Branched-Chain Amino Acid Degradation Pathway was Inactivated in Colorectal Cancer: Results from a Proteomics Study.

Background: Colorectal cancer (CRC) ranks third in terms of cancer incidence and fourth in terms of cancer-related deaths worldwide. Identifying potential biomarkers of CRC is crucial for treatment and drug development. Methods: In this study, we established a C57B/6N mouse model of colon carcinogenesis using azoxymethane-dextran sodium sulfate (AOM-DSS) treatment for 14 weeks to identify proteins associated with colon cancer. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis was conducted on the cell membrane components enriched in the colonic mucosa. Additionally, tumor tissues and adjacent normal colon tissues were collected from patients with colon cancer for comparative protein and metabolite analyses. Results: In total, 74 differentially expressed proteins were identified in the tumor tissue samples from AOM/DSS-treated mice compared to both the adjacent tissue samples from AOM/DSS-treated mice and tissue samples from saline-treated control mice. Bioinformatics analysis revealed eight downregulated proteins enriched in the branched-chain amino acids pathway (valine, leucine, and isoleucine degradation). Moreover, these proteins are already known to be associated with the survival rate of patients with cancer. Targeted metabolomics showed increased levels of valine, leucine, and isoleucine in tumor tissues compared to those in adjacent normal tissues in patients with colon cancer. Furthermore, a real-time PCR experiment demonstrated that Aldehyde dehydrogenase, mitochondrial (short protein name ALDH2, gene name Aldh2) and Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial (short protein name HCDH, gene name Hadh) (two genes) in the pathway of branched-chain amino acids) were downregulated in patients with colon cancer (colon tumor tissues vs. their adjacent colon tissues). ALDH2 expression was further validated by western blotting in AOM/DSS-treated mouse model and in clinical samples. Conclusion: This study highlighted the inactivation of the branched-chain amino acid degradation pathway in colon cancer and identified ALDH2 and HCDH as potential biomarkers for diagnosing colon cancer and developing new therapeutic strategies.

Preoperative Biomarkers and Survival in Chinese Breast Cancer Patients with HIV: A Propensity-Score-Matched-Cohort Study.

BACKGROUND: China initiated its national free antiretroviral therapy program in 2004 and saw a dramatic decline in mortality among the population with HIV. However, the morbidity of non-AIDS-defining cancers such as breast cancer is steadily growing as life expectancy improves. The aim of this study was to investigate the clinical characteristics and prognosis of breast cancer patients with HIV in China. MATERIALS AND METHODS: Data from 21 breast cancer patients with HIV and 396 breast cancer patients without HIV treated at the Shanghai public health clinical center from 2014-2022 was collected. After propensity score matching, 21 paired patients in the two groups were obtained and compared. The optimal cut-off value of preoperative biomarkers for recurrence was determined via maximally selected log-rank statistics. Preoperative biomarkers were categorized into high and low groups, based on the best cut-off values and compared using Kaplan-Meier survival curves and the log-rank test. The Cox proportional hazards regression model was used to perform univariate and multivariate analyses. RESULTS: The median follow-up time was 38 months (IQR: 20-68 months) for the propensity-score-matching cohort. The progression-free survival at 1, 2 and 3 years for patients with and without HIV were 74.51%, 67.74%, and 37.63% and 95.24%, 95.24%, and 90.48%, respectively. The overall survival for patients with HIV at 1, 2 and 3 years were 94.44%, 76.74%, and 42.63%. After multivariate analysis, Only HIV status (hazard ratios (HRs) = 6.83, 95% [confidence intervals (CI)] 1.22-38.12) were associated with progression-free survival. Based on the best cut-off value, CD8 showed discriminative value for overall survival (p = 0.04), whereas four variables, the lymphocyte-to-monocyte ratio (p = 0.02), platelet-to-lymphocyte ratio (p = 0.03), CD3 (p = 0.01) and CD8 (p < 0.01) were suggested be significant for progression-free survival. The univariate analysis suggested that CD3 (HRs = 0.10, 95% [CI] 0.01-0.90) and lymphocyte-to-monocyte ratio (HRs = 0.22, 95% [CI] 0.05-0.93) were identified as significant predictors for progression-free survival. CONCLUSION: In this study, breast cancer in patients with HIV in China reflected a more aggressive nature with a more advanced diagnostic stage and worse prognosis. Moreover, preoperative immune and inflammatory biomarkers might play a role in the prognosis of breast cancer patients with HIV.

Preoperative Platelet-Lymphocyte Ratio (PLR) as a prognostic inflammation biomarker in Asian HIV-infected patients with gastric cancer: a single-center study.

BACKGROUND: The serum systemic inflammation biomarkers have been established as predictors of prognosis in gastric cancer (GC) patients, but their prognostic value in human immunodeficiency virus (HIV)-infected patients with GC has not been well studied. This retrospective study aimed to evaluate the prognostic value of preoperative systemic inflammation biomarkers in Asian HIV-infected patients with GC. METHODS: We retrospectively analyzed 41 HIV-infected GC patients who underwent surgery between January 2015 and December 2021 at the Shanghai Public Health Clinical Center. Preoperative systemic inflammation biomarkers were measured and patients were divided into two groups based on the optimal cut-off value. Overall survival (OS) and progression-free survival (PFS) were measured using the Kaplan-Meier method and the log-rank test. Multivariate analysis of variables was performed using the Cox proportional regression model. As a comparison, 127 GC patients without HIV infection were also recruited. RESULTS: The median age of the 41 patients included in the study was 59 years, with 39 males and two females. The follow-up period for OS and PFS ranged from 3 to 94 months. The cumulative three-year OS rate was 46.0%, and the cumulative three-year PFS rate was 44%. HIV-infected GC patients had worse clinical outcomes compared to the normal GC population. The optimal cut-off value for preoperative platelet to lymphocyte ratio (PLR) was 199 in HIV-infected GC patients. Multivariate Cox regression analysis revealed that a low PLR was an independent predictor of better OS and PFS (OS: HR = 0.038, 95% CI: 0.006-0.258, P < 0.001; PFS: HR = 0.027, 95% CI: 0.004-0.201, P < 0.001). Furthermore, higher preoperative PLR in HIV-infected GC was significantly associated with lower BMI, hemoglobin, albumin, CD4 + T, CD8 + T, and CD3 + T cell counts. CONCLUSION: The preoperative PLR is an easily measurable immune biomarker that may provide useful prognostic information in HIV-infected GC patients. Our findings suggest that PLR could be a valuable clinical tool for guiding treatment decisions in this population.

Higher Neutrophil-to-Lymphocyte Ratio (NLR) Is a Preoperative Inflammation Biomarker of Poor Prognosis in HIV-Infected Patients with Colorectal Cancer: A Retrospective Study.

Background: The serum systemic inflammation biomarkers are known predictors of colorectal cancer (CRC) patient prognosis. However, their significance in human immunodeficiency virus (HIV)-infected patients with CRC has not been studied. To address this gap, we conducted a retrospective study to evaluate the prognostic value of preoperative systemic inflammation biomarkers in HIV-infected patients with CRC. Methods: The study enrolled 57 patients with colorectal cancer (CRC) and HIV who underwent surgery at the Shanghai Public Health Clinical Center between January 2015 and December 2021. Preoperative tests were conducted, and systemic inflammation biomarkers were measured. The patients were categorized into two groups using the optimal cut-off value. The Kaplan-Meier method and the log-rank test were used to determine overall survival (OS) and progression-free survival (PFS). Multivariate analysis was performed using the Cox proportional regression model. A time-dependent receiver operating characteristic (t-ROC) was used to compare the prognostic abilities of the biomarkers. Results: The study included 57 HIV-infected CRC patients, with a median age of 60 and a follow-up time ranging from 3 to 86 months. Of the patients, 49 were male and 8 were female. The cumulative three-year OS and PFS rates were 55.0% and 45.0%, respectively. The optimal cut-off value for preoperative NLR was found to be 2.8, which was significantly correlated with lower CD8+ T and CD3+ T lymphocyte counts. Multivariate Cox regression analysis revealed that a low NLR was an independent predictor of better OS and PFS (OS: HR = 0.094, 95% CI: 0.02-0.45, P=0.003; PFS: HR = 0.265, 95% CI: 0.088-0.8, P=0.019). The time-dependent receiver operating characteristic (t-ROC) analysis showed that NLR was a superior systemic inflammation biomarker for predicting the prognosis of HIV-infected CRC patients throughout the observation period. Conclusion: The preoperative neutrophil-to-lymphocyte ratio (NLR), an easily measurable immune biomarker, may provide useful prognostic information in HIV-infected colorectal cancer (CRC) patients.

PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis.

Background: Chronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation. Methods: The animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues. Results: AOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm2, which was significantly decreased to 5.85 ± 0.95 mm2 by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer. Conclusions: Persistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.

Lymphocytes Infiltration and Expression of PD-1 and PD-L1 in Colorectal Cancer Between HIV-Infected and Non-HIV-Infected Patients: A Propensity Score Matched Cohort Study.

Background: Tumor-infiltrating lymphocytes (TILs) and expression of programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) are crucial for antitumor immunity. However, the status remains undetermined in HIV-infected colorectal cancer (CRC), limiting the use of immunotherapy in HIV-infected CRC patients. Methods: We examined 27 HIV-infected patients and 120 non-HIV-infected patients with CRC from 2015-2020 at Shanghai Public Health Clinical Center. After matching the propensity score, 13 paired patients in the two groups were also compared. The expression of PD-1/PD-L1 as well as tumor-infiltrating CD4, CD8, and CD56 immune cells was examined using multiplex immunofluorescent analysis. The cell density for positive staining was calculated (cells/mm2) and compared between HIV-infected and non-HIV-infected groups. In addition, the co-expression of PD-1 on immune cells and PD-L1 on tumor cells was compared in these two groups. Results: The mean densities of tumor-infiltrating CD4, CD8, CD56 immune cells were 620.2, 261.2, and 0.2 cells/mm2, respectively, in HIV-infected colorectal tumors compared with 698.6, 243, and 14 cells/mm2 in non-HIV-infected tumors. PD-1 expression was 227 cells/mm2 in HIV-infected tumors and 365.2 cells/mm2 in non-HIV-infected tumors. Besides, PD-L1 expression was 108.5 cells/mm2 in HIV-infected tumors and 126.8 cells/mm2 in non-HIV-infected tumors, and no significant difference was found between the two groups. Similarly, there were no significant differences in the expression of PD-1 on TILs and PD-L1 on tumor cells. Conclusion: HIV-infected CRC patients had similar tumor-infiltrating lymphocytes (CD4 and CD8 T cells) compared to non-HIV-infected controls and substantially similar PD-1 expression on TILs and PD-L1 expression on tumors. These results support the inclusion of HIV-infected CRC patients in future immunotherapy trials.

RP11-616M22.7 recapitulates imatinib resistance in gastrointestinal stromal tumor.

Emerging evidence has shown that long non-coding RNAs (lncRNAs) play crucial roles in human cancers. However, systematic characterization of lncRNAs and their roles in gastrointestinal stromal tumor (GIST) therapy have been lacking. We performed high-throughput RNA sequencing (RNA-seq) of 20 GIST and paired adjacent normal samples. We characterized the transcriptional landscape and dysregulation of lncRNAs in GIST. We identified 866 upregulated and 1,268 downregulated lncRNAs in GIST samples, the majority of which were GIST-specific over other cancer types. Most hallmarks were found to be dysregulated in GIST samples, and lncRNAs were highly associated with cancer-related hallmarks. RP11-616M22.7 was identified to increase in imatinib-resistant samples compared to those in non-resistant samples. Further analysis revealed that RP11-616M22.7 was closely associated with the Hippo signaling pathway. By treating GIST cells with different doses of imatinib, we verified that RP11-616M22.7 knockdown promotes the sensitivity of tumor cells, whereas RP11-616M22.7 overexpression induces resistance to imatinib. We further confirmed reducing of resistance to imatinib by knocking down RP11-616M22.7 in vivo. Additionally, RP11-616M22.7 was observed to interact with RASSF1 protein. Our study revealed that deficiency of RP11-616M22.7 was able to reduce resistance of the GIST cell response to imatinib treatment both in vitro and in vivo.

Research on the efficacy of cisplatin and nimotuzumab combined with concurrent chemoradiotherapy on locally advanced cervical cancer.

PURPOSE: To evaluate the efficacy and safety of cisplatin and nimotuzumab combined with concurrent chemoradiotherapy on locally advanced cervical cancer. METHODS: 92 patients with cervical cancer in moderate and advanced stages treated in Shanghai Public Health Clinical Center from January 2014 to January 2017 were selected and divided into two groups with 46 cases in each group. They received cisplatin and nimotuzumab combined with concurrent chemoradiotherapy and cisplatin combined with concurrent chemoradiotherapy, respectively. The clinical efficacy, adverse reactions, overall survival (OS) and progression-free survival (PFS) were compared between the two groups. RESULTS: The general clinical characteristics of patients in both groups were comparable. The effective rate was 87.0% and 67.4%, respectively, in nimotuzumab group and cisplatin group, and the local tumor control and short-term efficacy were superior in the nimotuzumab group compared to those in the cisplatin group (p=0.045). There was no statistically significant difference in the incidence of complications after treatment between the two groups (p>0.05), and nimotuzumab did not increase the incidence and severity of adverse reactions. The 3-year OS rate was 87.0% (40/46) and 69.6% (32/46), respectively, in the two groups (log-rank, p=0.070). The 3-year PFS rate in the nimotuzumab group [73.9% (34/46)] was obviously higher than that in the cisplatin group [50.0% (23/46)] (p=0.042). CONCLUSIONS: Cisplatin and nimotuzumab combined with concurrent chemoradiotherapy is safe and effective in the treatment of locally advanced cervical cancer, both local tumor control and PFS rate are excellent, and the patient's tolerance is good, so it is worth of clinical popularization.

Comparison of the value of superficial mark guided localization and hook-wire guided localization techniques for non-palpable breast microcalcifications: A retrospective clinical research.

AIM: The present study compares the effect and accuracy of the superficial mark guided localization (SGL) and hook-wire guided localization (WGL) techniques for non-palpable breast microcalcifications. METHODS: This retrospective study was conducted to compare SGL and WGL techniques. These techniques were performed on 51 patients with non-palpable breast microcalcifications from January 2015 to May 2016. RESULTS: Among these 51 patients, 25 (49.01%) patients were subjected to WGL and 26 patients (50.99%) were subjected to SGL. The SGL technique had a higher rate of malignant cancer detection (WGL = 12.0% and SGL = 23.0%). Furthermore, no significant differences were found with regard to average age, the rate of a second excision and the diameter of the excised tissue. Moreover, no complications were observed in the SGL group, while four (16.0%) patients in the WGL group experienced problems. CONCLUSION: The SGL technique is as accurate as the WGL technique. Furthermore, the procedure has advantages of being less expensive and causing less complications.

PDK1 induces JunB, EMT, cell migration and invasion in human gallbladder cancer.

The protein 3-phosphoinositide-dependent protein kinase 1 (PDK1) is upregulated in cancer. Here we showed that PDK1 stimulated cell proliferation, invasion and metastasis in gallbladder cancer (GBC), by inducing JunB and epithelial-mesenchymal transition. JunB levels were increased in GBC samples and positively correlated with PDK1 levels in tumors. High levels of JunB predicted poor overall survival in GBC patients. Thus, PDK1 functions as a tumor promoter in human GBC by upregulating JunB.