XRCC2 knockdown effectively sensitizes esophageal cancer to albumin-paclitaxel in vitro and in vivo.

Esophageal cancer (EC), a prevalent malignancy, has a high incidence and mortality. X-ray repair cross complementing 2 (XRCC2) functions on DNA damage and repair that works the progression of various cancers. Nevertheless, the role and mechanism of XRCC2 remain unknown in EC. The XRCC2 expression was examined by reverse transcription quantitative polymerase chain reaction and western blot. The function of XRCC2 in EC were investigated through cell counting kit-8, colony formation, transwell, flow cytometry, chromatin immunoprecipitation, luciferase, and western blot experiments. Besides, the role of XRCC2 in EC was assessed by western blot and immunohistochemistry experiments after nude mice were injected with EC109 cells and treated with nab-paclitaxel. The XRCC2 expression was upregulated in EC. Knockdown of XRCC2 diminished cell viability, and the number of colonies, migration cells and invasion cells of KYSE150 and EC109 cells. Silencing of XRCC2 diminished the cell viability of both two cells with a lower IC50, whereas boosted the apoptosis rate of both cells with the treatment of albumin-paclitaxel. All these outcomes were reverse with the upregulation of XRCC2 in both two cells. Mechanically, XRCC2 was transcriptionally regulated by specificity protein 1 (SP1), and silencing of SP1 inhibited the cell growth of EC. In vivo, transfection of shXRCC2 with or without albumin-paclitaxel treatment both decreased the tumor size and weight, as well as the expression of XRCC2 and Ki-67 in xenografted mice. XRCC2 transcriptionally regulated by SP2 promoted proliferation, migration, invasion, and chemoresistance of EC cells.

Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes.

BACKGROUND: Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers. METHODS: The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. RESULTS: In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC. CONCLUSIONS: Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC.

Weekly versus triweekly cisplatin-alone adjuvant chemoradiotherapy after radical hysterectomy for stages IB-IIA cervical cancer with risk of recurrence.

Weekly and triweekly cisplatin-alone concomitant chemoradiotherapy regimens after radical surgery were compared in stages IB-IIA cervical cancer with intermediate- or high-risk factors to identify the better therapeutic regimen. We retrospectively analyzed patients with stages IB-IIA cervical cancer who received radical hysterectomy followed by concurrent adjuvant chemoradiotherapy to compare the efficiency between weekly and triweekly regimen groups. We evaluated between-group differences in survival, recurrence, compliance, and adverse effects. A total of 217 patients were included in this study (triweekly group vs. weekly group; 97 vs. 120). The mean follow-up was 47.2 months. The 5-year disease-free survival (DFS) was 84.4% or 76.5% for patients treated with triweekly cisplatin chemotherapy or the weekly regimen, respectively (P = 0.110). The 5-year overall survival (OS) was 82.4 and 78.6% for the same treatment groups, respectively (P = 0.540). The DFS of the patients with pelvic lymph node metastasis were marginally better in triweekly regimen group compared with the weekly group (P = 0.031). Grades 3-4 leukopenia was significantly more common in the triweekly group (P = 0.028). The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly cisplatin-alone chemotherapy group but with less toxicity. However, triweekly cisplatin regimen reduced the recurrence in patients with pelvic lymph node metastasis.

CD5+MYC+ predicts worse prognosis in diffuse large B-cell lymphoma.

The dual expression of CD5 and MYC protein (DECM) on B-lymphocytes may arise at a specific stage of de novo diffuse large B-cell lymphoma (DLBCL). This study retrospectively reviewed 210 patients with de novo DLBCL at the Affiliated Hospital of Jiangnan University between 2006 and 2017. DECM was significantly correlated with a worse prognosis than that in either the CD5+ or MYC+ or CD5-MYC- patients. Furthermore, patients with DECM showed a similar outcome to MYC+BCL2+ lymphoma patients who have extremely poor survival rates. Multivariate analysis demonstrated that DECM was a significant independent predictor for overall survival (P < .0001) and progression-free survival (P < .0001) in DLBCL. DLBCL patients with DECM showed significantly inferior clinical outcomes compared to the CD5+, MYC+ or CD5-MYC- patients. Combinational therapeutic modalities might be a candidate approach to improve the prognosis of these patients.

Composition, coagulation characteristics, and cheese making capacity of yak milk.

Yak is one of the few species of which the rennet-coagulated cheese making characteristics of its milk are still not well understood. This study investigated composition and rennet-induced coagulation properties of milk from 17 individual yak cows in comparison with milk from 32 individual Holstein cows. Yak cows produced milk with generally higher concentrations of milk components. The concentrations of fat, protein, solids-not-fat (SNF), and calcium in yak milk were 1.89-, 1.68-, 1.46-, and 2-fold those in Holstein milk, respectively. The hydrodynamic radii of casein micelles (187.25 nm) and chymosin-induced paracasein (1,620 nm) were about twice the sizes of those found in Holstein milk. Higher concentrations of calcium in yak milk, together with larger sizes of casein micelles, explains the reason for its fast rate of curd formation and firmer curd texture. Optical microrheology analysis also showed that Ca2+ concentration had greater influence on the coagulation of yak milk than on Holstein milk. Cheese making trials with yak and Holstein milk proved the higher cheese yield of yak milk: 1.67-fold that of Holstein milk. Therefore, yak milk could be a suitable source of milk for enzyme-coagulated cheese making.

Prognostic significance of serum aspartic transaminase in diffuse large B-cell lymphoma.

BACKGROUND: Liver function is routinely assessed in clinical practice as liver function tests provide sensitive indicators of hepatocellular injury. However, the prognostic value of enzymes that indicate hepatic injury has never been systematically investigated in lymphoma, including diffuse large B-cell lymphoma (DLBCL). METHODS: This study examined the prognostic value of baseline aspartic transaminase (AST) in DLBCL patients. The association between AST and clinical features was analyzed in 179 DLBCL patients treated from 2006 to 2016. All enrolled patients were treated with R-CHOP or R-CHOP-like chemotherapy. Log-rank test, univariable analysis, and subgroup analysis were performed to evaluate the impact of AST on survival. RESULTS: AST 33.3 U/L was considered to be the optimal threshold value for predicting prognosis. A higher AST level was associated with advanced stage (P = 0.001), poorer performance status (P = 0.014), elevated lactate dehydrogenase level (P <  0.0001), presence of B symptoms (P = 0.001), high-risk International Prognostic Index (IPI, IPI 3-5) (P = 0.002), non-germinal center B-cell subtypes (P = 0.038), hepatitis B virus surface antigen positivity (P = 0.045) and more extra nodal involvement (ENI, ENI ≥ 2) (P = 0.027). Patients with a higher AST level had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P <  0.001). Subgroup analysis indicated that higher AST levels have poorer prognostic values in patients without B symptoms and LDH positive groups. CONCLUSION: A pretreatment AST level is associated with OS in DLBCL patients treated with R-CHOP or similar chemotherapy regimens. A high pretreatment AST level might be a reliable prognostic factor for predicting a dismal outcome in DLBCL patients. Serum AST levels may be investigated for use as an easily determinable, inexpensive biomarker for risk assessment in patients with DLBCL.

Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway.

Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anti-cancer effects. Nonetheless, the anti-tumor effect of PL in lung cancer cells still remains unclear. In the present study, we reported the chemotherapeutic effects of PL using in vitro and in vivo models. We showed that PL displayed potent anti-neoplastic activity against lung cancer A549 cells as well as corresponding docetaxel-resistant A549/DTX cells. In addition, we found that PL induced apoptosis in both A549 and A549/DTX cells. PL also induced autophagy in A549/DTX cells. Moreover, autophagy-specific inhibitors (3-methyladenine) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced PL-induced apoptosis, indicating that PL-mediated autophagy may protect A549/DTX cells from undergoing apoptotic cell death. Furthermore, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by PL. Finally, PL inhibited the growth of A549/DTX xenograft tumors, which was associated with inhibition of cell proliferation, induction of apoptosis of tumor cells and decreased expression of p-Akt and p-mTOR in tumor xenograft tissues. In summary, our study demonstrated that PL induced apoptosis and autophagy through modulation of the PI3K/Akt/mTOR pathway in human lung cancer cells. This study may provide a rationale for future clinical application using PL as a chemotherapeutic agent for lung cancer.

[Effect of Brucea javanica fruit oil emulsion combined cisplatin on the growth inhibition of transplanted tumor in human ovarian cancer SKOV3 nude mice: an experimental study].

OBJECTIVE: To study the growth inhibition effect of Brucea javanica Fruit Oil Emulsion (BJFOE) on human ovarian caner SKOV3 cells and the transplanted tumor of SKOV3 nude mice. METHODS: Growth inhibition effects of different concentrations BJFOE alone or its combination with cisplatin on human ovarian cancer cell SKOV3 were measured using MTT method. The orthotopic transplantation tumor model of human ovarian cancer SKOV3 cell lines was established in nude mice. Totally 32 ovarian cancer nude mice were randomly divided into 4 groups, i.e., the blank control group (Group A), the BJFOE group (Group B), the BJFOE combined Cisplatin group (Group C), and the Cisplatin control group (Group D), 8 in each group. Mice in Group A were intraperitoneally injected with normal saline (0.2 mL/ 20 g), once per two days. Mice in Group B were intraperitoneally injected with BJFOE (0.2 mL/20 g), once per two days. Mice in Group C were intraperitoneally injected with cisplatin (3 mg/kg) 0.2 mL on the first day, and intraperitoneally injected with BJFOE on the second day. Mice in Group D were intraperitoneally injected with cisplatin (3 mg/kg) 0.2 mL, once per two days. All mice were injected for six times, and sacrificed 48 h after the last injection. The lesion formation of the abdominal tumor tissue was observed. Tumor specimens were obtained to perform HE staining. Expression levels of MRP-1/CD9 and integrinα-5 were detected using Western blot. RESULTS: The inhibition of BJFOE was time-dose depend- ently correlated with its inhibition effect of SKOV3 cells. The inhibition effect of BJFOE in combination of cisplatin was significantly superior to that of using any of the two drugs alone. Western blot results showed expression levels of MRP-1/CD9 and integrinα-5 were up-regulated in Group B and Group D with statistical difference (P < 0.05). But they were down-regulated in Group C with statistical difference (P < 0.05). CONCLUSIONS: Intraperitoneal injecting BJFOE was feasible and effective for treating ovarian cancer. BJFOE also could inhibit the invasion and migration of tumor cells targeting at MRP-1/CD9 and integrinα-5. But its specific anti-tumor mechanism was not clearly probed.

Positive peritoneal lavage fluid cytology based on isolation by size of epithelial tumor cells indicates a high risk of peritoneal metastasis.

Background: Peritoneal metastasis (PM) is the most prevalent type of metastasis in patients with gastric cancer (GC) and has an extremely poor prognosis. The detection of free cancer cells (FCCs) in the peritoneal cavity has been demonstrated to be one of the worst prognostic factors for GC. However, there is a lack of sensitive detection methods for FCCs in the peritoneal cavity. This study aimed to use a new peritoneal lavage fluid cytology examination to detect FCCs in patients with GC, and to explore its clinical significance on diagnosing of occult peritoneal metastasis (OPM) and prognosis. Methods: Peritoneal lavage fluid from 50 patients with GC was obtained and processed via the isolation by size of epithelial tumor cells (ISET) method. Immunofluorescence and fluorescence in situ hybridization (FISH) were used to identify FCCs expressing chromosome 8 (CEP8), chromosome 17 (CEP17), and epithelial cell adhesion molecule (EpCAM). Results: Using a combination of the ISET platform and immunofluorescence-FISH, the detection of FCCs was higher than that by light microscopy (24.0% vs. 2.0%). Samples were categorized into positive and negative groups, based on the expressions of CEP8, CEP17, and EpCAM. Statistically significant relationships were demonstrated between age (P = 0.029), sex (P = 0.002), lymphatic invasion (P = 0.001), pTNM stage (P = 0.001), and positivity for FCCs. After adjusting for covariates, patients with positive FCCs had lower progression-free survival than patients with negative FCCs. Conclusion: The ISET platform highly enriched nucleated cells from peritoneal lavage fluid, and indicators comprising EpCAM, CEP8, and CEP17 confirmed the diagnosis of FCCs. As a potential detection method, it offers an opportunity for early intervention of OPM and an extension of patient survival.

Preoperative serum C-reactive protein levels and early breast cancer by BMI and menopausal status.

Serum C-reactive protein (CRP), a sensitive marker of systemic inflammation, has been reported to be associated with the risk of a number of cancers including breast cancer. However, the results are inconsistent. To investigate the association between serum CRP levels and early breast cancer, we conducted a hospital-based case-control study among 506 newly diagnosed breast cancer patients and 506 controls with benign breast diseases matched by age and menopausal status. Odds ratios (ORs) were computed with unconditional logistic regression models, adjusted for major confounding factors. Relative to women with the lowest quartile of CRP level, women with the highest quartile had 1.65-fold increased breast cancer risk (OR: 1.65, 95% CI: 1.12-2.42) in a significant dose-response manner (p(trend) = .011). Stratification analysis revealed a positive association only for overweight postmenopausal women (highest CRP quartile versus lowest CRP quartile: OR: 2.78, 95% CI: 1.18-6.6). Multinominal logistic regression analysis showed that only hormonal receptor (HR) positive and human epidemiological receptor 2 (HER2) negative breast cancers had elevated serum CRP levels. We observed that elevated serum CRP levels are positively associated with early breast cancer, predominantly among overweight and postmenopausal women. This study provided epidemiological evidence that chronic inflammation might mediate the association between obesity and postmenopausal breast cancer. Although a positive association between serum CRP and HR positive/HER2 negative breast cancer is intriguing, further epidemiological studies are needed to confirm such findings.

[Synergistic effect of beta-elemene injection combined paclitaxel injection on human breast cancer MB-468 cells: an in vitro study].

OBJECTIVE: To observe the synergistic effect of beta-elemene Injection (betaI) combined Paclitaxel Injection (PI) on breast cancer MB-468 cells and to study possible mechanisms. METHODS: Breast cancer MB-468 cells were treated with betaI (2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0, and 640.0 microg/mL), PI (0.00100, 0.00200, 0.00400, 0.00800, 0.01600, 0.03125, 0.06250, 0.12500, and 0.25000 microg/mL), and betaI combined PI for 24 h and 48 h respectively. Cell proliferation was determined using SRB assay. Cell apoptosis and cell cycle phase distribution were detected using flow cytometry. The post-intervention expressions of cell cycle proteins [cyclin-dependent kinase (CDK1), cyclin-B1, P21(cip1), and P27(kip1)] were detected by Western blot. RESULTS: Beta-elemene or paclitaxel inhibited the growth of MB-468 cell line. The IC50 and IC20 values treated with beta-elemene for 24 h were 34.20 and 52.59 microg/mL and for 48 h were 10.15 and 17.81 microg/mL respectively, while the IC50 values treated with paclitaxel for 24 h and 48 h were 2.449 and 1.698 microg/mL respectively. Beta-elemene (20 and 40 microg/mL respectively) and Paclitaxel (0.016 and 0.008 microg/mL respectively) synergistically inhibited cell proliferation of MB-468 cells, with Q value > 1.15. Beta-elemene alone (52.59 microg/mL) apparently decreased the expression of cyclin-B1 protein. The expression of cyclin-B1 protein in the combined group was also lower than that in the PI group (1.698 microg/mL). The expression of P27(kip1) was up-regulated when compared with that in the betaI group or the PI group. CONCLUSION: Beta-elemene had synergistic effect with Paclitaxel, and its possible mechanism might be correlated with down-regulating the cell cycle protein cyclin-B1 expression and up-regulating the P27(kip1) expression.

[Efficacy and safety of docetaxol, pemetrexed and EGFR-TKIs as second-line treatment for patients with advanced non-small-cell lung cancer].

OBJECTIVE: To compare the efficacy and safety of docetaxol, pemetrexed and EGFR-TKIs in the second-line treatment for patients with advanced non-small cell lung cancer. METHODS: The clinical data of 170 patients with advanced non-small cell lung cancer who failed standard first-line chemotherapy were reviewed. Those who received docetaxol as second-line therapy were designated as group A (n = 60), those who received pemetrexed as second-line therapy were designated as group B (n = 49), and those who received EGFR-TKIs as second-line therapy were designated as group C (n = 61). PFS and MST were estimated by Kaplan-Meier method and the differences between groups were compared by log-rank test. RESULTS: The response rate in the groups A, B and C group was 15.0% (9/60), 24.5% (12/49) and 36.1% (22/61), respectively. The PFS after second-line therapy in the groups A, B and C was 5.49 months (95%CI: 4.03 - 6.95 months), 5.42 months (95%CI: 4.23 - 6.60 months) and 9.31 months (95%CI: 6.88 - 11.73 months), respectively (P = 0.045). The MST after second-line therapy in the groups A, B and C was 14.89 months (95%CI: 11.23 - 18.55 months), 15.81 months (95%CI: 12.11 - 19.52 months) and 17.47 months (95%CI: 13.38 - 21.56 months), respectively (P = 0.574). Regression analysis showed that the performance status score (PS) and response for second-line treatment are independent prognostic factors in each sub-group, and pathological type is an independent prognostic factor in the group C (P = 0.003). CONCLUSIONS: The safety of the three drugs used as second-line treatment for patients with advanced non-small-cell lung cancer, who failed standard first-line chemotherapy, is comparable, but the EGFR-TKIs group has the highest response rate, and the EGFR-TKIs group has the longest PFS with a statistically significant difference, while there is no significant difference in MST among the three groups. When patients receive second-line treatment, the performance status < 2 and the response rate for second-line treatment are independent prognostic factors. Furthermore, pathological type (adenocarcinoma) is also an independent prognostic factor for EGFR-TKIs as second-line treatment.

[Comparison of the efficacy of second line EGFR TKIs followed by third line pemetrexed or the reverse sequence in the treatment of advanced lung adenocarcinoma].

OBJECTIVE: To compare the efficacy of second-line EGFR-TKIs followed by third-line pemetrexed with second-line pemetrexed followed by third-line EGFR-TKIs in patients with advanced lung adenocarcinoma. METHODS: From March 2007 to August 2008, 83 patients with advanced lung adenocarcinoma who failed standard first-line chemotherapy were included in this study. The patients who received EGFR-TKIs as second-line therapy followed by third-line pemetrexed were designated as group A (n = 45). The patients who received pemetrexed as second-line therapy followed by third-line EGFR-TKIs were designated as group B (n = 38). PFS and MST were estimated with Kaplan-Meier analysis and the difference between groups were compared with Log-rank test. RESULTS: The progression-free survival (PFS) after second-line therapy in the groups A and B was 8.05 months (95% CI, 5.90 to 10.20) and 4.20 months (95% CI, 3.33 to 5.06), respectively (P = 0.001). The PFS after second-line therapy in smokers and non-smokers was 3.69 months (95% CI, 5.00 to 7.59) and 7.12 months (95% CI, 5.51 to 8.38), respectively (P = 0.007). The PFS of male and female patients was 5.56 months (95% CI, 4.02 to 7.10) and 6.85 months (95% CI, 4.98 to 7.58), respectively (P = 0.279). The PFS after third-line therapy in groups A and B was 6.88 months (95% CI, 5.07 to 8.69) and 7.60 months (95% CI, 5.59 to 9.12) respectively, (P = 0.899). The PFS after third-line therapy in smokers and non-smokers was 4.95 months (95% CI, 2.83 to 7.05) and 8.49 months (95% CI, 6.27 to 10.76), respectively (P = 0.050). The PFS after third-line therapy in male and female patients was 5. 96 months (95% CI, 4.02 to 7.91) amd 8.38 months (95% CI, 5.68 to 11.07), respectively (P = 0.176). The MST in groups A and B was 23.60 months (95% CI, 19.23 to 28.00) and 15.58 months (95% CI, 11.85 to 19.32), respectively (P = 0.021). The MST in smokers and non-smokers was 11.99 months (95% CI, 8.55 to 15.49) and 23.18 months (95% CI, 19.33 to 27.02), respectively (P = 0.001). The MST in male and female patients was 17.40 months (95% CI, 13. 19 to 21.61) and 22.74 months (95% CI, 18.29 to 27.19), respectively (P = 0.111). CONCLUSIONS: Second line EGFR TKIs followed by third line pemetrexed regimen improves the PFS and MST compared with the regimen second line pemetrexed followed by third line EGFR TKIs in patients with advanced lung adenocarcinoma. Smoking status is an independent prognostic factor. Survival is not influenced by gender. Prospective clinical trials are needed to confirm these findings.

Efficacy of logistic regression model based on multiparametric ultrasound in assessment of cervical lymphadenopathy - a retrospective study.

OBJECTIVES: To investigate whether a multiparametric ultrasound (MPUS) diagnostic model improves differential diagnosis of benign and malignant cervical lymph nodes. METHODS: MPUS evaluation was performed on 87 lesions in 86 patients, and related characteristics and parameters of the patients and lesions were studied and logistic regression models based on the MPUS characteristics of cervical lymph nodes were built. A receiver operating characteristic curve and area under the curve (AUC) were built for the evaluation of diagnostic performances. RESULTS: Of the 87 lesions in 86 patients, there were 31 benign and 56 malignant lesions. Regression models for Duplex ultrasound and MPUS were established. The Duplex ultrasound regression model showed a sensitivity, specificity, positive predictive value and negative predictive value of 94.4, 61.3, 86.3 and 80.9%, respectively. The predictive accuracy was 82.4%, and the AUC was 0.861. The MPUS regression model showed a sensitivity, specificity, positive predictive value and negative predictive value of 98.1, 61.3, 81.5 and 95.0%, respectively. The predictive accuracy was 84.7%, and the AUC was 0.894. The differences in AUCs between the Duplex ultrasound model and MPUS model, ultrasound model and ultrasonic elastography (UE), and Duplex ultrasound and UE were not significant (all p > 0.05); the differences in AUCs between the MPUS model and Duplex ultrasound, Duplex ultrasound model and Duplex ultrasound, and MPUS model and UE were significant (all p < 0.05). CONCLUSIONS: The Duplex ultrasound and MPUS models achieve significantly higher diagnostic performance for differentiating between benign and malignant cervical lymph nodes.

Cold atmospheric plasmas target breast cancer stemness via modulating AQP3-19Y mediated AQP3-5K and FOXO1 K48-ubiquitination.

Cold atmospheric plasma (CAP) is selective against many cancers with little side effect, yet its molecular mechanism remains unclear. Through whole transcriptome sequencing followed by assays in vitro, in vivo and using clinical samples, we propose CAP as a promising onco-therapy targeting cancer stemness via the AQP3/FOXO1 axis. CAP-generated reactive species penetrated cells via AQP3 and suppressed RPS6KA3, a shared kinase of AQP3 and FOXO1. Reduced AQP3-19Y phosphorylation suppressed SCAF11-mediated AQP3-5K K48-ubiquitination that led to sabotaged FOXO1 stability. Inhibited FOXO1 phosphorylation retarded its regulatory activities in maintaining cancer stemness including ALDH1 and IL6. Enhanced anti-cancer efficacy was observed through combining CAP with Atorvastatin in vitro and in vivo. We propose CAP as a 'selective' onco-therapeutic against cancer stemness, with the AQP3/FOXO1 axis being one molecular mechanism. We report SCAF11 as an E3 ubiquitin ligase of both AQP3 and FOXO1, identify AQP3-5K as an AQP3 K48-ubiquitination site, and emphasize the essential role of AQP3-19Y in this process. We reposition Atorvastatin into the onco-therapeutic portfolio by synergizing it with CAP towards enhanced efficacy. We anticipate the efficacy of CAP in targeting malignancies of high stemness alone or as an adjuvant therapy towards the hope of ultimate cancer cure.

Treatment with pyrotinib-based therapy in lapatinib-resistant HER2-positive metastatic breast cancer: a multicenter real-world study.

Background: Tyrosine kinase inhibitors (TKIs) are effective for treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, therapies subsequent to TKI progression remain controversial, and effective treatments for TKI resistance are urgently needed. We evaluate the practice of exchange of TKIs, which involves treatment with a different TKI following prior TKI failure. Specifically, this study investigated the efficacy of pyrotinib-based therapy in lapatinib-resistant HER2-positive metastatic breast cancer (NCT04899128). Methods: This real-world study included 76 patients diagnosed with HER2-positive metastatic breast cancer who received pyrotinib-based therapy after lapatinib progression at four Chinese institutions between August 2018 and March 2020. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and toxicity profiles were reported. Results: All patients received pyrotinib-based therapy in two or later line therapy. The median PFS was 8.0 months (95% CI 5.1-10.9). OS has not reached. The ORR and CBR were 17.1% and 60.5%, respectively. The median PFS was 7.1 months (95% CI 5.633-8.567) and intracranial ORR was 42.9% in patients who had brain metastasis (n = 14). Patients who benefited from lapatinib ⩾ 6.0 months prior exhibited a longer PFS (10.6 versus 6.0 months, p = 0.034, stratified hazard ratio (HR) 0.534, 95% CI 0.293-0.975). The most common adverse effects were diarrhea (n = 34, 44.7%) and hand-foot syndrome (n = 10, 13.2%). Conclusion: Pyrotinib-based therapy has the potential to improve survival in patients with lapatinib-resistant HER2-positive metastatic breast cancer, including those with brain metastases. Pyrotinib could provide a clinically significant increase in PFS for patients who benefited from prior lapatinib.

Three vascular endothelial growth factor polymorphisms (-460C>T, -2578C>A, 1612G>A) with cancer risk: a meta-analysis based on 30 case-control studies.

We evaluated cancer risk with three VEGF polymorphisms (-460C>T, -2578C>A, 1612G>A) based on current available studies. -460C>T did not appear to influence cancer risks. -2578C carriers had a 30% reduction of colorectal cancer (CRC) risk in comparison with AA homozygote (OR: 0.70, CI: 0.56-0.88). 1612G carriers had a striking 84% reduction of gastric cancer risk in comparison with AA homozygote. Multiple pair-wise comparisons suggested a recessive role for both -2578A and 1612A risk allele. Further studies with larger samples, well-matched controls and homogenous ethnic background are warranted to confirm these findings. We recommend more efforts into the investigation of 1612G>A with cancer risks.

High CTC-TRPC5 Expression Significantly Associated With Poor Prognosis in Radical Resected Colorectal Cancer Patients.

Recurrence is the main reason of treatment failure of redical resected colorectal cancer (CRC). Although some factors including staging and differentiation have been proven to useful for recurrence evaluation, prognosis of certain patients does not conform to this evaluation approach. Circulating tumor cells (CTC) have been found to have prognostic value in CRC, and previous studies on CTC have primarily focused on their numbers. CTC are functionally heterogeneous cell populations, and different CTC subgroups may have different functions and clinical values. In our previous study, we discovered that elevated expression of the transient receptor potential channel TRPC5 was associated with a significantly poor prognosis in CRC. In this study, we collected peripheral blood from CTC-positive CRC patients, identified the TRPC5 protein expression on CTC (CTC-TRPC5), and analyzed the relationship between CTC-TRPC5 expression levels and the prognosis. The results showed that CTC-TRPC5 level is significantly related to the T stage and differentiation of tumors. High level of CTC-TRPC5 is more common in a high T stage as well as poorly differentiated tumors and is significantly associated with shorter disease free survival (DFS). The median DFS of CRC patients with high and low CTC-TRPC5 level was 17.1 and 22.0 months, respectively (p < 0.05). This study revealed a clinically significant CTC subgroup of CRC, providing a new indicator for clinical evaluation of CRC prognosis.

Cold atmospheric plasma selectively induces G0/G1 cell cycle arrest and apoptosis in AR-independent prostate cancer cells.

Purpose: Androgen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies. Materials and Methods: We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers via cell viability, transwell assay, wound healing, cell apoptosis assay, flow cytometry, intracellular hydrogen peroxide determination assay, RONS scavenger assay and western blot using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells. Results: We show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. Conclusion: Our study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

Validity of measurements of testicular volume obtained by a built-in software of ultrasound systems: with formula recommended by updated guidelines as reference.

Aim: To investigate the validity of measurement of testicular volume acquired by a built-in software in different ultrasound systems with reference to the updated guidelines. Materials and methods: Archives of 1,976 patients who had undergone scrotal ultrasound evaluation were reviewed. A total of 973 patients with 1,909 testes, who had undergone ultrasound measurement of the testicular volume, were included in the study, and 1,003 patients were excluded. The age of enrolled patients ranged from 17 to 66 years (median age of 39 years). The ultrasound systems included Siemens Sonoline S2000, Philips EPIQ5, GE Logiq E9, Hitachi Aloka prosoundα7, Mindray DC-8 and Mindray Resona7. The transducers have imaging frequencies of 5-14 MHz. Validity of the measurement of testicular volume acquired by a built-in software in different ultrasound systems was assessed with reference to the formula that Volume (V) = Length (L) × Width (W) × Height (H) × 0.71, recommended by the updated guidelines, by recalculating the original numbers using a calculator. Results: The values obtained by the built-in software of Mindray DC-8 and Mindray Resona7 ultrasound systems and measurements recalculated on a computer were all in concordance; and the values obtained by the built-in software of Siemens Sonoline S2000, Philips EPIQ5, GE Logiq E9, and Hitachi Aloka prosoundα7 ultrasound systems and measurements recalculated on computer were all discordant. The same testicular measurements calculated with different formulas (V = L×W×H×0.71 vs. V = L×W×H×0.52) produced 26.76% difference. Conclusion: Values of testicular volume obtained by some ultrasound systems are not accurate with reference to the formula recommended by the updated guidelines.