Immune-Enhancing Treatment among Acute Necrotizing Pancreatitis Patients with Metabolic Abnormalities: A Post Hoc Analysis of a Randomized Clinical Trial.

Background/Aims: : Metabolic syndrome is common in patients with acute pancreatitis and its components have been reported to be associated with infectious complications. In this post hoc analysis, we aimed to evaluate whether metabolic abnormalities impact the effect of immune-enhancing thymosin alpha-1 (Tα1) therapy in acute necrotizing pancreatitis (ANP) patients. Methods: : All data were obtained from the database for a multicenter randomized clinical trial that evaluated the efficacy of Tα1 in ANP patients. Patients who discontinued the Tα1 treatment prematurely were excluded. The primary outcome was 90-day infected pancreatic necrosis (IPN) after randomization. Three post hoc subgroups were defined based on the presence of hyperglycemia, hypertriglyceridemia, or both at the time of randomization. In each subgroup, the correlation between Tα1 and 90-day IPN was assessed using the Cox proportional-hazards regression model. Multivariable propensity-score methods were used to control potential bias. Results: : Overall, 502 participants were included in this post hoc analysis (248 received Tα1 treatment and 254 received matching placebo treatment). Among them, 271 (54.0%) had hyperglycemia, 371 (73.9%) had hypertriglyceridemia and 229 (45.6%) had both. Tα1 therapy was associated with reduced incidence of IPN among patients with hyperglycemia (18.8% vs 29.7%: hazard ratio, 0.80; 95% confidence interval, 0.37 to 0.97; p=0.03), but not in the other subgroups. Additional multivariate regression models using three propensity-score methods yielded similar results. Conclusions: : Among ANP patients with hyperglycemia, immune-enhancing Tα1 treatment was associated with a reduced risk of IPN (ClinicalTrials.gov, Registry number: NCT02473406).

A Prognostic Model Based on the Immune-Related lncRNAs in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors with a poor prognosis. At present, the pathogenesis is not completely clear. Therefore, finding reliable prognostic indicators for CRC is of important clinical significance. In this study, bioinformatics methods were used to screen the prognostic immune-related lncRNAs of CRC, and a prognostic risk scoring model based on immune-related lncRNAs signatures were constructed to provide a basis for prognostic evaluation and immunotherapy of CRC patients. METHODS: The clinical information and RNA-seq data of CRC patients were obtained from The Cancer Genome Atlas (TCGA) database. The information of immune-related lncRNA was downloaded from the immunology database and analysis portal. The differentially expressed immune-related lncRNAs (IRLs) were screened by the edgeR package of R software. The prognostic value of IRLs was studied. Based on Cox regression analysis, a prognostic index (IRLPI) based on IRLs was established, and the relationship between the risk score and the clinicopathological characteristics of CRC was analyzed to determine the effectiveness of the risk score model as an independent prognostic factor. RESULTS: A total of 240 differentially expressed IRLs were identified between normal colorectal cancer tissues and normal colorectal cancer tissues, in which 8 were significantly associated with the survival of CRC patients (P < 0.05), including LINC00461, LINC01055, ELFN1-AS1, LMO7-AS1, CYP4A22-AS1, AC079612.1, LINC01351, and MIR31HG. And most of the lncRNAs related to survival were risk factors for the prognosis of CRC. The index established based on the 7 survival-related IRLs found to be highly accurate in monitoring CRC prognosis. Besides, IRLPI was significantly correlated with a variety of pathological factors and immune cell infiltration. CONCLUSION: Eight immune-related lncRNAs closely related to the prognosis of CRC patients were identified from the TCGA database. At the same time, an independent IRLPI was constructed, which may be helpful for clinicians to assess the prognosis of patients with CRC and to formulate individualized treatment plans.

Platinum accumulation in oxaliplatin-induced peripheral neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.

Curcumol improves cisplatin sensitivity of human gastric cancer cells through inhibiting PI3K/AKT pathway.

BACKGROUND: Curcumol was presented to unleash antitumor effects in a variety of cancers, including gastric cancer. However, the relevance between curcumol and cisplatin resistance in gastric cancer still remains unclear. Therefore, the current research was performed to survey the role of curcumol in cisplatin sensitivity in gastric cancer. METHODS: First, BGC-823 and BGC-823/DDP cells were incubated with cisplatin for 48 hr and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) analysis was applied to determine the inhibition rate of cell proliferation and the half-maximal inhibitory concentration (IC50 ) of cisplatin. In addition, BGC-823 and BGC-823/DDP cells were treated with curcumol for 48 hr followed with detection of cell viability and apoptosis using MTT and flow cytometry assay, respectively. Moreover, MTT analysis was applied to test the effects of curcumol on cisplatin sensitivity in gastric cancer cells. Lastly, Western blot assay and qRT-PCR analysis were utilized to check the functions of curcumol on PI3K/AKT pathway-related markers. RESULTS: We found that BGC-823/DDP cells exhibited stronger resistance to cisplatin compared with BGC-823 cells. Furthermore, curcumol evidently reduced cell proliferation and facilitated cell apoptosis in BGC-823/DDP and BGC-823 cells. Moreover, results from MTT assay demonstrated that curcumol notably promoted the suppression effect of cisplatin and decreased the IC50 of cisplatin in BGC-823/DDP and BGC-823 cells. It was also presented that curcumol suppressed the PI3K/AKT pathway dose-dependently in BGC-823/DDP and BGC-823 cells. CONCLUSION: The findings in the current research demonstrated that curcumol could promote the sensitivity of gastric cancer cells to cisplatin-based chemotherapies via inhibiting the phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT) pathway.

Bronchopleural fistula in squamous cell lung cancer following anlotinib treatment: A case report.

Anlotinib is a multi-target tyrosine kinase inhibitor and has been approved for the treatment of patients with advanced non-small cell lung cancer. The most common adverse events of this treatment include hypertension, fatigue, thyroid-stimulating hormone elevation, hypertriglyceridemia, hand-foot syndrome and hypercholesterolemia. The present study reported the case of a 69-year-old man with squamous cell lung cancer that experienced disease progression following first-line and second-line chemotherapy. Subsequently, anlotinib was administered as a third-line therapy. Following the second cycle of oral targeted therapy, the patient was admitted to the hospital with a one-week history of chest tightnesss, shortness of breath and cough blood-stained sputum and necrosis. Computed tomography scan showed: Bronchopleural fistula (BPF) complicating lung cancer. However, symptoms were not relieved following anti-infective treatment and the patient subsequently died of respiratory failure. To the best of our knowledge, this is the first case of bronchopleural fistula associated with the use of anlotinib in a patient with squamous cell lung cancer.

FuFangChangTai Decoction Activates Macrophages via Inducing Autophagy.

The traditional Chinese medicine decoction FuFangChangTai (FFCT) has been used in the therapy of colon cancer clinically, yielding alleviated toxicity and enhanced immunity. In our previous study, FFCT exerted its antitumor activity not only by inducing apoptosis but also by activating autophagy to eliminate tumor cells. However, its mechanism is not well understood. The purpose of this study was to investigate the relationship between macrophages activation and FFCT-induced autophagy. Results showed that FFCT could induce autophagy in colon cancer, as demonstrated by increased level of intracellular autophagy marker LC3 II in CT26.WT cells by fluorescence microscope and western blot assay. FFCT also facilitated numbers of vesicular bodies with bilayer membrane in CT26.WT cells, which were indicative of autophagosomes formation. Autophagosomes secreted by FFCT-treated CT26.WT cells can activate M1 type macrophages, accompanied with increased expression of costimulatory molecules CD86 and CD40 on the surface of RAW264.7 cells, and more inflammatory cytokines secretion, such as TNF-α, IL-6, MCP-1, and IL-1ß. mRNA expressions of M2 macrophages markers, such as IL-10, CD206, Arg-1, and FIZZ-1, were downregulated. And this process helps regulate the polarization of macrophages and promote the immune response. These findings support a mechanism of FFCT-induced autophagy and provide novel evidence demonstrating that macrophages are involved in FFCT-induced autophagy progression.

Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer.

Girdin is an actin-binding protein playing key roles in the development of various carcinomas. Although online tools have predicted nuclear localization of girdin with a high probability, convincing proof has rarely been provided until now. The purpose of this study was to discover girdin's precise subcellular distribution and the potential prognostic value corresponding to its localization. The subcellular distribution of girdin was detected in a human breast cancer cell line and in >800 samples of human breast tissue by clinical pathologic analysis. In this study, we discovered for the first time that girdin could attach to chromatin and interact with topoisomerase-IIα in nucleus. Cytoplasmic and nuclear girdin exhibited different roles in prognosis of breast cancer: cytoplasmic girdin expression was an independent prognostic factor for progression-free survival (PFS), whereas nuclear girdin expression was an independent prognostic factor for overall survival (OS). More important, combination cytoplasmic and nuclear girdin was an independent prognosis factor of both OS and PFS. In conclusion, our research results strongly recommend combination analysis of cytoplasmic and nuclear girdin for a precise prognostic prediction in breast cancer.-Zhang, H., Yu, F., Qin, F., Shao, Y., Chong, W., Guo, Z., Liu, X., Fu, L., Gu, F., Ma, Y. Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer.

Combination of AQP1 and ß-catenin expression is an independent prognosis factor in astrocytoma patients.

Previous research usually focused on single protein or gene in tumor development, actually highly heterogeneous nature and different signaling pathways largely contribute to tumor progression and tumor patients' outcomes. Therefore, using combinatorial biomarkers to evaluate the prognostic features and guide management is gradually accepted and urgently needed. ß-catenin is a well-known crucial factor in astrocytoma progression and it is involved in aquaporin1 (AQP1) mediated cell migration. In this study, we revealed the function of AQP1 in astrocytoma progression and provided the first clinical evidence that AQP1 expression was positively correlated with ß-catenin. Furthermore, we proved the functional role of AQP1/ß-catenin pathway in astrocytoma progression. More importantly, we discovered that combination of AQP1 and ß-catenin expression was an independent prognosis factor for astrocytoma patients and it was a better survival predictor than either AQP1 or ß-catenin alone. In conclusion, our study provided a novel more precise prognostication for predicting astrocytoma prognosis based on combinatorial analysis of AQP1 and ß-catenin expression.

Effect of dihydropyrimidine dehydrogenase single nucleotide polymorphisms on prognosis of breast cancer patients with chemotherapy.

Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. DPD (dihydropyrimidine dehydrogenase, encoded by DPYD gene) is the initial and rate-limiting enzyme of metabolic pathway of fluoropyrimidines, and fluoropyrimidines are common used drug therapies for breast cancer. Previous studies on DPYD polymorphism were mainly focused on its association with fluoropyrimidines toxicity. In our present study, 5 DPYD single nucleotide polymorphisms status was detected from tumor tissues of 331 invasive breast cancer patients using standard techniques. We for the first time investigated the prognostic significance of DPYD polymorphisms in breast cancer. We demonstrated non-luminal breast cancer patients carrying DPYD c.1627A>G AG/GG treated with fluoropyrimidine-based regimen presented a shorter overall survival and progression-free survival than carriers treated with non-fluoropyrimidine regimen. However, non-luminal DPYD c.1627A>G AG/GG carriers treated with TE (taxane and anthracycline)-based regimen showed a better prognosis compared with carriers treated with non-TE regimen. Our results suggested TE-based chemotherapy was a suitable regimen for non-luminal patients with DPYD c.1627A>G AG/GG genotype and fluoropyrimidine-based regimen should not be recommended for those patients. Our findings provided a novel strategy, which will guide clinicians to choose more precise chemotherapy treatment for breast cancer patients.

Expression of aquaporin1, a water channel protein, in cytoplasm is negatively correlated with prognosis of breast cancer patients.

Aquaporin1 (AQP1) belongs to a highly conserved family of aquaporin proteins which facilitate water flux across cell membranes. Although emerging evidences indicated the cytoplasm was important for AQP1 localization, the function of AQP1 corresponding to its cytoplasmic distribution has rarely been explored until present. In our clinical study, we reported for the first time that AQP1 was localized dominantly in the cytoplasm of cancer cells of invasive breast cancer patients and cytoplasmic AQP1 was an independent prognostic factor. High expression of AQP1 indicated a shorter survival, especially in luminal subtype. Moreover, in line with our findings in clinic, cytoplasmic expression of AQP1 was further validated in both primary cultured breast cancer cells and AQP1 over-expressing cell lines, in which the functional importance of cytoplasmic AQP1 was confirmed in vitro. In conclusion, our study provided the first evidence that cytoplasmic expression of AQP1 promoted breast cancer progression and it could be a potential prognostic biomarker for breast cancer.

Low expression of BMPRIB indicates poor prognosis of breast cancer and is insensitive to taxane-anthracycline chemotherapy.

Bone morphogenetic protein receptor type IB (BMPRIB) is one osteogenesis factor, which function in breast cancer has been rarely explored until recently. In the clinical study presented here, involving a cohort of 368 invasive ductal carcinoma (IDC) patients, we identified that patients with low expression of BMPRIB exhibited poor prognosis, especially in the luminal B subtype. We also provided the first piece of evidence that low level of BMPRIB was a promoting factor for breast cancer patients to develop bone metastasis, but not lung, liver or brain. The first of its kind, we reported that patients with high expression of BMPRIB exhibited favorable prognosis by a retrospective analysis consisting of 168 patients treated with TE (taxane and anthracycline) regimens. And the patients with high expression of BMPRIB were more sensitive to TE regimens in the detection of 32 paired pre-neoadjuvant and post-neoadjuvant specimens. Overall, our study concluded that low expression of BMPRIB indicated poor prognosis of breast cancer and was insensitive to taxane-anthracycline chemotherapy. Our findings also lay a foundation to help clinicians improve identification of patients for TE regimens by BMPRIB in the era of precision medicine.

Function of Slit/Robo signaling in breast cancer.

Slit and Robo are considered tumor suppressors because they are frequently inactivated in various tumor tissue. These genes are closely correlated with CpG hypermethylation in their promoters. The Slit/Robo signaling pathway is reportedly involved in breast cancer development and metastasis. Overexpression of Slit/ Robo induces its tumor suppressive effects possibly by inactivating the ß-catenin/LEF/TCF and PI3K/Akt signaling pathways or by altering ß-catenin/E-cadherin-mediated cell-cell adhesion in breast cancer cells. Furthermore, loss of Slit proteins or their Robo receptors upregulates the CXCL12/CXCR4 signaling axis in human breast carcinoma. In addition, this pathway regulates the distant migration of breast cancer cells not only by mediating the phosphorylation of the downstream molecules of CXCL12/CXCR4 and srGAPs, such as PI3K/ Src, RAFTK/ Pyk2, and CDC42, but also by regulating the activities of MAP kinases. This review includes recent studies on the functions of Slit/Robo signaling in breast cancer and its molecular mechanisms.

Low Expression of Slit2 and Robo1 is Associated with Poor Prognosis and Brain-specific Metastasis of Breast Cancer Patients.

Brain metastasis is a significant unmet clinical problem in breast cancer treatment. It is always associated with poor prognosis and high morbidity. Recently, Slit2/Robo1 pathway has been demonstrated to be involved in the progression of breast carcinoma. However, until present, there are no convincing reports that suggest whether the Slit2/Robo1 axis has any role in brain metastasis of breast cancer. In this study, we investigated the correlation between Slit2/Robo1 signaling and breast cancer brain metastasis for the first time. Our results demonstrated that (1) Invasive ductal carcinoma patients with low expression of Slit2 or Robo1 exhibited worse prognosis and brain-specific metastasis, but not liver, bone or lung. (2) Lower expression of Slit2 and Robo1 were observed in patients with brain metastasis, especially in their brain metastasis tumors, compared with patients without brain metastasis. (3) The interval from diagnosis of breast cancer to brain metastasis and brain metastasis to death were both much shorter in patients with low expression of Slit2 or Robo1 compared with the high expression group. Overall, our findings indicated that Slit2/Robo1 axis possibly be regarded as a significant clinical parameter for predicting brain metastasis in breast cancer patients.

Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation.

Glioblastomas, the most aggressive form of primary brain tumors with a tendency to invade surrounding healthy brain tissues, remains an incurable disease. Intersectin (ITSN) is a multidomain adapter protein implicated in endocytosis, exocytosis, and multiple signaling pathways. Prior research of ours has shown intersectin1-S (ITSN1-S) is critical for the migration and invasion of glioma cells by regulating several key proteins. In this study, we established ITSN1-S expression patterns in human tumor tissues. We discovered that ITSN1-S expression was positively correlated with histological grade of gliomas and with poor patient prognosis. We also found that the expression of ITSN1-S protein was essential to glioblastoma cell proliferation. Furthermore, through a series of expression constructs encoding different ITSN1-S domains, we identified the critical roles of ITSN1-S SH3 domains in the regulation of cell proliferation. This study also demonstrates evidence suggesting that the regulation of ITSN1-S on glioblastoma cells proliferation is through the Raf/MEK/ERK pathway. In conclusion, this study suggests critical roles of ITSN1-S in malignant glioma proliferation, indicating a potential usage of ITSN1-S in the therapeutic intervention as a novel molecular target.

Chinese medicine formula "Weikang Keli" induces autophagic cell death on human gastric cancer cell line SGC-7901.

Weikang Keli (constitutes of Root of Codonopsis pilosula, Rhizoma Atractylodis Macrocephalae, Rhizoma Curcumae Aeruginosae, Rhizoma Pinelliae, Actinidia chinensis Planch, and Rhodiola rosea) is a well known Chinese herbal formula for gastric cancer therapy in clinical treatment. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that Weikang Keli could induce patterns of autophagy in SGC-7901 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion. Hoechst 33258 staining and Western blot analysis of apoptosis-related proteins showed that WK induced SGC-7901 cell death was not through apoptosis. In vivo study also revealed that i.g. administration of Weikang Keli once a day for 25 days could significantly reduce tumor volumes by about 50%. Collectively, the current data indicated that Weikang Keli induced gastric cancer cell death by autophagy effects.