Association between NET-1 Level in Placenta from Preeclampsia Pregnancies and Trophoblast Proliferation and Apoptosis: A Correlation Analysis.

Objective: This study investigates the expression pattern of neuroepithelial cell transforming 1 (NET-1) in placental tissues from pregnancies with preeclampsia (PE) and explores its role in mediating proliferative and apoptotic capacities of trophoblasts. Methods: The relative mRNA levels of NET-1 in placental tissues obtained from preeclampsia (PE) pregnancies (n = 60) and healthy pregnancies (n = 60) were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Pearson correlation test was conducted to assess the correlation between NET-1 level and systolic (Sp) and diastolic pressure (Dp) in PE pregnancies. After the knockdown of NET-1 in HTR-8/SVneo cells, changes in proliferation and apoptosis were examined using cell counting kit-8 (CCK-8) and flow cytometry, respectively. Results: NET-1 was highly expressed in placental tissues from PE pregnancies. PE patients with a high level of NET-1 had higher Sp and Dp, and NET-1 level was positively correlated with both Sp and Dp. Knockdown of NET-1 in HTR-8/SVneo cells decreased the proliferative rate but increased the apoptotic rate. Conclusions: NET-1 stimulates the development of PE by triggering trophoblast proliferation and inhibiting apoptosis. Therefore, NET-1 could be a potential therapeutic target for treating PE and other related hypertensive disorders during pregnancy.

Exploring the perceptions of the educational environment in online acupuncture learning during the COVID-19 pandemic.

OBJECTIVE: Students have had to adapt to a "new normal" of online education at home during the COVID-19 pandemic. This poses a considerable challenge to the conduct of online acupuncture courses. Here, we provide our experience and guidance for conducting an online experimental acupuncture course during the COVID-19 pandemic. We aimed to compare the different perceptions of undergraduates to the educational environment between online and face-to-face learning approaches. METHODS: This study included senior undergraduates majoring in acupuncture during the academic years 2015 (face-to-face) and 2020 (online only) for the Experimental Acupuncture course. A survey was conducted at the end of this course. The Dundee Ready Educational Environment Measure (DREEM) questionnaire was used to assess students' perceptions. The results of students' responses to online learning were compared with those assessed for face-to-face learning. RESULTS: In total, 56/70 (80%) students in 2015 and 49/54 (91%) students in 2020 completed the questionnaire, respectively. Total DREEM scores were higher in the online learning group than in the face-to-face learning group (160.3 ± 21.9 vs 147.6 ± 17.9, p = 0.007), with improved students' perceptions on four out of five dimensions (social self-perception, learning, atmosphere and academic self-perception). The positive aspects of their online learning experience included the acquisition of new knowledge and skills. The significant limitations of this course included the lack of practical classes. CONCLUSION: Students' perceptions regarding the Experimental Acupuncture program were satisfactory for both online and face-to-face learning approaches, but even better with online learning. Online learning may be encouraged in traditional Chinese medicine (TCM) education. However, a combination of face-to-face and online methods is likely to be required to maximize the benefits. We hope that our online Experimental Acupuncture program practices may assist in the development of online curricula for acupuncture during the COVID-19 pandemic.

Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2.

Neuroendocrine prostate cancer (NEPC) is a more aggressive subtype of castration-resistant prostate cancer (CRPC). Although it is well established that PHF8 can enhance prostate cancer cell proliferation, whether PHF8 is involved in prostate cancer initiation and progression is relatively unclear. By comparing the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without Phf8 knockout, we systemically examined the role of PHF8 in prostate cancer development. We found that PHF8 plays a minimum role in initiation and progression of adenocarcinoma. However, PHF8 is essential for NEPC because not only is PHF8 highly expressed in NEPC but also animals without Phf8 failed to develop NEPC. Mechanistically, PHF8 transcriptionally upregulates FOXA2 by demethylating and removing the repressive histone markers on the promoter region of the FOXA2 gene, and the upregulated FOXA2 subsequently regulates the expression of genes involved in NEPC development. Since both PHF8 and FOXA2 are highly expressed in NEPC tissues from patients or patient-derived xenografts, the levels of PHF8 and FOXA2 can either individually or in combination serve as NEPC biomarkers and targeting either PHF8 or FOXA2 could be potential therapeutic strategies for NEPC treatment. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Case Report: Co-Existence of BRCA2 and PALB2 Germline Mutations in Familial Prostate Cancer With Solitary Lung Metastasis.

BACKGROUND: Mutation-caused loss-of-function of factors involved in DNA damage response (DDR) is responsible for the development and progression of ~20% of prostate cancer (PCa). Some mutations can be used in cancer risk assessment and informed treatment decisions. METHODS: Target capture-based deep sequencing of 11 genes was conducted with total DNA purified from the proband's peripheral blood. Sanger sequencing was conducted to screen potential germline mutations in the proband's family members. Targeted sequencing of a panel of 1,021 genes was done with DNA purified from the tumor tissue. RESULTS: Two previously unreported germline mutations in the DDR pathway, BRCA2 (c.8474_8487delCATACCCTATACAG, p.A2825Vfs*15) and PALB2 (c.472delC, p.Q158Rfs*19) were identified in a patient with metastatic PCa. A specific therapeutic regimen including androgen deprivation therapy, locally radical radiotherapy, and systemic platinum chemotherapy worked well against his cancer. In addition, the metastatic ovarian cancer in the proband's half-sister harboring the same BRCA2 germline mutation also responded well to platinum chemotherapy. CONCLUSIONS: The newly identified germline mutations in DDR plays important role in PCa development. Since specific regimen worked well against this cancer, screening of DDR mutation could provide better management for patients with these mutation-mediated PCa.

Correlation of APE1 with VEGFA and CD163+ macrophage infiltration in bladder cancer and their prognostic significance.

The present study sought to estimate the applicability of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), vascular endothelial growth factor A (VEGFA) expression and CD163+ tumor-associated macrophage (TAM) ratio as prognostic factors in bladder cancer (BCa). A total of 127 patients with bladder urothelial cancer who underwent radical cystectomy at Daping Hospital were recruited between January 2013 and January 2017, including 45 cases of non-muscle invasive BCa (NMIBC) and 82 of MIBC. Immunohistochemical detection of APE1, VEGFA and CD163, as well as multiple immunofluorescence staining for APE1, VEGFA, CD163 and CD34, were performed on tissue samples. For APE1 and VEGFA, the staining was graded based on intensity (0-3), while CD163 was graded (0-3) based on the percentage of positively stained cells. The prognostic value of APE1, VEGF and CD163 was assessed using Kaplan-Meier and Cox regression analysis. The results suggested that in BCa, high APE1 expression was associated with high VEGFA expression and more infiltration of CD163+ TAM. Furthermore, high expression of APE1 was associated with lymphovascular invasion of BCa, as well as reduced survival time. This indicates that APE1 may be associated with CD163+ TAM infiltration in BCa, with VEGFA as a possible influencing factor.

LSD1 Promotes Bladder Cancer Progression by Upregulating LEF1 and Enhancing EMT.

Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with ß-catenin to transcriptionally upregulate LEF1 and subsequently enhances EMT-mediated cancer progression. More importantly, LSD1 specific inhibitor GSK2879552 is capable of repressing tumor progression in patient-derived tumor xenograft. These findings altogether suggest that LSD1 can serve as not only a prognostic biomarker but also a promising therapeutic target in bladder cancer treatment.

The correlation of BER protein, IRF3 with CD8+ T cell and their prognostic significance in upper tract urothelial carcinoma.

OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) play a crucial role in anti-tumor immunity. Basic studies have found that stimulator of interferon genes (STING), activated by sensing DNA damage, plays a role in recruiting and activating TILs in tumors. However, the correlation between base excision repair (BER) pathway, STING pathway and TILS and their effect on prognosis in upper urinary tract urothelial carcinoma (UTUC) are still unclear. The aim of this study was to investigate the prognostic effect of those proteins expression for disease-free survival (DFS) and overall survival (OS) and explore the correlation between these makers. METHODS: We evaluated immunohistochemical expression of BER pathway (APE1, NTH1, OGG1, XRCC1, polß), STING pathway (STING, IRF3), TILs (CD4, CD8, CD20) and PD-L1, PD-L2 in 88 UTUC patients to determine the predictive significance in DFS, OS and the correlation between them. RESULTS: We found that interferon regulatory factor3 (IRF3) (HR: 0.451, 95% CI 0.243-0.837, p=0.024) and CD8 (HR: 0.522, 95% CI 0.295-0.926, p=0.014) are independent prognostic factors for DFS, APE1 (HR: 1.932, 95% CI 1.005-3.714, P=0.048), polß (HR: 2.620, 95% CI 1.373-5.000, P=0.003), CD8 (HR: 0.323, 95% CI 0.151-0.693, P=0.004) were independent prognostic factors for OS. A model consisting of stage, grade, lymphovascular invasion and expression of APE1, polß, IRF3, CD4, CD8 that predicts 3-year OS. Furthermore, DNA damage repair protein polß is associated with CD8+ T cells in TME. CONCLUSION: We found that DNA damage, IRF3 and TILs are independent predictors for prognosis. We also provided clinical evidence that DNA damage repair-activated STING pathway can induce the recruitment and activation of TILs, which is consistent with preclinical models.

A Renal Cell Carcinoma with Biallelic Somatic TSC2 Mutation: Clinical Study and Literature Review.

OBJECTIVE: To elucidate the effect of the biallelic somatic TSC2 mutations, identified in one adolescent patient, in renal cell carcinoma (RCC). METHODS: Mutation analyses, immunohistochemistry and real-time polymerase chain reaction (PCR) were conducted. RESULTS: Two novel somatic mutations of TSC2 in unilateral and solitary RCC samples from a 14-year-old female were identified. The pathological features suggest the tumor as a clear-cell renal cell carcinoma. In addition, immunohistochemistry revealed elevated levels of phosphorylated S6K1. Results from in vitro cellular experiments suggest that the mutant TSC2 proteins were quickly degraded and they failed to repress the phosphorylation of S6K1 and STAT3, which leads to constitutive activation of mTORC1 pathway and ultimately cause the development of RCC. CONCLUSION: Detecting TSC2 mutation in patients with early RCC onset would be beneficial and mTOR inhibitor could be a therapeutic option for TSC2 mutation-induced RCC.

Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

Giant bilateral adrenal myelolipomas in two Chinese families with congenital adrenal hyperplasia.

CONTEXT AND OBJECTIVES: Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes. PARTICIPANTS AND METHODS: A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, 5 patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using Target Capture-Based Deep Sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations. RESULTS: In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C>G / c.518T>A, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A>T, p.H373L / c.1459_1467del9, p.D487_F489del) in CYP17A1. CONCLUSION: To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH.

The roles of the COX2/PGE2/EP axis in therapeutic resistance.

Therapeutic resistance has been and remains to be the major challenge in developing successful treatments for different cancers and therefore, understanding the underlying mechanisms in the development of therapeutic resistance is crucial in combating cancers. Multiple mechanisms underlie the development of therapeutic resistance, and the signaling pathways involved in cancer stem cell repopulation, enhanced epithelial-mesenchymal transition (EMT), inflammatory infiltration, and immunosuppression play pivotal roles in this process. Accumulating evidence indicates that the COX2/PGE2/EP axis plays crucial roles not only in tumor development including initiation and progression but also in the development of therapeutic resistance. In this review, we will first dissect the relationship between the COX2/PGE2/EP axis and therapeutic resistance by focusing on the roles of the COX2/PGE2/EP axis in cancer stem cell repopulation, EMT, and anti-cancer immunity. Then, we will summarize the currently available compounds/drugs targeting each component of this axis as well as some of the underlying mechanisms. We hope that better understanding the underlying mechanisms of the functional compounds will be helpful in seeking additive and/or synergistic effects against therapeutic resistance without or with minimal adverse consequence.

Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration.

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.

A retrospective case study of sunitinib treatment in three patients with Von Hippel-Lindau disease.

Von Hippel-Landau (VHL) disease is characterized by malignant and benign tumors in multiple organs. Sunitinib, a tyrosine kinase inhibitor, has been clinically available for treating sporadic patients with recurrent or unresectable and metastatic clear renal cell carcinomas (cRCCs) and metastatic lesions of the lung, but its effect on VHL disease-associated tumors remains poorly understood. This retrospective case series examined the effect of sunitinib on RCC, hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors in patients with confirmed VHL. Of note, three patients with VHL disease who were treated with sunitinib were identified from a review of their medical records. The efficacy of sunitinib was evaluated by comparing computed tomography (CT) or magnetic resonance imaging (MRI) scans conducted before and after treatment. Adverse side effects associated with sunitinib were assessed and recorded. All three patients with VHL disease exhibited clinical improvement after treatment with sunitinib. Patient 1 exhibited a decrease in the size of both their pheochromocytoma and RCC after 19 months of sunitinib treatment. RCCs in Patients 2 and 3 exhibited stable response to sunitinib for approximately 1 and 6 years, respectively. All the patients reported tolerable side effects. Therefore sunitinib treatment was associated with either partial response or stable control of VHL-related RCCs, pheochromocytomas and pancreatic neuroendocrine tumor (NET) with acceptable side effects. Further evaluation of sunitinib in patients with VHL disease in larger prospective studies is warranted.

Novel genotype-phenotype correlations in five Chinese families with Von Hippel-Lindau disease.

CONTEXT: Von Hippel-Lindau (VHL) disease manifests as a variety of benign and malignant neoplasms. Previous studies of VHL disease have documented several genotype-phenotype correlations; however, many such correlations are still unknown. Increased identification of new mutations and patients with previously described mutations will allow us to better understand how VHL mutations influence disease phenotypes. PATIENTS AND DESIGN: A total of 45 individuals from five unrelated families were evaluated, of which 21 patients were either diagnosed with VHL disease or showed strong evidence related to this disease. We compared the patients' gene sequencing results with their medical records including CT or MRI scans, eye examinations and laboratory/pathological examinations. Patients were also interviewed to obtain information regarding their family history. RESULTS: We identified four missense mutations: c.239G>T (p.Ser80Ile), linked with VHL Type 2B, was associated with renal cell carcinoma, pheochromocytoma and hemangioma in the cerebellum; c.232A>T (p.Asn78Tyr) manifested as RCC alone and likely caused VHL Type 1; c.500G>A (p.Arg167Gln) mutation was more likely to cause VHL Type 2 than Type 1 as it preferentially induced Pheo and HB in the retina, cerebellum and spinal cord; c.293A>G (p.Try98Cys) was associated with Pheo and thus likely induced VHL Type 2. CONCLUSIONS: Characterizing VHL disease genotype-phenotype correlations can enhance the ability to predict the risk of individual patients developing different VHL-related phenotypes. Ultimately, such insight will improve the diagnostics, surveillance and treatment of VHL patients. PRECIS: Four missense mutations in VHL have been identified in 21 individuals when five unrelated Chinese families with VHL disease were analyzed; VHL mutations are highly associated with unique disease phenotypes.

A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy.

Genetic factors contribute to more than 40% of prostate cancer risk, and mutations in BRCA1 and BRCA2 are well-established risk factors. By using target capture-based deep sequencing to identify potential pathogenic germline mutations, followed by Sanger sequencing to determine the loci of the mutations, we identified a novel pathogenic BRCA2 mutation caused by a cytosine-to-guanine base substitution at position 4211, resulting in protein truncation (p.Ser1404Ter), which was confirmed by immunohistochemistry. Analysis of peripheral blood also identified benign polymorphisms in BRCA2 (c.7397T>C, p.Val2466Ala) and SRD5A2 (c.87G>C, p.Lys29Asn). Analysis of tumor tissues revealed seven somatic mutations in prostate tumor tissue and nine somatic mutations in esophageal squamous carcinoma tissue (single nucleotide polymorphisms, insertions, and deletions). Five-year follow-up results indicate that ADT combined with radiotherapy successfully treated the prostate cancer. To our knowledge, we are the first to report the germline BRCA2 mutation c.4211C>G (p.Ser1404Ter) in prostate cancer. Combined ADT and radiotherapy may be effective in treating other patients with prostate cancer caused by this or similar mutations.

The influence of neoadjuvant therapy for the prognosis in patients with rectal carcinoma: a retrospective study.

Rectal cancer, defined as a cancerous lesion of the colon distal to the rectosigmoid junction, is the fourth most common cancer cause of death globally. There were 474 patients with rectal cancer who underwent surgery between October 2007 and May 2013 enrolled in our center. Patients were respectively categorized by neoadjuvant therapy. This study aimed to explore the predictive factors that affected the Progression-free survival and overall survival of the patients with rectal cancer. Clinical characteristics of patients were compared with the groups and potential prognostic factors were analyzed by SPSS 19.0. In our study, neoadjuvant therapy increased the anus-retained rate (64.4 vs 53.4 % P = 0.016) and remission rate in the treatment group, compared to the non-treatment group (62.6 vs 34.8 %; P = 0.000). The neoadjuvant concurrent chemoradiotherapy, more operative duration, anus retained and micturition damaged are positive prognostic factors of PFS to patients. Poor differentiation, the tumor of ulcer, invasive, and pT4 stage, contributed the poor factors for PFS of patients (P < 0.05). Additionally, the patients with neoadjuvant concurrent chemoradiotherapy and adjuvant chemotherapy underwent the better prognosis of OS. Adjuvant chemotherapy cannot increase PFS of the patients who accepted neoadjuvant therapy after surgery get pCR, but can improve OS. The anus-retained and neoadjuvant radiotherapy, duration of surgery in rectal cancer have the positive correlation. Micturition damaged and neoadjuvant radiotherapy were positively correlated as well. In conclusion, adjuvant chemotherapy does not improve the PFS of patients with pCR to neoadjuvant therapy, but is good for OS. Further prospective and large population-based clinical studies are needed to establish clinical guidelines for the use of neoadjuvant therapy and adjuvant chemotherapy in patients with rectal cancer.

The prediction of survival of patients with gastric cancer with PD-L1 expression using contrast-enhanced ultrasonography.

Gastric cancer is the one of the most common cancers around the world. The prognosis of gastric cancer remains poor, due to the biological characteristics of the primary tumor as well as the recurrence after treatment. Accumulating evidence suggests the implication of programmed death ligand-1 (PD-L1) in the pathogenesis and prognosis of cancer. This study aimed to explore the CEUS as a valuable tool to improve the assessment of the therapeutic effect of the PD-L1 blocker in the treatment of gastric cancer. A total number of 105 patients with gastric cancer were enrolled in this study from June 2008 to December 2011 in our hospital. The association of PD-L1 expression level (105 cases) and CEUS parameters (100 cases) with the prognosis of gastric cancer was examined. The results showed that PD-L1-positive staining was associated with the depth of invasion, differentiation, and poor prognosis of patients with gastric cancer. The CEUS intensity (positive) exhibited poor prognosis compared to the negative counterpart. Moreover, PD-L1 and CEUS co-positivity was significantly related to a poor prognosis. The characteristic of ultrasonography images correlated with the expression of PD-L1 (r = 0.46, P = 0.0003). Collectively, the mean intensity of contrast-enhanced ultrasonography is a useful predictor in the PD-L1 expression in gastric cancer. The ultrasonography and CEUS parameter could be considered as the predictor of response to PD-L1 blocker treatment in the clinical practice.

Polymorphisms of BCL2 and BAX Genes Associate with Outcomes in Advanced Non-small cell lung cancer Patients treated with platinum-based Chemotherapy.

Single-nucleotide polymorphisms (SNP) of the gene belonging to the BCL2 family are thought to play a role in chemotherapy resistance. This study investigated the association of BCL2-938C>A(rs2279115) and BAX-248G>A(rs4645878) promoter region SNPs and the clinical responses and outcomes of 235 non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. The data suggested that BAX-248GA and GA+AA genotype was associated with poor response [odds ratio (OR) 1.943, p = 0.039; OR 1.867, p = 0.038, respectively] to chemotherapy, and BCL2-938CA, CA+AA and BAX-248GA, AA and GA+AA were associated with poor progression-free survival (PFS) [hazard ratio (HR) 1.514, p = 0.004; HR 1.456, p = 0.009; HR 1.449, p = 0.013; HR 2.006, p = 0.010; HR 1.506, p = 0.003, respectively] and BCL2-938CA, AA and CA+AA and BAX-248GA, AA and GA+AA were associated with poor overall survival (OS) (HR 2.006, p < 0.001; HR 2.322, p < 0.001; HR 2.096, p < 0.001; HR 1.632, p = 0.001; HR 2.014, p = 0.010; HR 1.506, p < 0.001, respectively). Furthermore, combination of these two polymorphisms showed patients with 2-4 variant alleles of these two genes associated with poor PFS and OS (HR 1.637, p = 0.001; HR 2.365, p < 0.001). The data from the current study provide evidence that BCL2-938C>A and BAX-248G>A polymorphisms may be useful in predicting clinical outcomes of patients with advanced inoperable NSCLC to platinum-based chemotherapy.

Lost expression of ADAMTS5 protein associates with progression and poor prognosis of hepatocellular carcinoma.

Altered expression of ADAMTS5 is associated with human carcinogenesis and tumor progression. However, the role of ADAMTS5 in hepatocellular carcinoma (HCC) is unclear. This study analyzed ADAMTS5 expression in HCC tissues and tested for association with clinicopathological and survival data from HCC patients and then explored the role of ADAMTS5 in HCC cells in vitro. Paraffin blocks from 48 HCC patients were used to detect ADAMTS5 and vascular endothelial growth factor (VEGF) expression and microvessel density (MVD). A normal liver cell line and HCC cell lines were used to detect ADAMTS5 expression and for ADAMTS5 manipulation. ADAMTS5 cDNA was stably transfected into HCC cells and ADAMTS5 expression assessed by Western blot analysis. Tumor cell-conditioned growth medium was used to assess human umbilical vein endothelial cell migration and Matrigel tube formation. Xenograft assay was performed to determine the role of ADAMTS5 in vivo. The data showed that the expression of ADAMTS5 was reduced in HCC, which was inversely associated with VEGF expression, MVD, and tumor size and associated with poor overall survival of HCC patients. Lentivirus-mediated ADAMTS5 expression significantly inhibited tumor angiogenesis by downregulating in vitro expression of VEGF and inhibiting migration and tube formations, and also inhibited tumor growth and VEGF expression and reduced MVD in vivo in a mouse xenograft model. Taken together, these results suggest that ADAMTS5 plays a role in suppression of HCC progression, which could be further studied as a promising novel therapeutic target and a potential prognostic marker in HCC.

Association Between a Variant in ADAMTS5 and the Susceptibility to Hepatocellular Carcinoma in a Chinese Han Population.

A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is considered to be an important anti-angiogenic protein, in which the first TSR domain is crucial for its anti-angiogenic activity. Previous study showed that ADAMTS5 plays a role in suppression of hepatocellular carcinoma (HCC) progression through its anti-angiogenic activity. The rs2380585 G>A single-nucleotide polymorphism (SNP) is a missense mutation, located in the ADAMTS5 first TSR domain coding sequence (CDS). In this study, we investigated the impacts of ADAMTS5 rs2380585 polymorphism on the risk and progress of hepatocellular carcinoma. A total of 220 HCC patients and 220 controls in a Chinese Han population were enrolled and genotyped. The associations between SNPs and HCC incidence and progression were analyzed with logistic regression model. We found that individuals with the ADAMTS5 rs2380585 A allele was significantly associated with decreased HCC risk (OR = 0.348, 95 % CI 0.236-0.512; p = 0.000). Individuals having the ADAMTS5 rs2380585 polymorphic genotype (GA+AA) had an OR of 0.348 (95 % CI 0.201-0.600; p = 0.000) for developing HCC, compared with individuals having the ADAMTS5 rs2380585 ancestral genotype. However, stratified analyses did not find any evident gene-covariates interaction. The SNP of rs2380585 was irrelevant to the frequencies of clinicopathological characteristics. Our results for the first time indicate that ADAMTS5 rs2380585 polymorphism contributes to HCC susceptibility.