Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer.

Background: The ChaiShao Shugan Formula (CSSGF) is a traditional Chinese medicine formula with recently identified therapeutic value in triple-negative breast cancer (TNBC). This study aimed to elucidate the underlying mechanism of CSSGF in TNBC treatment. Methods: TNBC targets were analyzed using R and data were from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The major ingredients and related protein targets of CSSGF were explored via the Traditional Chinese Medicine Systems Pharmacology database, and an ingredient-target network was constructed via Cytoscape to identify hub genes. The STRING database was used to construct the PPI network. GO and KEGG enrichment analyses were performed via R to obtain the main targets. The online tool Kaplan‒Meier plotter was used to identify the prognostic genes. Molecular docking was applied to the core target genes and active ingredients. MDA-MB-231 and MCF-7 cell lines were used to verify the efficacy of the various drugs. Results: A total of 4562 genes were screened as TNBC target genes. The PPI network consisted of 89 nodes and 845 edges. Our study indicated that quercetin, beta-sitosterol, luteolin and catechin might be the core ingredients of CSSGF, and EGFR and c-Myc might be the latent therapeutic targets of CSSGF in the treatment of TNBC. GO and KEGG analyses indicated that the anticancer effect of CSSGF on TNBC was mainly associated with DNA binding, transcription factor binding, and other biological processes. The related signaling pathways mainly involved the TNF-a, IL-17, and apoptosis pathways. The molecular docking data indicated that quercetin, beta-sitosterol, luteolin, and catechin had high affinity for EGFR, JUN, Caspase-3 and ESR1, respectively. In vitro, we found that CSSGF could suppress the expression of c-Myc or promote the expression of EGFR. In addition, we found that quercetin downregulates c-Myc expression in two BC cell lines. Conclusion: This study revealed the effective ingredients and latent molecular mechanism of action of CSSGF against TNBC and confirmed that quercetin could target c-Myc to induce anti-BC effects.

Neoadjuvant-Adjuvant vs Neoadjuvant-Only PD-1 and PD-L1 Inhibitors for Patients With Resectable NSCLC: An Indirect Meta-Analysis.

Importance: Neoadjuvant therapy combining programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors with platinum-based chemotherapy has demonstrated significant improvement in pathologic response and survival rates among patients with resectable non-small cell lung cancer (NSCLC). However, it remains controversial whether PD-1 blockade therapy given before and after surgery (neoadjuvant-adjuvant treatment) is associated with better outcomes than when given only before surgery (neoadjuvant-only treatment). Objective: To compare the efficacy and safety associated with neoadjuvant-adjuvant anti-PD-1 and anti-PD-L1 therapy with neoadjuvant-only anti-PD-1 and anti-PD-L1 therapy for patients with resectable NSCLC. Data Sources: A systematic search was conducted across databases including PubMed, Embase, and the Cochrane Library, as well as major oncology conferences, through July 31, 2023. Study Selection: Randomized clinical trials comparing neoadjuvant-adjuvant or neoadjuvant-only PD-1 and PD-L1 inhibitor therapy vs chemotherapy alone for patients with resectable NSCLC were selected. Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 authors independently extracted data. Hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) were extracted and then pooled through the generic inverse-variance methods. Relative risks (RRs) for treatment-related adverse events (TRAEs) were derived via the Mantel-Haenszel method. Using chemotherapy as a common comparator, indirect comparisons between neoadjuvant-adjuvant immunotherapy and neoadjuvant-only immunotherapy were conducted using frequentist methods. A random or fixed model was used based on intertrial heterogeneity identified through the Cochran Q test. Main Outcomes and Measures: The primary outcome was EFS, with secondary outcomes including OS and TRAEs. Results: The study encompassed 4 trials of neoadjuvant-adjuvant immunotherapy and 1 trial of neoadjuvant-only immunotherapy, involving 2385 patients. Direct meta-analysis revealed significant improvements in EFS for both neoadjuvant-adjuvant and neoadjuvant-only immunotherapy compared with chemotherapy alone. In indirect meta-analysis, the addition of adjuvant immunotherapy to neoadjuvant immunotherapy was not associated with improved EFS (HR, 0.90; 95% CI, 0.63-1.30; P = .59) or OS (HR, 1.18; 95% CI, 0.73-1.90; P = .51) compared with neoadjuvant-only immunotherapy. Moreover, the incidence of any grade of TRAEs significantly increased with the addition of adjuvant immunotherapy (RR, 1.08; 95% CI, 1.00-1.17; P = .04). Conclusions and Relevance: This meta-analysis suggests that adding PD-1 or PD-L1 inhibitors in the adjuvant phase to neoadjuvant treatment with PD-1 or PD-L1 inhibitors and chemotherapy may not improve survival outcomes for patients with resectable NSCLC and may be associated with increased adverse events. Future validation of these findings is warranted through head-to-head randomized clinical trials.

Insect-Inspired Strategy for Conferring Reversible, High Responsivity on Microgels to Dilute-Source CO2.

We described an insect-inspired strategy for conferring reversible, high responsivity on polymer microgels to dilute-source CO2 (≤5000 ppm in gas mixtures). This is demonstrated on oligo(ethylene oxide)-based microgels that contain tertiary amines on the polymer chains with proper organic small molecular carbonates in the polymer-solvent system. Similar to the synergistic contribution of the CO2 receptor subunits in mosquitoes for CO2 response, laser light scattering and related studies indicated that the CO2-response of the microgels in terms of the volume changes works through the coordination of different functional moieties in the system, making it different from the conventional CO2-response mechanism. While this pushes the lower response threshold of CO2 concentration down to ca. 1000 ppm, this unique strategy can also satisfy the urge to achieve both effective CO2 capture and facile CO2 release, making it possible to couple the detection with the capture and utilization of indoor excess CO2.

Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: A meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China).

OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.

Analysis of Risk Factors for Distant Metastasis of Pancreatic Ductal Adenocarcinoma without Regional Lymph Node Metastasis and a Nomogram Prediction Model for Survival.

Background: Negative regional lymph nodes do not indicate a lack of distant metastasis. A considerable number of patients with negative regional lymph node pancreatic cancer will skip the step of regional lymph node metastasis and directly develop distant metastasis. Methods: We retrospectively analyzed the clinicopathological characteristics of patients with negative regional lymph node pancreatic cancer and distant metastasis in the Surveillance, Epidemiology, and End Results database from 2010 to 2015. Multivariate logistic analysis and Cox analysis were used to determine the independent risk factors that promoted distant metastasis and the 1-, 2-, and 3-year cancer-specific survival in this subgroup. Results: Sex, age, pathological grade, surgery, radiotherapy, race, tumor location, and tumor size were significantly correlated with distant metastasis (P < 0.05). Among these factors, pathological grade II and above, tumor site other than the pancreatic head, and tumor size >40 mm were independent risk factors for distant metastasis; age ≥60 years, tumor size ≤21 mm, surgery, and radiation were protective factors against distant metastasis. Age, pathological grade, surgery, chemotherapy, and metastasis site were identified as predictors of survival. Among them, age ≥40 years, pathological grade II and above, and multiple distant metastasis were considered independent risk factors for cancer-specific survival. Surgery and chemotherapy were considered protective factors for cancer-specific survival. The prediction performance of the nomogram was significantly better than that of the traditional American Joint Committee on Cancer tumor, node, metastasis staging system. We also established an online dynamic nomogram calculator, which can predict the survival rate of patients at different follow-up time points. Conclusion: Pathological grade, tumor location, and tumor size were independent risk factors for distant metastasis in pancreatic ductal adenocarcinoma with negative regional lymph nodes. Older age, smaller tumor size, surgery, and radiotherapy were protective factors against distant metastasis. A new nomogram that was constructed could effectively predict cancer-specific survival in pancreatic ductal adenocarcinoma with negative regional lymph nodes and distant metastasis. Furthermore, an online dynamic nomogram calculator was established.

FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway.

BACKGROUND: Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. METHODS: RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. RESULTS: FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. CONCLUSION: Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.

CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis.

Anoikis resistance was a prominent hallmark of cancer metastasis, and lipo-genic characteristics have been identified as another metabolic alteration during tumorigenesis. However, their crosstalk has not been fully elucidated, especially in advanced esophageal squamous cell carcinoma (ESCC). In this study, we showed, for the first time, that the key enzyme carnitine O-palmitoyl transferase 1 (CPT1A), which is involved in fatty acid oxidation (FAO), was markedly upregulated in ESCC cells upon detached culture via a metabolism PCR array. Overexpression of CPT1A was associated with poor survival of ESCC patients and could protect ESCC cells from apoptosis via maintaining redox homeostasis through supply of GSH and NADPH. Mechanistically, detached culture conditions enhanced the expression of the transcription factor ETV4 and suppressed the expression of the ubiquitin enzyme RNF2, which were responsible for the elevated expression of CPT1A at the mRNA and protein levels, respectively. Moreover, genetic or pharmacologic disruption of CPT1A switched off the NADPH supply and therefore prevented the anchorage-independent growth of ESCC cells in vitro and lung metastases of xenografted tumor models in vivo. Collectively, our results provide novel insights into how ESCC cancer cells exploit metabolic switching to form distant metastases and some evidence for the link between anoikis and FAO.

Reversible Regulating the Substrate Specificity of Enzymes in Microgels by a Phase Transition in Polymer Networks.

Here, we report a distinct approach for regulating the substrate specificity of enzymes immobilized in microgels by a phase transition in polymer networks. The finding is demonstrated on glucose oxidase that is immobilized in thermoresponsive poly(N-isopropylacrylamide)-based microgels. Laser light scattering and enzymatic oxidation tests indicate that the broadened specificity appears at low temperatures, at which the gel matrix is in the relatively swollen state relative to its state at microgel synthesis temperature; upon heating to the relative higher temperatures, the gel matrix is not able to shrink further that offers a tight space in which the enzyme resides to retain high glucose specificity. It is proposed that polymer phase transition in the gel matrix mainly alter protein gates that control passage of substrates into active sites, making them open or close to a certain extent that enable reversible regulating the substrate specificity. The finding is also observed on bulk gels under a rational design, making it of potential interest in enzymatic biofuel cell applications.

Myopia prevalence and ocular biometry: a cross-sectional study among minority versus Han schoolchildren in Xinjiang Uygur autonomous region, China.

OBJECTIVES: To describe and compare the prevalence of refractive error and its associated ocular biometric parameters in a large multi-racial sample of schoolchildren from Xinjiang. METHODS: A total of 67,102 school children of five ethnicity groups aged 6-23 years from 46 schools in Xinjiang participated in this study. The children underwent a comprehensive eye examination for vision screening, including uncorrected visual acuity and standardized refraction. Refractive error was determined by autorefractors and subjective refraction. Refraction was recorded in spherical equivalent (SE). The age- and sex- adjusted prevalence of myopia (SE ≤ -0.5 D), low myopia (-6 D < SE ≤ -0.5 D), high myopia (SE ≤ -6.0 D), astigmatism (cylinder < -0.5 D), and anisometropia (difference in SE between two eyes of 1.0 D) in the five ethnic groups were calculated. Ocular biometric parameters including axial length (AL) and corneal radius of curvature (CR) were measured by AL-scan optical biometer. RESULTS: The age- and sex- adjusted prevalence of myopia in the Han, Hui, Uyghur, Kyrgyz and Kazakh were 65.8% (95% confidence interval [CI] 65.4, 66.3); 59.1% (95% CI 57.8, 60.4); 30.1% (95% CI 29.2, 30.9); 30.2 (95% CI 28.9, 31.4); and 30.0% (95% CI 27.6, 32.3), respectively. The Han and Hui children also had longer ALs (Han, 23.8; Hui, 23.6, Uyghur, 23.1; Kyrgyz, 23.1; Kazakh, 23.3 mm) and larger AL/CR (Han, 3.04; Hui, 3.00; Uyghur, 2.95; Kyrgyz, 2.96; Kazakh, 2.97) values than the other three minorities (P < 0.01). Overall, girls had shorter ALs, steeper corneas, and smaller AL/CR values than boys (P < 0.01). CONCLUSIONS: Significant ethnic difference in the prevalence of myopia was observed in this study on school-aged children in Xinjiang (Han > Hui > Kyrgyz > Uyghur > Kazakh). This study among different ethnic groups in a multiethnic population is valuable for enriching the ethnical information resources for refractive errors and ocular biometry parameters, as well as facilitating further research on myopia-related diseases and risks.

PUF60/AURKA Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer.

Abnormal expression or mutation of RNA splicing proteins are widely observed in human cancers. Here, we identified poly(U) binding splicing factor 60 (PUF60) as one of the most differentially expressed genes out of 97 RNA splicing proteins between normal and bladder cancer tissues by bioinformatics analysis of TCGA bladder cancer expression data. The expression of PUF60 was significantly higher in tumor tissues, while high PUF60 expression was associated with malignant phenotypes of bladder cancer and shorter survival time. Moreover, we identified aurora kinase A (AURKA) as a new downstream target of PUF60 in bladder cancer cells. PUF60 knockdown significantly inhibited cell viability and colony formation capacity in bladder cancer cells, whereas AURKA overexpression reversed this inhibition effect. Overexpression of PUF60 significantly promoted cell viability and colony formation in bladder cancer cells, while treatment with AURKA specific inhibitor reversed this promotive effect. Mechanistically, PUF60 specifically bound to the AURKA promoter, thereby activating its transcription and expression. Furthermore, we showed that there was a significant positive correlation between PUF60 and AURKA expression in bladder cancer tissues, and PUF60 and AURKA expression contributed to tumor progression and malignant phenotypes in the patients with bladder cancer. Collectively, these results indicate that the PUF60/AURKA axis plays a key role in regulating tumorigenesis and progression of bladder cancer, and may be a potential prognostic biomarker and therapeutic target for bladder cancer patients.

Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase.

Background: Abnormal transcriptional upregulation of telomerase reverse transcriptase (TERT) plays a dominant role in telomerase activation in various cancers. TERT promoter mutations (TPMs) have been identified as a key mechanism in TERT upregulation. However, the mechanism of TERT upregulation in cancers with low frequency of TPMs are not fully elucidated so far. Methods: The expression of PUF60 and TERT was detected by real-time PCR, western blot and immunohistochemistry. TERT promoter binding proteins were identified by streptavidin-agarose pulldown assay and mass spectrum (MS) analysis. The role of PUF60/TERT in renal cancer was evaluated on cell growth in vitro and in vivo. Results: In this study, we identify the regulation mechanism of TERT in renal cell carcinoma (RCC) cells which have rare TPMs but exert significant upregulation of TERT. We found that TERT was highly expressed in RCC tumor tissues, and elevated TERT expression was associated with poor prognosis for patients. We also detected the relatively rare TPM status in both RCC tumor tissues and RCC cell lines. Mechanistically, PUF60, a RNA binding protein, was identified as a novel TERT regulator which bound to the TERT and transcriptionally upregulated TERT expression in RCC cells. The in vitro and in vivo experiments also demonstrated that PUF60 could promote RCC cell growth through activation of TERT expression in a TPM status independent way. Furthermore, we showed that there was a strong correlation of the expression of PUF60 and TERT in RCC tumor tissues and RCC cell lines, and the patients with high expression of PUF60 and TERT had significantly shorter survival. Conclusions: Collectively, these results indicated that PUF60 transcriptionally upregulated TERT expression to promote RCC growth and progression in a TPM status independent way, suggesting that the PUF60/TERT signaling pathway may serve as potential prognostic biomarkers and therapeutic targets for RCC.

Merging C-H Vinylation with Switchable 6π-Electrocyclizations for Divergent Heterocycle Synthesis.

Pyridinium-containing polyheterocycles exhibit distinctive biological properties and interesting electrochemical and optical properties and thus are widely used as drugs, functional materials, and photocatalysts. Here, we describe a unified two-step strategy by merging Rh-catalyzed C-H vinylation with two switchable electrocyclizations, including aza-6π-electrocyclization and all-carbon-6π-electrocyclization, for rapid and divergent access to dihydropyridoisoquinoliniums and dihydrobenzoquinolines. Through computation, the high selectivity of aza-electrocyclization in the presence of an appropriate "HCl" source under either thermal conditions or photochemical conditions is shown to result from the favorable kinetics and symmetries of frontier orbitals. We further demonstrated the value of this protocol by the synthesis of several complex pyridinium-containing polyheterocycles, including the two alkaloids berberine and chelerythrine.

PD-L1 promotes tumor growth and progression by activating WIP and ß-catenin signaling pathways and predicts poor prognosis in lung cancer.

PD-L1 is overexpressed in tumor cells and contributes to cancer immunoevasion. However, the role of the tumor cell-intrinsic PD-L1 in cancers remains unknown. Here we show that PD-L1 regulates lung cancer growth and progression by targeting the WIP and ß-catenin signaling. Overexpression of PD-L1 promotes tumor cell growth, migration and invasion in lung cancer cells, whereas PD-L1 knockdown has the opposite effects. We have also identified WIP as a new downstream target of PD-L1 in lung cancer. PD-L1 positively modulates the expression of WIP. Knockdown of WIP also inhibits cell viability and colony formation, whereas PD-L1 overexpression can reverse this inhibition effects. In addition, PD-L1 can upregulate ß-catenin by inhibiting its degradation through PI3K/Akt signaling pathway. Moreover, we show that in lung cancer cells ß-catenin can bind to the WIP promoter and activate its transcription, which can be promoted by PD-L1 overexpression. The in vivo experiments in a human lung cancer mouse model have also confirmed the PD-L1-mediated promotion of tumor growth and progression through activating the WIP and ß-catenin pathways. Furthermore, we demonstrate that PD-L1 expression is positively correlated with WIP in tumor tissues of human adenocarcinoma patients and the high expression of PD-L1 and WIP predicts poor prognosis. Collectively, our results provide new insights into understanding the pro-tumorigenic role of PD-L1 and its regulatory mechanism on WIP in lung cancer, and suggest that the PD-L1/Akt/ß-catenin/WIP signaling axis may be a potential therapeutic target for lung cancers.

Association of body composition with survival and inflammatory responses in patients with non-metastatic nasopharyngeal cancer.

OBJECTIVES: It is unknown whether or not the body composition is correlated with the prognosis and inflammatory response in patients with nasopharyngeal cancer (NPC). MATERIALS AND METHODS: This cohort included 1767 patients with NPC. Visceral, subcutaneous and intra muscular adipose tissues (VAT, SAT and IMAT), and skeletal muscle index were quantified with computed tomography. We used the optimal stratification to select cut points for VAT, SAT and IMAT. We defined sarcopenia according to a widely used cut-point. The primary endpoint was overall survival (OS). The association between body composition and inflammatory response was also examined. RESULTS: Low VAT, SAT, IMAT and sarcopenia were observed in 260 (14.7%), 451 (25.5%), 773 (43.7%) and 683 (38.7%) patients, respectively. Low VAT (P < 0.001, hazard ratio [HR], 1.884; 95% confidence interval [CI], 1.436-2.473,) and SAT (P = 0.022, HR, 1.334, 95%CI, 1.043-1.706) were both associated worse survival. IMAT and sarcopenia were not with prognostic value. In multivariate analysis, we found the prognostic value of the VAT (HR: 1.544, 95% CI: 1.128-2.114; P = 0.007) was independent of T stage, N stage, disease stage, lactic dehydrogenase, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), the systemic immune-inflammation index (SII), EBV-DNA and body mass index. We observed higher NLR (P = 0.028) and PLR (P < 0.001) in patients with low SAT. Both low VAT (P = 0.009) and SAT (P = 0.005) were associated with decreased stromal lymphocyte infiltrating intensity. CONCLUSIONS: Among body composition parameters, VAT was an independent prognostic factor, especially in patients with locally advanced NPC.

KMT2A regulates cervical cancer cell growth through targeting VDAC1.

Cervical cancer is an aggressive cutaneous malignancy, illuminating the molecular mechanisms of tumorigenesis and discovering novel therapeutic targets are urgently needed. KMT2A is a transcriptional co-activator regulating gene expression during early development and hematopoiesis, but the role of KMT2A in cervical cancer remains unknown. Here, we demonstrated that KMT2A regulated cervical cancer growth via targeting VADC1. Knockdown of KMT2A significantly suppressed cell proliferation and migration and induced apoptosis in cervical cancer cells, accompanying with activation of PARP/caspase pathway and inhibition of VADC1. Overexpression of VDAC1 reversed the KMT2A knockdown-mediated regulation of cell proliferation, migration and apoptosis. The in vivo results from a cervical cancer xenograft mouse model also validated that KMT2A knockdown suppressed tumor growth by inhibiting VDAC1, whereas KMT2A overexpression promoted cervical cancer growth. Moreover, analyses of Biewenga cervix database and clinical samples showed that both KMT2A and VDAC1 were upregulated in cervix squamous cell carcinoma compared with cervix uteri tissues, and their expression was negatively correlated with the differentiation grade of cervical cancer. Our results therefore indicated that the KMT2A/VDAC1 signaling axis may be a potential new mechanism of cervical carcinogenesis.

Immune Cell Infiltration of the Primary Tumor Microenvironment Predicted the Treatment Outcome of Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients.

BACKGROUND: With the interest in cancer immunotherapy, it may be possible to combine immunotherapy with bevacizumab and chemotherapy. We evaluated whether tumor-infiltrating immune cells are associated with the efficacy of chemotherapy with or without bevacizumab for the treatment of metastatic colorectal cancer (mCRC). METHODS: This study enrolled mCRC patients on standard treatment with available detailed data and tumor tissue at Sun Yat-sen University Cancer Center between July 1, 2005, and October 1, 2017. CD3+ and CD8+ T cell densities examined by immunohistochemistry in both the tumor core (CT) and invasive margin (IM) were summed as the Immunoscore, and the CD8+/CD3+ T cell ratio was calculated. The predictive and prognostic efficacies of tumor-infiltrating immune cells for progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier and Cox analyses. RESULTS: The CD8+/CD3+ T cell ratio in the microenvironment was an independent prognostic factor for OS (28.12 mo vs. 16.56 mo, P = 0.017) among the 108 studied patients. In the chemotherapy only group, patients with a high Immunoscore had a high overall response rate (ORR, 40.0% vs. 60.0%, P = 0.022), those with a low CD8+/CD3+ T cell ratio in the microenvironment had a significantly longer PFS (8.64 mo vs. 6.01 mo, P = 0.017), and those with a high CD3+ T cell density in the CT had a longer OS (16.56 mo vs. 25.66 mo, P = 0.029). In the chemotherapy combined with bevacizumab group, patients with a higher CD8+ T cell density in the IM had a longer PFS (7.62 mo vs. 11.66 mo, P = 0.034) and OS (14.55 mo vs. 23.72 mo, P = 0.033). CONCLUSION: Immune cells in primary tumors play an important role in predicting mCRC treatment efficacy. CD8 predicts the effect of bevacizumab plus chemotherapy, while CD3 and CD8/CD3 predict chemotherapy efficacy.

Salt-Enhanced CO2-Responsiveness of Microgels.

Here, we report a distinct mechanism for harnessing CO2-responsiveness through enhancing CO2 capture ability. The finding is demonstrated on the microgels that are composed of oligo(ethylene glycol) and sulfonate moieties. Laser light scattering studies on dilute aqueous dispersion of these microgels indicated a low CO2-responsivity, which can be significantly enhanced by adding NaCl and other salts. This salt-enhanced CO2-responsiveness of microgels can be elucidated by the antipolyelectrolyte behavior and its superposition of forming cross-links physically with CO2 as an intermediate. Further results of the filtration experiments on microgel translocation through pores suggest the feasibility of the explanation. The finding is also supported by the CO2 capture-release experiments on the dispersion, which can reversibly absorb and desorb CO2.

Cutaneous extranodal natural killer (NK) / T - cell lymphoma: A comprehensive clinical features and outcomes analysis of 71 cases.

BACKGROUND: The skin is the common extranasal sites in extranodal natural killer (NK) / T - cell lymphoma, (ENKTL). However, data regarding cutaneous ENKTL are relatively scarce. Thus, we performed a large retrospective study to analyze clinical features and treatment outcomes of cutaneous ENKTL. PATIENTS AND METHODS: Seventy-one patients with cutaneous ENKTL newly diagnosed between 2001 and 2018 were retrospectively analyzed from Sun Yat-sen cancer center. RESULTS: The median overall survival (OS) was 15.5 months (95 % confidence interval: 8.0-22.1 months). Age, treatment strategy, and treatment response were independent prognostic factors for cutaneous ENKTL. Patients who could undergo chemotherapy followed by radiotherapy showed a significantly better survival than those treated with chemotherapy alone (p < 0.001). The 3 - year OS rates were 73.9 % for patients who achieved complete response (CR) compared with 10.3 % for patients who did not (p < 0.001). CONCLUSION: We reported by far the largest series of cutaneous ENKTL, and demonstrated its aggressive clinical behavior and unsatisfying response to the current therapeutic strategies. Further investigations are required for the better understanding and management of this uncommon disease.

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer.

BACKGROUND: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). METHODS: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. RESULTS: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. CONCLUSIONS: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.

Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway.

Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. However, it is unclear whether Ku80 regulates tumor growth in human melanoma. In this study, we screened a siRNA library targeting 6024 human genes and identified Ku80 as a potential therapeutic target in melanoma cells. Knockdown of Ku80 significantly suppressed melanoma cell proliferation and induced apoptosis, as well as enhanced the antitumor effect of melatonin in melanoma in vitro and in vivo. Overexpression of Ku80, however, promoted melanoma growth and increased the insensitivity of melanoma cells to melatonin. Mechanistically, we found that Ku80 bound to the PDK1 promoter and activated the transcription of PDK1. Moreover, we showed that the binding of Ku80 at the PDK-1 promoter was HIF1-α dependent, and melatonin degraded HIF1-α in melanoma cells. Furthermore, clinical data revealed that the expression of Ku80 and PDK-1 proteins were positively correlated and elevated in the tumor tissues of melanoma patients, and high expression of Ku80 predicted a poor prognosis in melanoma. Collectively, our study demonstrated that Ku80 promoted melanoma growth and regulated antitumor activity of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway, suggesting that Ku80 may be a potential molecular target for melanoma treatment.