Gut microbiota and microbiota-derived metabolites in colorectal cancer: enemy or friend.

Colorectal cancer (CRC) is a highly prevalent gastrointestinal cancer worldwide. Recent research has shown that the gut microbiota plays a significant role in the development of CRC. There is mounting evidence supporting the crucial contributions of bacteria-derived toxins and metabolites to cancer-related inflammation, immune imbalances, and the response to therapy. Besides, some gut microbiota and microbiota-derived metabolites have protective effects against CRC. This review aims to summarize the current studies on the effects and mechanisms of gut microbiota and microbiota-produced metabolites in the initiation, progression, and drug sensitivity/resistance of CRC. Additionally, we explore the clinical implications and future prospects of utilizing gut microbiota as innovative approaches for preventing and treating CRC.

Prognostic analysis of radiotherapy for cervical lymph node recurrence after curative resection of thoracic esophageal squamous cell carcinoma.

To identify efficacy and prognosis of radiotherapy (RT) for cervical lymph node recurrence (CLNR) in thoracic esophageal squamous cell carcinoma (TESCC) after curative resection. The clinical data from 65 patients were retrospectively analyzed. The Kaplan-Meier method was employed to analyze the survival of patients. The Cox proportional hazards model was then exploited for multivariate analysis. The median overall survival (OS) was 20 months; one-year, two-year, three-year and five-year survival rates were 68.3%, 47.3%, 33.4% and 10.6%. The median progression-free survival (PFS) was 14 months. Univariate analysis indicated that time from surgery to recurrence, number of recurrent lymph nodes and dose of RT were significant prognostic factors, whereas multivariate analysis showed that number of recurrent lymph nodes and radiation dose were independent factors. RT was an effective salvage treatment for patients with CLNR after surgery. Those patients who showed single lymph node recurrence and who were exposed to ≥60 Gy of RT experienced a favorable prognosis.

Curcuminoids inhibit human and rat placental 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, curcuma longa L has been applied to treat pain and tumour-related symptoms for over thousands of years. Curcuminoids, polyphenolic compounds, are the main pharmacological component from the rhizome of Curcuma longa L. Pharmacological investigations have found that curcuminoids have many pharmacological activities of anti-inflammatory, anti-tumour, and anti-metastasis. AIM OF THE STUDY: 3ß-Hydroxysteroid dehydrogenase (3ß-HSD1) catalyses the production of steroid precursors for androgens and estrogens, which play an essential role in cancer metastasis. We explored the potency and mode of action of curcuminoids and their metabolites of inhibiting 3ß-HSD1 activity and compared the species difference between human and rat. MATERIALS AND METHODS: In this study, we investigated the direct inhibition of 6 curcuminoids on human placental 3ß-HSD1 activity and compared the species-dependent difference in human 3ß-HSD1 and rat placental homolog 3ß-HSD4. RESULTS: The inhibitory potency of curcuminoids on human 3ß-HSD1 was demethoxycurcumin (IC50, 0.18 µM) > bisdemethoxycurcumin (0.21 µM)>curcumin (2.41 µM)> dihydrocurcumin (4.13 µM)>tetrahydrocurcumin (15.78 µM)>octahydrocurcumin (ineffective at 100 µM). The inhibitory potency of curcuminoids on rat 3ß-HSD4 was bisdemethoxycurcumin (3.34 µM)>dihydrocurcumin (5.12 µM)>tetrahydrocurcumin (41.82 µM)>demethoxycurcumin (88.10 µM)>curcumin (137.06 µM)> octahydrocurcumin (ineffective at 100 µM). Human choriocarcinoma JAr cells with curcuminoid treatment showed that these chemicals had similar potency to inhibit progesterone secretion under basal and 8bromo-cAMP stimulated conditions. Docking analysis showed that all chemicals bind pregnenolone-binding site with mixed/competitive mode for 3ß-HSD. CONCLUSION: Some curcuminoids are potent human placental 3ß-HSD1 inhibitors, possibly being potential drugs to treat prostate cancer and breast cancer.

Emerging role of non-coding RNAs in glucose metabolic reprogramming and chemoresistance in colorectal cancer.

Metabolic reprogramming plays a critical role in colorectal cancer (CRC). It contributes to CRC by shaping metabolic phenotypes and causing uncontrolled proliferation of CRC cells. Glucose metabolic reprogramming is common in carcinogenesis and cancer progression. Growing evidence has implicated the modifying effects of non-coding RNAs (ncRNAs) in glucose metabolic reprogramming and chemoresistance in CRC. In this review, we have summarized currently published studies investigating the role of ncRNAs in glucose metabolic alterations and chemoresistance in CRC. Elucidating the interplay between ncRNAs and glucose metabolic reprogramming provides insight into exploring novel biomarkers for the diagnosis and prognosis prediction of CRC.

The association of sex-biased ATRX mutation in female gastric cancer patients with enhanced immunotherapy-related anticancer immunity.

BACKGROUND: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. METHODS: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). RESULTS: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). CONCLUSIONS: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.

Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is the third prevalent cancer worldwide, the morbidity and mortality of which have been increasing in recent years. As molecular targeting agents, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (McAbs) have significantly increased the progression-free survival (PFS) and overall survival (OS) of metastatic CRC (mCRC) patients. Nevertheless, most patients are eventually resistant to anti-EGFR McAbs. With the intensive study of the mechanism of anti-EGFR drug resistance, a variety of biomarkers and pathways have been found to participate in CRC resistance to anti-EGFR therapy. More and more studies have implicated non-coding RNAs (ncRNAs) primarily including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely involved in tumorigenesis and tumor progression. They function as essential regulators controlling the expression and function of oncogenes. Increasing data have shown ncRNAs affect the resistance of molecular targeted drugs in CRC including anti-EGFR McAbs. In this paper, we have reviewed the advance in mechanisms of ncRNAs in regulating anti-EGFR McAbs therapy resistance in CRC. It provides insight into exploring ncRNAs as new molecular targets and prognostic markers for CRC.

Nimotuzumab Combined With Irradiation Enhances the Inhibition to the HPV16 E6-Promoted Growth of Cervical Squamous Cell Carcinoma.

Human papillomavirus (HPV) 16 E6 has been proved to increase the radiosensitivity and lead to the EGFR overexpression in cervical cancer cells. In this study, to investigate the inhibition of nimotuzumab-mediated EGFR blockade combined with radiotherapy, we established a C33A cervical squamous cell line overexpressed HPV16-E6 and a nude mouse model bearing these cell lines. The CCK-8 assay was used to detect the effects of various treatments on the proliferation of C33A cells. Flow cytometry was used to detect the rates of apoptosis and cell cycle arrest. Gene transcription and protein expression were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Immunohistochemical staining was used to evaluate protein expression in tumor tissue. We revealed that E6-overexpressing C33A cells grew faster and were more sensitive to radiotherapy than control cells in vitro and in vivo. The expression levels of EGFR, as well as those of downstream signaling molecules AKT and ERK 1/2, were significantly upregulated in C33A cells that overexpressed E6. We observed that nimotuzumab combined with radiotherapy could enhance the inhibition of C33A cell growth induced by E6, both in vitro and in vivo. We also observed enhanced effect after combination on G2/M cell cycle arrest and apoptosis in E6-overexpressing C33A cells. Furthermore, the combined therapy of nimotuzumab and radiation remarkably reduced the protein expression levels of EGFR, AKT, ERK 1/2 in vitro, and in vivo. In conclusion, HPV16 E6 expression is positively correlated with levels of EGFR, AKT, and ERK 1/2 protein expression. The combined treatment with nimotuzumab and radiotherapy to enhance radiosensitivity in E6-positive cervical squamous cell carcinoma was related to enhanced G2/M cell cycle arrest and caspase-related apoptosis.

Weighted Gene Co-Expression Network Analysis Identifies Hub Genes Associated with Occurrence and Prognosis of Oral Squamous Cell Carcinoma.

BACKGROUND The aim of this study was to identify biomarkers closely related to the pathogenesis and prognosis of oral squamous cell carcinoma (OSCC) by using weighted gene co-expression network analysis (WGCNA) based on integrative transcriptome datasets. MATERIAL AND METHODS Gene expression profiles of OSCC were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained and we then performed with Gene ontology (GO) and pathway enrichment analysis as well as protein-protein interactions (PPI) network analysis. WGCNA was used to construct the co-expression network. Multipart results were intersected to acquire the candidate genes, and survival analysis was used to identify the hub genes. RESULTS A total of 568 DEGs, including 272 upregulated genes and 296 downregulated genes, were identified. GO and pathway analyses revealed that these DEGs were mainly enriched in extracellular matrix (ECM), ECM organization, structural constituent of muscle, and ECM-receptor interaction. The PPI network of DEGs was established, comprising 428 nodes and 1944 edges. In the co-expression network, pink module was the key module, in which 34 genes with high connectivity were identified. After the intersection of multipart results, 24 common genes were chosen as the candidate genes, among which 7 hub genes (PLAU, SERPINE1, LAMC2, ITGA5, TGFBI, FSCN1, and HLF) were identified using survival analysis. CONCLUSIONS Seven potential biomarkers were identified as being closely related with the initiation and prognosis of OSCC and might serve as potential targets for early diagnosis and personalized therapy of OSCC.

Microevolution of the VQ gene family in six species of Fragaria.

VQ motif-containing proteins play crucial roles in plant growth, development, and stress responses. However, no information of VQ motif-containing proteins has been studied at the microevolutionary level in species of Fragaria. In this study, a total of 19, 21, 23, 23, 23, and 25 genes containing the VQ motif were identified from the genomes of F. nipponica, F. iinumae, F. orientalis, F. vesca, F. nubicola, and F. x ananassa, respectively. We classified the VQ genes into 15 clades with grapevine VQ genes, which indicated that at least 15 ancient VQ genes existed before the divergence of the six studied species of Fragaria. Phylogenetic analysis indicated that 28 gene duplication events have occurred in the evolutionary process of the six species of Fragaria. Structural analysis showed that most of the VQ genes have no introns and that VQ proteins in each clade have a similar motif composition. The majority of gene pairs had Ka/Ks ratios less than 1, which illustrated that most of the VQ genes underwent purifying selection in the six species of Fragaria. Four types of cis-elements in promoters of VQ genes were detected, which is an important basis for further studies about plant stress responses. Furthermore, the expression analysis of FvVQ genes indicated that these genes are expressed differentially in the examined organs and tissues. The identification of VQ genes and the analysis of VQ gene duplication and polyploidization events in the six species of Fragaria provide important information on the evolutionary fate of VQ genes during the divergence of the six species of Fragaria.

Expression and clinical significance of cyclooxygenase 2 and survivin in human gliomas.

The present study aimed to determine cyclooxygenase 2 (COX-2) and survivin expression levels in glioma tissues, and to investigate their association with clinicopathological factors and patient survival. Immunohistochemistry was performed to evaluate COX-2 and survivin expression levels in paraffin-embedded surgically resected tissues from 70 patients with glioma and 7 individuals with normal brain tissues. The association between COX-2 and survivin expression levels and clinicopathological features was investigated using the χ2 test, and the survival time was analyzed using the Kaplan Meier method with log-rank test. COX-2 and survivin were overexpressed in glioma tissues, and higher expression levels were observed in glioma tissues of histological grades III-IV compared with those in grade I-II tumor tissues (P<0.05); however, the expression levels were not associated with gender, age, tumor size or location (P>0.05). There was a significant positive association between the expression levels of COX-2 and survivin in the glioma tissues. Additionally, COX-2 and survivin expression levels were significantly negatively correlated with the rate of survival. In conclusion, COX-2 and survivin expression is positively associated with the pathological grade of a glioma and may contribute to glioma tumorigenesis. Therefore, COX-2 and survivin may be sensitive predictors of a negative clinical prognosis for patients with glioma.

Is a clinical target volume (CTV) necessary for locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy? -a dosimetric evaluation of three different treatment plans.

BACKGROUND: The aim of this study was to determine the feasibility of omitting the clinical target volume (CTV) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT) by comparing dosimetric characteristics of three different IMRT plans with or without CTV implementation. METHODS: Thirteen patients with stage III NSCLC were reviewed. Target volumes were contoured such that the planning target volume (PTV) derived from the gross tumor volume (GTV) directly was named PTV_g and that from GTV plus CTV margin was named PTV_c. The PTV margin to generate PTV_g or PTV_c was the same within each case. Three IMRT plans were retrospectively generated to deliver: (I) 60 Gy to PTV_g in plan_routine; (II) 60 Gy to PTV_c in plan_CTV, and (III) 50 Gy to PTV_c while the dose was simultaneously escalated to 60 Gy to PTV_g in plan_SIB, achieved using the simultaneous integrated boost (SIB) technique. Optimization was performed to minimize the dose volumes of the irradiated normal lung, heart, esophagus, and spinal cord. Dose distributions and dosimetric indexes for the target volumes and critical structures in the three plans were computed and compared. RESULTS: In plan_routine, the 50-Gy isodose line covered at least 95% of the GTV plus CTV margins in all 13 patients. The statistics showed better sparing of the organs at risk (OAR) in plan_routine than in plan_CTV, and the best OAR sparing in plan_SIB. CONCLUSIONS: In patients with locally advanced lung cancer, IMRT planning without CTV implementation provides sufficient dose coverage of subclinical disease while reducing the dose to normal tissues. The omission of CTV was feasible in our cohort of patients. However, when CTV was implemented, IMRT planning that included the SIB technique had further dosimetric benefits to the patients. This strategy thus merits further evaluation in clinical trials.

Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes.

Type 2 diabetes (T2D) is characterized by progressive and inexorable ß-cell dysfunction, leading to insulin deficiency. Novel strategies to preserve the remaining ß-cells and restore ß-cell function for the treatment of diabetes are urgently required. Mesenchymal stem cells (MSCs) have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. The aim of the present clinical trial was to assess the safety and efficacy of umbilical cord-derived MSC (UCMSC) transplantation for patients with T2D. The safety and efficacy of UCMSC application were evaluated in six patients with T2D during a minimum of a 24-month follow-up period. Following transplantation, the levels of fasting C-peptide, the peak value and the area under the C-peptide release curve increased significantly within one month and remained high during the follow-up period (P<0.05). Three of the six patients became insulin free for varying lengths of time between 25 and 43 months, while the additional three patients continued to require insulin injections, although with a reduced insulin requirement. Fasting plasma glucose and 2-h postprandial blood glucose levels were relatively stable in all the patients following transplantation. There was no immediate or delayed toxicity associated with the cell administration within the follow-up period. Therefore, the results indicated that transplantation of allogeneic UCMSCs may be an approach to improve islet function in patients with T2D. There were no safety issues observed during infusion and the long-term monitoring period.