Knowledge, attitudes, and practices of human papillomavirus and self-sampling among adult women: a cross-sectional study.

Background: This study aimed to investigate the knowledge, attitude, and practice (KAP) of human papillomavirus (HPV) and self-sampling among adult women. Methods: The cross-sectional, questionnaire-based study included adult women at Shanghai Pudong Hospital from October 14, 2022, to March 31, 2023. The questionnaire contained demographic information, knowledge, attitude and practice dimensions. Factors associated with KAP and self-sampling were identified by multivariate logistic regression. Results: A total of 1843 valid questionnaires were collected. The average knowledge, attitude, and practice score was 10.09 ± 5.60, 26.76 ± 3.80, and 6.24 ± 2.20, respectively. Urban residents (estimate = 0.705, p < 0.001), suburban residents (estimate = 0.512, p < 0.001), as well as individuals with undergraduate degrees and higher (estimate = 0.535, p < 0.001), were associated with good knowledge, while individuals lacking a history of HPV infection (estimate = -0.461, p < 0.001) and married individuals (estimate = -0.185, p < 0.001) were less likely to have good knowledge. Higher knowledge scores (estimate = 0.087, p < 0.001) and individuals with undergraduate education and above (estimate = 1.570, p < 0.001) were associated with a positive attitude. Being married (estimate = 0.291, p = 0.049) was associated with good practice, whereas not engaging in sexual activity (estimate = -0.959, p < 0.001) or lacking a history of HPV infection (estimate = -0.499, p = 0.011) were associated with unfavorable practices. Minorities (OR = 2.787, p = 0.038) and individuals with multiple sexual partners (OR = 2.297 for two partners, OR = 2.767 for three or more partners, p = 0.020 and p = 0.022) were positively associated with self-sampling. However, higher knowledge (OR = 0.952, p = 0.026) and attitude scores (OR = 0.929, p = 0.015) were negatively associated with self-sampling. Conclusion: Demographic and behavioral factors significantly influenced KAP scores and self-sampling behaviors regarding HPV. Urban residency, higher education levels, positive attitudes, and minority status correlated with favorable outcomes, while factors like marriage and lack of sexual activity were associated with less favorable practices.

Influence of initial check, information exchange, final accuracy check, reaction information nursing on the psychology of elderly with lung cancer.

BACKGROUND: As one of the fatal diseases with high incidence, lung cancer has seriously endangered public health and safety. Elderly patients usually have poor self-care and are more likely to show a series of psychological problems. AIM: To investigate the effectiveness of the initial check, information exchange, final accuracy check, reaction (IIFAR) information care model on the mental health status of elderly patients with lung cancer. METHODS: This study is a single-centre study. We randomly recruited 60 elderly patients with lung cancer who attended our hospital from January 2021 to January 2022. These elderly patients with lung cancer were randomly divided into two groups, with the control group taking the conventional propaganda and education and the observation group taking the IIFAR information care model based on the conventional care protocol. The differences in psychological distress, anxiety and depression, life quality, fatigue, and the locus of control in psychology were compared between these two groups, and the causes of psychological distress were analyzed. RESULTS: After the intervention, Distress Thermometer, Hospital Anxiety and Depression Scale (HADS) for anxiety and the HADS for depression, Revised Piper's Fatigue Scale, and Chance Health Locus of Control scores were lower in the observation group compared to the pre-intervention period in the same group and were significantly lower in the observation group compared to those of the control group (P < 0.05). After the intervention, Quality of Life Questionnaire Core 30 (QLQ-C30), Internal Health Locus of Control, and Powerful Others Health Locus of Control scores were significantly higher in the observation and the control groups compared to the pre-intervention period in their same group, and QLQ-C30 scores were significantly higher in the observation group compared to those of the control group (P < 0.05). CONCLUSION: The IIFAR information care model can help elderly patients with lung cancer by reducing their anxiety and depression, psychological distress, and fatigue, improving their tendencies on the locus of control in psychology, and enhancing their life qualities.

Chemical Composition and Antibacterial and Antiulcerative Colitis Activities of Essential Oil from Pruni Semen.

This study was sought to investigate the chemical composition and antibacterial and antiulcerative colitis (UC) effects of essential oil from Pruni Semen (PSEO). A GC-MS assay showed that the major compounds in PSEO were products of amygdalin hydrolysis, which possessed great antibacterial and anti-inflammatory potential. In vitro antibacterial experiments demonstrated that PSEO treatment inhibited activity of four kinds of intestinal pathogens probably by disrupting the cell wall. Further in vivo studies showed that PSEO administration significantly improved physiological indexes, attenuated histopathological characteristics, and inhibited proinflammatory cytokine production in dextran sulfate sodium (DSS)-induced UC mice. Network pharmacology and molecular docking results predicted that PSEO might prevent UC via regulating the PI3K/AKT pathway. Western blotting and immunofluorescence assays were further conducted for verification, and the results evidenced that PSEO intervention significantly regulated the PI3K/AKT pathway and the expression of its downstream proteins in DSS-induced mice. PSEO might provide a new dietary strategy for UC treatment.

Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment.

Several studies have demonstrated the role of the oncogenic mutant p53 in promoting tumor progression; however, there is limited information on the effects of secreted oncogenic mutant p53 on the tumor microenvironment and tumor immune escape. In this study, we found that secretion of mutant p53, determined by exosome content, is dependent on its N-terminal dileucine motif via its binding to ß-adaptin, and inhibited by the CHK2-mediated-Ser 20 phosphorylation. Moreover, we observed that the mutant p53 caused downregulation and dysfunction of CD4+ T lymphocytes in vivo and downregulated the levels and activities of rate-limiting glycolytic enzymes in vitro. Furthermore, inhibition of mutant p53 secretion by knocking down AP1B1 or mutation of dileucine motif could reverse the quantity and function of CD4+ T lymphocytes and restrain the tumor growth. Our study demonstrates that the tumor-derived exosome-mediated secretion of oncogenic mutant p53 inhibits glycolysis to alter the immune microenvironment via functional suppression of CD4+ T cells, which may be the underlying mechanism for tumor immune escape. Therefore, targeting TDE-mediated p53 secretion may serve as a potential therapeutic target for cancer treatment.

A randomized, controlled trial to investigate cognitive behavioral therapy in prevention and treatment of acute oral mucositis in patients with locoregional advanced nasopharyngeal carcinoma undergoing chemoradiotherapy.

Purpose: Oral mucositis is a common side effect of concurrent chemoradiotherapy (CCRT). This study aimed to determine whether cognitive behavioral therapy (CBT) could help prevent oral mucositis during chemoradiation therapy for locoregional advanced nasopharyngeal carcinoma (LA-NPC). Methods and materials: Between July 15, 2020, and January 31, 2022, a randomized controlled phase II trial was conducted. Eligible patients (N=282, 18-70 years old) with pathologically diagnosed LA-NPC were randomly assigned to receive CBT or treatment as usual (TAU) during CCRT (computer-block randomization, 1:1). The primary endpoints were the incidence and latency of oral mucositis. Results: The incidence of oral mucositis was significantly lower in the CBT group (84.8%; 95% confidence interval [CI], 78.7%-90.9%) than in the TAU group (98.6%; 95% CI, 96.6%-100%; P<0.001). The median latency period was 26 days and 15 days in the CBT and TAU groups, respectively (hazard ratio, 0.16; 95% CI, 0.12-0.22; P<0.001). CBT significantly reduced ≥ grade 3 oral mucositis (71.9% vs. 22.5%, P<0.001), dry mouth (10.8% vs. 3.7%, P=0.021), dysphagia (18% vs. 5.1%, P=0.001), and oral pain (10% vs. 3.6%, P=0.034) compared with TAU. Patients receiving CBT and TAU during CCRT had similar short-term response rates. Conclusions: CBT reduced the occurrence, latency, and severity of oral mucositis in patients with LA-NPC during CCRT.

Herpesvirus entry mediator regulates the transduction of Tregs via STAT5/Foxp3 signaling pathway in ovarian cancer cells.

The ratio of regulatory T cells (Treg) in peripheral blood of cancer patients has a closely correlation to the occurrence and development of ovarian cancer. In this study, our aim to explore the expression of herpesvirus entry mediator (HVEM) in ovarian cancer and its correlation with Tregs. The expression of HVEM in peripheral blood of ovarian cancer patients was detected by ELISA, and the ratio of CD4+ CD25 + Foxp3 positive Tregs cells was detected by flow cytometry. Ovarian cancer cell lines with high- and low-HVEM expression were constructed. CD4+ cells were co-cultured with ovarian cancer (OC) cells, and the expressions of IL-2 and TGF-ß1 in the supernatant of cells were detected by ELISA, and western blot was used to detect the expressions of STAT5, p-STAT5, and Foxp3. The results indicated that the number of Treg cells in the peripheral blood of OC patients increased, and the expression of HVEM increased, the two have a certain correlation. At the same time, the overexpression of HVEM promoted the expression of cytokines IL-2 and TGF- ß1, promoted the activation of STAT5 and the expression of Foxp3, leading to an increase in the positive rate of Treg, while the HVEM gene silence group was just the opposite. Our results showed that the expression of HVEM in OC cells has a positive regulation effect on Tregs through the STAT5/Foxp3 signaling pathway. To provide experimental basis and related mechanism for the clinical treatment of ovarian cancer.

Network pharmacology, molecular docking and in vivo and in vitro experiments to explore the molecular mechanism of licorice green tea beverage to scavenge oxygen free radicals.

Excessive oxygen free radicals can lead to aging, cancer, and other diseases. Therefore, searching for effective antioxidants to scavenge oxygen free radicals has become the focus of modern medicine. In this study, the molecular mechanism of Licorice Green Tea Beverage (LGTB) in scavenging oxygen free radicals was investigated by means of network pharmacology, molecular docking and experimental verification. Network pharmacology studies have shown that paeonol, eugenol, cinnamaldehyde, swertisin, rutin, glycyrrhetinic acid, oleic, pelargonidin-3-O-glucoside and quercetin, kaferempol were the main active components of LGTB, and SOD and CAT are important targets for LGTB in scavenging oxygen free radicals. The results of molecular docking showed that these representative compounds had good affinity to SOD and CAT target proteins. In vitro free radical scavenging experiments showed that LTGB had significant scavenging effects on both DPPH and ABTS radicals, and had strong total reducing power. In vitro cell experiments showed that LGTB could protect HaCaT cells from oxidative stress induced by H2 O2 . The mechanism of LGTB was related to the increase of SOD and CAT activity. Western blotting showed that LGTB could inhibit PI3K/AKT/HIF-1 signaling pathway and improve the antioxidant capacity of HaCaT cells. In vivo experiments showed that LGTB could significantly increase mouse visceral index, increase serum SOD and GSH-Px activity, decrease the content of MDA, and improve liver and kidney pathological state. This study reported the molecular mechanism of LTGB scavenging oxygen free radicals, which provided scientific basis for the treatment and clinical research of aging and other diseases caused by excessive free radicals. PRACTICAL APPLICATIONS: Free radicals are produced by the normal response of cells during aerobic respiration and perform various functions, such as signaling and providing protection against infection. However, excessive free radicals can lead to aging, cancer, and other diseases. The antioxidant can overcome the harm caused by excessive free radicals. In this study, we investigated the molecular mechanism of scavenging oxygen free radicals of Licorice Green Tea Beverage (LGTB) through network pharmacology and molecular docking, and its efficacy was verified by free radical scavenging experiment in vitro, HaCaT cell oxidative stress injury induced by H2 O2 , D-galactose to establish an aging model in mice and Western blotting experiment. It not only elucidates its mechanism at the system level, but also proves its validity at the biological level. It provides the theoretical basis and experimental evidence for the follow-up research and promotion of the product.

Predictive and Prognostic Role of Peripheral Blood T-Cell Subsets in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), as a highly aggressive and metastatic tumor, can still not contain the medical needs. It has become an urgent problem to develop prognostic markers further and realize precision medicine. The predictive and prognostic significance of peripheral blood lymphocytes, as well as the clinicopathological factors affecting them, were explored in the present study. METHODS: The clinicopathological data of 278 patients with TNBC were collected and analyzed retrospectively. Peripheral blood lymphocytes (pBL) and blood routine indexes before treatment were quantified by flow cytometry analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier curve and Cox hazard proportion regression model. The associations between hematologic parameters and treatment response and clinicopathological characteristics were estimated by the Mann-Whitney test and Spearman test. RESULTS: Compared with all blood routine indexes, only a significant correlation between better treatment efficacy and higher peripheral CD4 +/CD8 + ratio of TNBC patients was observed (P=0.059), particularly those treated with chemotherapy combined with immune checkpoint inhibitors (P=0.048). Among the pBL subsets, CD4 + T lymphocyte was the only independent factor that could predict the prognosis of metastatic TNBC. Patients presenting higher values of peripheral CD4 + T lymphocytes showed longer PFS (median PFS 9 months vs. 5 months; HR =0.65, 95%CI: 0.440-0.973, P = 0.032) and OS (median OS 31 months vs. 16 months; HR=0 .63, 95%CI: 0.417-0.940, P< 0.01). Especially CD4+ was found predictive for prognosis in TNBC patients who received chemotherapy (P<0.05). Finally, the older age, higher clinical stage, and more advanced treatment lines were related to the lower level of CD4 +. The older age and having received neoadjuvant therapy were related to the lower CD4 +/CD8 + ratio (P<0.05). CONCLUSION: The baseline CD4+/CD8+ cell ratio in peripheral blood is associated with therapeutic response, especially for chemotherapy combined with immunotherapy. Peripheral CD4+ cells can steadily predict all clinical outcomes for patients with mTNBC, and this clinical prognosis prediction is significantly related to chemotherapy. Peripheral CD4+ and CD4+/CD8+ are both closely associated with clinicopathological parameters.

General anaesthetics reduce acute lymphoblastic leukaemia malignancies in vitro and in vivovia CXCR4 and osteopontin mediated mechanisms.

Background: Acute lymphoblastic leukaemia (ALL) is a common type of cancer in children. General anaesthetics are often used on patients undergoing painful procedures during ALL treatments but their effects on ALL malignancy remain unknown. Herein, we aim to study the effect of propofol and sevoflurane on the migration, homing and chemoresistance of ALL cells. Methods: NALM-6 and Reh cells were treated with propofol (5 and 10 µg/ml) or sevoflurane (3.6%) in vitro for six hours. Then, cells were harvested for adhesion assay and migration assay in vitro. In in vivo experiments, GFP-NALM-6 cells were pre-treated with propofol (10 µg/ml) or sevoflurane (3.6%) for six hours. Then, cells were injected intravenously to C57BL/6 female mice followed by intravital microscopy. For chemoresistance study, cells were treated with rising concentrations of Ara-c (0.05-50 nM) plus 10µg/ml of propofol or Ara-C plus 3.6% of sevoflurane for 4 hours, followed by the assessment of cell viability via CCK-8 assay and detection of autophagy via flow cytometry. Results: Both anaesthetics reduced in vivo migration and in vivo homing as exemplified by 1) the reduction in the number of cells entering the bone marrow and 2) the disturbance in homing location in relation to endosteal surface. Our results indicated that general anaesthetics reduced the surface CXCR4 expression and the adhesion of leukaemia cells to thrombin cleaved osteopontin (OPN) was reduced. Those changes might result in the alterations in migration and homing. In addition, both anaesthetics sensitised ALL cells to Ara-c possibly through CXCR4 mediated mechanisms. Propofol but not sevoflurane enhanced chemo-related cell death via inducing cytotoxic autophagy. Conclusion: Together, our data suggest that both propofol and sevoflurane could reduce ALL migration, and homing in vivo and in vitro via CXCR4 and OPN mediated mechanisms. Both anaesthetics could sensitise ALL cells to chemotherapy possibly via CXCR4 mediated mechanisms.

Primary pancreatic paraganglioma harboring lymph node metastasis: A case report.

BACKGROUND: Primary pancreatic paragangliomas are extremely rare tumors. Limited by the diagnostic efficacy of histopathological examination, their malignant behavior is thought to be associated with local invasion or metastasis, with only four malignant cases reported in the literature to date. As pancreatic paragangliomas share similar imaging features with other types of pancreatic neuroendocrine neoplasms, they are difficult to diagnose accurately without the support of pathological evidence. As primary pancreatic paragangliomas are rare, especially those accompanied by lymph node metastasis, there is currently no consensus on treatment. Herein, we report a case of primary pancreatic paraganglioma with lymph node metastasis. CASE SUMMARY: A mass located in the pancreatic body was incidentally discovered on computed tomography in a 41-year-old Tibetan man. Distal pancreatectomy was subsequently performed and a 4.1 cm × 4.2 cm tumor was found embedded in the body of the pancreas during surgery. Histological examination confirmed the characteristics of paraganglioma in which the neoplastic chief cells were arranged in a classic Zellballen pattern under hematoxylin-eosin staining. Further, immunohistochemistry demonstrated that the sustentacular cells in the tumor tissue were positive for S-100 protein, and neoplastic cells and pancreatic draining lymph nodes were positive for chromogranin A and synaptophysin; thus, the presence of lymph node metastasis (two of the eight resected pancreatic draining lymph nodes) was also confirmed. A diagnosis of primary pancreatic paraganglioma with lymph node metastasis was finally established. The patient remained disease-free for 1 year after the surgery. CONCLUSION: A definite diagnosis of pancreatic paraganglioma mainly depends on postoperative histopathological and immunohistochemical examinations. Surgical resection may be the first treatment of choice for patients with primary pancreatic paraganglioma that has metastasized to the lymph nodes.

Lanatoside C inhibits human cervical cancer cell proliferation and induces cell apoptosis by a reduction of the JAK2/STAT6/SOCS2 signaling pathway.

Cervical cancer is one of the leading causes of cancer-associated mortality in gynecological diseases and ranks third among female cancers worldwide. Although early detection and vaccination have reduced incidence rates, cancer recurrence and metastasis lead to high mortality due to the lack of effective medicines. The present study aimed to identify novel drug candidates to treat cervical cancer. In the present study, lanatoside C, an FDA-approved cardiac glycoside used for the treatment of heart failure, was demonstrated to have anti-proliferative and cytotoxic effects on cervical cancer cells, with abrogation of cell migration in a dose-dependent manner. Lanatoside C also triggered cell apoptosis by enhancing reactive oxygen species production and reducing the mitochondrial membrane potential, which induced cell cycle arrest at the S and G2/M phases. Furthermore, lanatoside C inhibited the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 6 (STAT6), while inducing the expression of suppressor of cytokine signaling 2, a negative regulator of JAK2-STAT6 signaling. Taken together, the results of the present study suggest that lanatoside C suppresses cell proliferation and induces cell apoptosis by inhibiting JAK2-STAT6 signaling, indicating that lanatoside C is a promising agent for the treatment of cervical cancer.

Four new dammarane triterpenoid glycosides from the leaves of Cyclocarya paliurus and their SIRT1 activation activities.

Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides SV (1-4), along with nine known dammarane triterpenoid glycosides (5-13) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC50 of 10 µM and 20 µM, respectively.

Gypenoside LVI improves hepatic LDL uptake by decreasing PCSK9 and upregulating LDLR expression.

BACKGROUNDS: Atherosclerotic Cardiovascular Disease (ASCVD) is defined as ischemic or endothelial dysfunction-various inflammatory diseases, which is mainly caused by excessive low-density lipoprotein cholesterol (LDL-C) in circulating blood. Gynostemma pentaphyllum is a traditional Chinese medicine, and total Gypenosides are used for the treatment of hyperlipidemia and to reduce circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) level. However, which gypenoside involved in the modulation of PCSK9 expression is still unknown. PURPOSE: This study aimed to discover effective PCSK9 inhibitors from Gypenosides in accordance with the 2019 ESC/EAS guidelines. METHODS: HPLC was employed to determine major six components of Gypenosides. The inhibitory activity on secreted PCSK9 in HepG2 of six major compounds from Gypenosides were screened by ELISA. The level of low-density lipoprotein (LDL) receptor (LDLR) was determined by Flow cytometry and Immunofluorescence. The expression levels of PCSK9, LDLR and Sterol-regulatory element binding proteins-2 (SREBP-2) were analyzed by qPCR and Western blot. DiI-LDL was added to evaluated LDL uptake into HepG2. RESULTS: The results suggested that the mRNA and protein levels of PCSK9 were down-regulated by Gypenoside LVI and the LDLR degradation in lysosomes system was inhibited, thereby leading to an increasing in LDL uptake into HepG2 cells. Furthermore, Gypenoside LVI decreased PCSK9 expression induced by stains. Altogether, Gypenoside LVI enhances LDL uptake into HepG2 cells by increased LDLR level on cell-surface and suppressed PCSK9 expression. CONCLUSION: This indicates that Gypenoside LVI can be used as a useful supplement for statins in the treatment of hypercholesterolemia. This is firstly reported that monomeric compound of G. pentaphyllum planted in Hunan province has the effect of increasing LDL-C uptake in hepatocytes via inhibiting PCSK9 expression.

Activation of PsMYB10.2 Transcription Causes Anthocyanin Accumulation in Flesh of the Red-Fleshed Mutant of 'Sanyueli' (Prunus salicina Lindl.).

Plum is one of the most important stone fruits in the world and anthocyanin-rich plums are increasingly popular due to their health-promoting potential. In this study, we investigated the mechanisms of anthocyanin accumulation in the flesh of the red-fleshed mutant of the yellow-fleshed plum 'Sanyueli'. RNA-Seq and qRT-PCR showed that anthocyanin biosynthetic genes and the transcription factor PsMYB10.2 were upregulated in the flesh of the mutant. Functional testing in tobacco leaves indicated that PsMYB10.2 was an anthocyanin pathway activator and can activate the promoter of the anthocyanin biosynthetic genes PsUFGT and PsGST. The role of PsMYB10.2 in anthocyanin accumulation in the flesh of plum was further confirmed by virus-induced gene silencing. These results provide information for further elucidating the underlying mechanisms of anthocyanin accumulation in the flesh of plum and for the breeding of new red-fleshed plum cultivars.

Insulin reverses choriocarcinoma 5- fluorouracil resistance.

Choriocarcinoma (CC) is a gestational trophoblastic tumor secondary to a gravid or non-gravid pregnancy. It is characterized by rapid growth, high invasion, and high metastatic potential and chemotherapy resistance that significantly affect survival rate of CC patients. Insulin is implicated in alleviation of chemotherapy resistance in CC. However, the mechanism of reversing resistance in CC has not been explored. Our purpose was to explore insulin effect on 5-fluorouracil (5-FU) resistance in CC and elucidate its potential mechanism in vitro and in vivo. CKK-8, colony formation, Transwell, and flow cytometry were used to detect the effect of insulin on 5-FU resistance in CC cells JEG-3 and JARS. Xenograft mice were used to evaluate the effect of insulin on 5-FU resistance. Results showed that insulin combined with 5-FU suppressed cell viability by 30% in JEG-3 and 43% in JAR compared with 5-FU alone in 72 h. What's more, insulin combined with 5-FU promoted cell apoptosis, inhibited cell proliferation, migration, and phosphorylation of survivin at residue threonine 34 (Thr34) and drug resistance-related proteins, P-GP and MRP1 levels (p < 0.05). In vivo experiment showed Insulin combined with 5-FU suppressed tumor volume by 35% compared with 5-FU alone and 73% compared with control in CC xenograft mice. In summary, the findings of this study show that insulin reversed chemoresistance of CC cells to 5-FU by inhibiting phosphorylation of survivin. Development of a therapeutic strategy that combines insulin with the chemotherapeutic agent 5-FU has a great potential in improving survival of CC patients.

Ganglioside Monosialic Acid Alleviates Peripheral Neuropathy Induced by Utidelone Plus Capecitabine in Metastatic Breast Cancer From a Phase III Clinical Trial.

PURPOSE: This study aimed to assess the efficacy of utidelone, a novel genetically engineered epothilone analog, combined with capecitabine in our center and, furthermore, to identify whether ganglioside monosialic acid (GM1) improved chemotherapy-induced peripheral neurotoxicity (CIPN). METHODS: Fifty-five eligible female patients with metastatic breast cancer were enrolled in our single-center phase III BG01-1323L trial. Utidelone combined with capecitabine-induced peripheral neuropathy was analyzed, and susceptible genes were detected in a germline panel by next-generation sequencing (NGS). RESULTS: In our single-center study, median progression-free survival and overall survival (OS) improved in the utidelone plus capecitabine group (mPFS: 238 vs. 189 days, P = 0.263; OS: 20.9 vs. 12.9 months, P = 0.326). The median time to severe CIPN reported was 29 days in grade 1, 49 days in grade 2, and 103 days in grade 3. Greatly longer improvement time was indicated in grade 1 (77 vs. 20 days in grade 2, 13 days in grade 3). In the combined group, 19 patients with G2 or G3 CIPN were assigned to the GM1 group and 9 patients to the control group. After intervention, the GM1 group was reported to demonstrate a statistically lower incidence of grade 3 CIPN [GM1 group: 1 of 19 (5.3%); control group: 4 of 9 (44.4%), P = 0.026]. However, there were no statistically significant differences in germline single nucleotide polymorphism (SNP) between grade 3 and grade 1 CIPN cohorts. CONCLUSION: Ganglioside monosialic acid potentially decreases severe utidelone plus capecitabine-induced peripheral neuropathy in metastatic breast cancer, and further investigation is needed to validate the manageable efficacy of GM1 in CIPN. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02253459.

The NAD-dependent deacetylase SIRT2 regulates T cell differentiation involved in tumor immune response.

Sirtuin 2 (SIRT2), an NAD+-dependent deacetylase, regulates multiple biologic and pathologic processes including mitosis, genomic integrity, cell homeostasis and tumorigenesis. However, the role of SIRT2 in the immune response to cancer remains largely elusive. In this study, we found significantly lower expression of SIRT2 in peripheral T lymphocytes from breast cancer patients when compared to normal individuals. Moreover, SIRT2 levels positively correlated with CD8+ effector memory T (TEM) cells in breast cancer patients. In keeping with these findings, altered T cells differentiation manifested as decreased TEM cells and increased naive T cells were observed in Sirt2 deficient mice. The upregulation of CD8+ TEM by SIRT2 might attribute to the activation of aerobic oxidation as well as the inhibition of GSK3ß acetylation in CD8+ T cells. Taken together, these results suggest that SIRT2 participate in tumor immune response by regulating T cell differentiation, which may provide novel insight for tumor prevention and immune therapy.

Combined use of apatinib mesylate and vinorelbine versus vinorelbine alone in recurrent or metastatic triple-negative breast cancer: study protocol for a randomized controlled clinical trial.

BACKGROUND: The emergence of new molecular targeted drugs provides new prospects for the treatment of advanced breast cancer; the future therapeutic trend includes chemotherapy combined with molecular targeted therapy. Apatinib mesylate, a novel, small anti-angiogenic agent, highly selectively inhibits the activity of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib mesylate also blocks the signaling of vascular endothelial growth factor binding to its receptor, thereby strongly inhibiting tumor angiogenesis and exerting an anti-tumor effect. However, there have been no reports of a randomized controlled clinical trial of apatinib combined with vinorelbine for the treatment of triple-negative breast cancer (TNBC). We will compare the therapeutic effect of vinorelbine alone or in combination with apatinib mesylate, in patients with recurrent or metastatic TNBC in North China who have received at least two drug treatments, including anthracyclines and taxanes. METHODS/ANALYSIS: This study is a triple-blind, randomized, placebo-controlled, parallel-group clinical trial. We plan to include 238 female patients with locally recurrent or metastatic TNBC, admitted to the Liaoning Cancer Hospital & Institute, Northeast China. All enrolled patients will be randomized to oral vinorelbine alone (40 mg, thrice a week (Mondays, Wednesdays, and Fridays) in each 3-week cycle), or in combination with oral apatinib mesylate (500 mg, once daily in each 3-week cycle). Radiographic assessment will be performed every 6 weeks for 36 weeks and every 9 weeks thereafter. The primary outcome is progression-free survival and secondary outcomes include overall survival, disease control rate, objective response rate, and incidence of adverse events at grades 3 and 4, as defined by the National Cancer Institute Common Toxicity Criteria Version 4.0. Outcome measures will be evaluated at baseline (< 2 weeks before starting treatment), every 6 weeks during treatment, and at 4 weeks and every 3 months after treatment discontinuation. DISCUSSION: Based on the data from this trial, we hope to identify a treatment plan that is suitable for female patients with TNBC, who have been treated with anthracyclines and taxanes, in Northeast China. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03932526. Registered on 30 April 2019.

Synthesis and biological evaluation of novel pyrazolo[3,4-b]pyridines as cis-restricted combretastatin A-4 analogues.

Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effectagainst four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent tubulin inhibitors as anticancer agents.

Triterpenic acids-enriched fraction from Cyclocarya paliurus attenuates insulin resistance and hepatic steatosis via PI3K/Akt/GSK3ß pathway.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver diseases. Cyclocarya paliurus (C. paliurus), an edible and medicinal plant in Chinese folk, has been demonstrated to ameliorate diabetes, obesity and lipid metabolism disorders. However, its effects on NAFLD and its potential molecular mechanism have not been clearly expounded. PURPOSE: The present study was designed to explore the therapeutic potential of triterpenic acids-enriched fraction from C. paliurus (CPT), as well as its underlying mechanism in vivo and in vitro models of NAFLD. METHODS: The metabolic effects and possible molecular mechanism of CPT were examined using HepG2 cells and primary hepatocytes (isolated from C57BL/6 J mice) models of fatty liver induced by palmitic acid (PA) and a high fat diet mouse model. RESULTS: In high fat diet-induced C57BL/6 J mice, CPT significantly reduced liver weight index, serum alanine transaminase (ALT), aspartate transaminase (AST), triacylglycerol (TG), total cholesterol (TC) and hepatic TG, TC levels. Moreover, CPT dramatically decreased the contents of blood glucose, insulin, and insulin resistance (HOMA-IR) index. Meanwhile, CPT significantly increased the tyrosine phosphorylation level of IRS and the uptake of 2-deoxyglucose (2DG) in PA-induced HepG2 cells and primary hepatocytes fatty liver models. Furthermore, in PA-induced HepG2 cells and primary hepatocytes, CPT significantly decreased the number of lipid droplets and intracellular TG content. In addition, mechanism investigation showed that CPT increased the phosphorylation of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase-3ß (GSK3ß) in vivo and in vitro models, which were abrogated by PI3K inhibitor LY294002 in vitro models. CONCLUSION: These findings indicate that CPT may exert the therapeutic effects on NAFLD via regulating PI3K/Akt/GSK3ß pathway.