biomarker for diagnosis of LN or CKD.

Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were useful markers in assessment of inflammatory response and disease activity in SLE patients.

OBJECTIVE: Although there have been extensive investigations on neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) in many diseases, their roles in systemic lupus erythematosus (SLE) remain unclear. The purpose of the present study was to evaluate NLR, PLR, and MPV levels in adult SLE patients and explore their clinical significance. METHODS: A retrospective study involving 154 adult SLE patients and 151 healthy controls was performed. All clinical characteristics of the SLE patients were extracted from their medical records. NLR, PLR, and MPV levels between SLE patients and healthy controls were compared, and correlations between these indexes and clinical characteristics were analyzed. RESULTS: Increased NLR, PLR, and MPV were observed in SLE patients. NLR was positively correlated with C-reaction protein (r = 0.509, p < 0.01), erythrocyte sedimentation rate (r = 0.610, p < 0.01), and SLE Disease Activity Index (SLEDAI) scores (r = 0.471, p < 0.01). PLR was positively correlated with SLEDAI scores (r = 0.44, p < 0.01). SLE patients with nephritis had higher NLR and PLR levels than those without nephritis (p < 0.01, p = 0.03). In addition, an NLR level of 2.065 was determined as predictive cut-off value of SLE (sensitivity 74.7%, specificity 77.5%, AUC = 0.828). Multiple regression analysis suggested that NLR was independently associated with SLE disease activity. CONCLUSIONS: NLR and PLR could reflect inflammatory response and disease activity in SLE patients.

Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis.

OBJECTIVE: Epidemiological studies of primary Sjögren's syndrome (pSS) are crucial for describing the burden to society and the public medical system and for shedding light on aetiology. Previous reports of the epidemiology of pSS show variable outcomes. We conducted a systematic review of the epidemiology of pSS to assess the prevalence rates (PRs) and incidence rates (IRs), and to investigate possible geographic variations in pSS. METHODS: A systematic literature search of PubMed and Embase (updated to 22 October 2013) was performed to identify all published reports on the epidemiology of pSS. The incidence and prevalence rates of pSS were summarised with IRs or PRs and 95% CIs. RESULTS: The literature search yielded 1880 related citations. Only 21 fulfilled the inclusion criteria. According to a random-effects model, the pooled IR for pSS was 6.92 (95% CI 4.98 to 8.86) per 100 000 person-years. The overall PR was 60.82 (95% CI 43.69 to 77.94) cases per 100 000 inhabitants with a slightly lower estimate of Baodong Qin is BDQ, Jiaqi Wang is JQW, Zaixing Yang is ZXY, Renqian Zhong is RQZ. 43.03 (25.74 to 60.31) cases per 100 000 inhabitants when only considering population-based studies. The female/male ratio in incidence data was 9.15 (95% CI 3.35 to 13.18). The female/male ratio in prevalence data was 10.72 (95% CI 7.35 to 15.62). The overall age of pSS patients was 56.16 years (95% CI 52.54 to 59.78). CONCLUSIONS: Incidence and prevalence rates of pSS vary widely around the world. The results help us better understand the global epidemiology of pSS. Large population-based studies combining meticulous case-finding and case-ascertainment strategies are needed.

Adjuvant therapy in the treatment of gallbladder cancer: a meta-analysis.

BACKGROUND: The benefit of adjuvant therapy (AT) for gallbladder cancer (GBC) is unclear as evidenced by conflicting results from nonrandomized studies. Here we aimed to perform a meta-analysis to determine the impact of AT on overall survival (OS). METHODS: We used data from MEDLINE, EMBASE and the Cochrane Collaboration Library and published between October 1967 and October 2014. Studies that evaluated AT compared with curative-intent surgery alone for resected GBC were included. Subgroup analyses of benefit based on node status, margins status, and American Joint Committee on Cancer (AJCC) staging were prespecified. Data were weighted and pooled using random-effect modeling. RESULTS: Ten retrospective studies involving 3,191 patients were analyzed. There was a nonsignificant improvement in OS with AT compared with surgery alone (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.56-1.03). A significant improvement was observed in OS with chemotherapy (CT) compared with surgery alone (HR, 0.42; 95% CI, 0.22-0.80) by sensitivity analysis. The greatest benefit for AT was also observed in those with R1 disease (HR, 0.33; 95% CI, 0.19-0.59), LN-positive disease (HR, 0.71; 95% CI, 0.63-0.81), and AJCC staging meeting or exceeding tumor Stage II (HR, 0.45; 95% CI, 0.26-0.79), but not in those with LN-negative or R0 disease. CONCLUSION: Our results strongly support the use of CT as an AT in GBC. Moreover, patients with node positivity, margin positivity, or non-stage I disease are more likely to benefit from AT.

Hematocrit Level could Reflect Inflammatory Response and Disease Activity in Patients with Systemic Lupus Erythematosus.

BACKGROUND: The previous study has reported the association of hematocrit (HCT) with inflammation in several diseases. But the role of HCT in systemic lupus erythematosus (SLE) remained unclear. We tried to evaluate the clinical significance of HCT levels in patients with SLE. METHODS: A retrospective study including 127 adult SLE patients and 146 normal healthy controls was performed. HCT levels between SLE patients and normal healthy controls were compared, and correlations between HCT and clinical characteristics were evaluated. RESULTS: HCT levels in SLE patients were significantly decreased as compared with the normal healthy controls and negatively correlated with C-reactive protein (CRP) (r = -0.336, p < 0.01), erythrocyte sedimentation rate (ESR) (r = -0.332, p < 0.01), and SLEDAI scores (r = -0.376, p < 0.01). HCT levels were also significantly lower in SLE patients with decreased C3 and C4 as compared with those in SLE patients with normal C3 and C4, indicating that HCT was positively correlated with C3 and C4 levels (r = 0.272, p < 0.01; r = 0.273, p < 0.01). HCT was decreased in SLE patients with the presence of anti-Sm and anti-RNP antibodies as compared with those without these auto-antibodies (p = 0.013, p < 0.01). After adjusting RBC count and hemoglobin level, multiple linear regression analysis showed that HCT was independently associated with disease activity in SLE patients. In addition, HCT levels were elevated after treatment. CONCLUSIONS: HCT is correlated with CRP, ESR, and SLEDAI, suggesting that HCT could reflect inflammatory response and disease activity in SLE patients.

Neutrophil- and platelet-to-lymphocyte ratios are correlated with disease activity in rheumatoid arthritis.

BACKGROUND: Both neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are reported to be increased in various inflammation-related diseases, but their clinical significance in rheumatoid arthritis (RA) remains unclear. The aim of the present study was to explore whether NLR and PLR were candidate indices for RA disease-activity assessment. METHODS: The medical records of 128 RA patients and 78 healthy individuals were retrospectively reviewed. Correlations of NLR and PLR with the disease activity of RA were evaluated. RESULTS: NLR and PLR were increased significantly in RA patients. NLR was significantly positively correlated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Disease-Activity Score including 28 joints (DAS28) in RA patients, while PLR was positively correlated with CRP and DAS28, but not with ESR. CONCLUSIONS: Both NLR and PLR values may prove to be potential indices for RA disease-activity assessment.

Primary Sjogren's syndrome and malignancy risk: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between primary Sjögren's syndrome (pSS) and the risks of malignancy including overall malignancy and site-specific malignancies through a systematic review and meta-analysis. METHODS: We searched Pubmed before January 2013, with a restriction to English language publications. Studies were included if they met the following criteria: (1) a cohort or observational study; (2) pSS as one of the exposure interests; (3) cancer as an outcome of interest; (4) relative risk (RR) or standardised incidence rate (SIR) with 95% CIs. We used a random or fixed effects model to calculate the pooled RR according to the heterogeneity test. RESULTS: Fourteen studies involving more than 14 523 patients with pSS were included. Compared with the general population, patients with pSS had significantly increased risks of overall cancer (pooled RR 1.53; 95% CI 1.17 to 1.88), non-Hodgkin lymphoma (NHL) (pooled RR 13.76; 95% CI 8.53 to 18.99) and thyroid cancer (pooled RR 2.58; 95% CI 1.14 to 4.03). A significant association was found in various subgroup meta-analyses for NHL but, for overall malignancy, a significant association was only found in some groups. Additionally, the number of studies exploring the association of pSS with the risk of solid malignancies was so small that we could not carry out subgroup meta-analyses. CONCLUSIONS: This meta-analysis indicates that pSS is significantly associated with increased risks of overall malignancy, NHL and thyroid cancer. However, it is not yet known whether the apparent increased risk of overall malignancy in patients with pSS is due to the relatively high prevalence of NHL in that group.

A meta-analysis of the association of IL-6 -174 G/C and -572 G/C polymorphisms with systemic lupus erythematosus risk.

The results from previous studies on association of IL-6 -174 G/C and -572 G/C polymorphisms with the risk of systemic lupus erythematosus (SLE) remained inconsistent. Therefore, a meta-analysis was performed to assess the association between these two polymorphisms and SLE susceptibility. A literature-based search was conducted to identify all relevant studies. Pooled data were estimated by fixed- and random-effects models when appropriate. Nine publications were included in the meta-analysis, seven for -174 G/C polymorphism and three for -572 G/C polymorphism. The results indicated that IL-6 -174 G/C polymorphism was significantly associated with SLE risk for recessive model and allele analysis in overall populations (OR 1.64, 95 % CI 1.10-2.45, P = 0.016; and 1.34, 1.05-1.72, P = 0.019, respectively, for recessive model and allele analysis) or in Caucasians (OR 1.37, 95 % CI 1.04-1.82, P = 0.027; and 1.27, 1.04-1.54, P = 0.018, respectively, for recessive model and allele analysis). Also, significant association between IL-6 -572 G/C polymorphism and SLE was found under recessive model (OR 1.49, 95 % CI 1.10-2.01, P = 0.009), but not under dominant model and allele analysis (OR 1.05, 95 % CI 0.77-1.43, P = 0.750; and 1.21, 1.00-1.48, P = 0.054, respectively, for dominant model and allele analysis). Additionally, our meta-analysis showed that IL-6 -174 G/C polymorphism was significantly associated with discoid skin lesions (P < 0.05). The present study indicates that IL-6 -174 G/C and -572 G/C polymorphisms could be candidates for susceptibility to SLE. Furthermore, a large number of studies should be performed to explore the association of IL-6 polymorphisms with the risk and clinical characteristics of SLE patients in different ethnics.

New clinical trial design in precision medicine: discovery, development and direction.

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Analysis of altered microRNA expression profiles in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.

BACKGROUND AND AIM: MicroRNA, as an important regulator of gene expression, has been found to be associated with several diseases. MicroRNA expression profiles have been identified in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the expression profile in peripheral blood mononuclear cells (PBMCs) from primary biliary cirrhosis (PBC) patients and the role of microRNA in PBC remained unclear. The present study aimed to explore abnormal microRNA regulation in PBC. METHODS: MicroRNA array was performed in PBMCs obtained from PBC patients versus healthy controls. Then, six of the 17 differentially expressed microRNAs were confirmed using quantitative real-time polymerase chain reaction. Based on bioinformatics analysis, we identified the potential biological processes and significant signaling pathways affected by these microRNAs, and generated the microRNA-gene network. RESULTS: According to microRNA array, a total of 17 microRNAs were found to be differentially expressed. Six microRNAs have been validated using quantitative real-time polymerase chain reaction, and the results were consistent with microRNA array analysis. The bioinformatics analysis showed that the potential target genes of these microRNAs were involved in cell proliferation, cell differentiation, apoptosis, and signal transduction. Similarly, these microRNAs also affected endocytosis, mitogen-activated protein kinase signaling pathway, transforming growth factor-ß signaling pathway, Wnt signaling pathway, calcium signaling pathway, etc. CONCLUSION: In the present study, 17 microRNAs were identified to be differentially expressed in PBMCs from PBC patients. Functional bioinformatics analysis demonstrated that prediction genes targeted by these microRNAs were involved in multiple biological processes and signaling pathways. The present study offers intriguing new perspectives on the involvement of microRNA in PBC, but the precise mechanisms need to be validated further.

Meta-analysis of the association between the IL-12B +1188 A/C polymorphism and cancer risk.

BACKGROUND: Because of inconsistent results from previous studies on the association of IL-12B +1188 A/C polymorphism with cancer risk, a meta-analysis was performed to assess the association. MATERIALS AND METHODS: A literature search was performed to identify all relevant studies to May 31, 2012, with a restriction to English and Chinese publications. Pooled data were estimated using a random-effects model. RESULTS: 17 publications were included in the meta-analysis. The results indicated that the polymorphism was significantly associated with a decreased risk for overall cancer (odds ratio (OR), 95% confidence interval (CI): 0.86, 0.76-0.97, p = 0.007; 0.80, 0.68-0.95, p = 0.012; and 0.88, 0.78-0.99, p = 0.032, respectively for dominant model, recessive model, and allele analysis) or nasopharyngeal cancer and hepatocellular carcinoma. This association was also found in Asians (OR, 95% CI: 0.89, 0.80-0.99, p = 0.031; 0.82, 0.68-0.98, p = 0.027; and 0.89, 0.80-1.00, p = 0.047, respectively for dominant model, recessive model, and allele analysis), but not in Europeans and Americans. CONCLUSION: The present study indicates that the IL-12B +1188 A/C polymorphism could play a protective role in the development of cancer. More investigations involving various cancer types among various populations are needed.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

TLR9 polymorphisms and systemic lupus erythematosus risk in Asians: a meta-analysis study.

The results from previous studies on association of TLR9 polymorphisms with the risk of systemic lupus erythematosus (SLE) remained contradictory. Therefore, a meta-analysis was performed to assess the association between TLR9 polymorphisms and SLE susceptibility. A literature-based search was conducted to identify all relevant studies. Pooled data were estimated by fixed- and random-effects models when appropriate. We examined seven publications, showing that there were only three polymorphisms (-1486C/T, +1174A/G and +1635C/T) existing in Asian populations. The meta-analysis indicated that none of these three polymorphisms showed any significant association with SLE risk in Asian populations. In conclusion, the present study indicates that TLR9 polymorphisms are not candidates for susceptibility to SLE, at least, in eastern Asian population. Furthermore, a large number of studies should be performed to explore the association of TLR9 polymorphisms with the risk of SLE in other populations, such as Europeans, Americans and Africans.