A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer.

PURPOSE: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2- mBC. PATIENTS AND METHODS: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. RESULTS: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8-20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001). CONCLUSIONS: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

Interface engineering strategy construction of covalent organic framework for promoting highly reversible zinc metal.

Zn-ion energy storage devices will play important roles in the future energy storage field. However, Zn-ion device development suffers significantly from adverse chemical reactions (dendrite formation, corrosion, and deformation) on the Zn anode surface. Zn dendrite formation, hydrogen evolution corrosion, and deformation combine to degrade Zn-ion devices. Zincophile modulation and protection using covalent organic frameworks (COF) inhibited dendritic growth by induced uniform Zn ion deposition, which also prevented chemical corrosion. The Zn@COF anode circulated stably for more than 1800 cycles even at high current density in symmetric cells and maintained a low and stable voltage hysteresis. This work explains the surface state of the Zn anode and provides information for further research.

Melittin treatment prevents colorectal cancer from progressing in mice through ER stress-mediated apoptosis.

OBJECTIVES: The primary goal of the current study was to investigate the effect of melittin on colorectal cancer (CRC). METHODS: The viability of cancer cells was tested using the MTT assay, and the apoptosis of tumour cells was assayed using Annexin V/PI staining in vitro or TUNEL staining in vivo. The in vivo toxicity and efficacy of melittin were assessed in a xenograft mouse model. RESULTS: Melittin inhibited the viability of CRC cell lines and induced apoptosis in SW480 cells by regulating apoptosis-related proteins. Melittin triggered endoplasmic reticulum (ER) stress and caused an imbalance in calcium homeostasis in SW480 cells. An absence of melittin triggered ER stress via the calcium chelating agent BAPTA/AM, and the IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) impaired melittin-induced apoptosis in SW480 cells. Melittin treatment suppressed tumour growth but did not affect the body weight of SW480 tumour-bearing mice. Unlike cisplatin and 5-fluorouracil, melittin treatment did not change the biochemical and haematological parameters of the tumour-bearing mice. Finally, in these mice, melittin treatment induced ER stress, which was then blocked by BAPTA/AM, whilst 2-APB impaired the growth inhibitory effect of melittin. CONCLUSION: Melittin treatment inhibits CRC progression by inducing ER stress and an imbalance in calcium homeostasis.

Tumor Mutational Burden as a Predictor of Survival with Durvalumab and/or Tremelimumab Treatment in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC. PATIENTS AND METHODS: Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb. RESULTS: In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28-0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24-0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20-0.76) and 0.38 (95% CI, 0.19-0.78), respectively] but not bTMB < 16 mut/Mb [HR, 0.92 (0.61-1.37) and 0.92 (95% CI, 0.62-1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb. CONCLUSIONS: Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.

Excellent response of refractory triple-negative breast cancer to sintilimab plus chemotherapy: a case report.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high propensity for invasion and a high incidence of lymph node metastasis. Systemic chemotherapy is considered the primary treatment for patients with TNBC; however, immune checkpoint inhibitors in addition to chemotherapy have been associated with better outcomes. Sintilimab, an anti-PD-1 antibody, was developed in China. Herein, the authors report a 49-year-old woman diagnosed with TNBC with extensive lung and sternal metastases. Treatment with sintilimab plus paclitaxel and carboplatin was found highly effective after failure of first-line chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no target for endocrine or targeted therapy, and the standard treatment for patients with TNBC was chemotherapy alone. Recent studies have suggested that immune checkpoint inhibitors plus chemotherapy might be effective and safe for advanced TNBC. Pembrolizumab and atezolizumab have been approved by the US FDA for the treatment of PD-L1-positive TNBC patients. Sintilimab, a Chinese immune checkpoint inhibitor, has not been reported in the treatment of TNBC. This case report presents excellent outcomes of a patient with TNBC who received sintilimab plus chemotherapy after the failure of standard chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials.

Meta-analysis of the efficacy of acupuncture in the treatment of the vascular cognitive impairment associated with cerebral small vessel disease.

OBJECTIVE: To systematically evaluate the efficacy and safety of acupuncture in the treatment of the vascular cognitive impairment (VCI) associated with cerebral small vessel disease (CSVD-VCI) and to provide a theoretical basis for clinical acupuncture treatment for CSVD-VCI. METHOD: Various databases, including China National Knowledge Infrastructure, Wanfang Data, Chinese Science and Technology Journal Database, Chinese BioMedical Literature Service System, PubMed, the Cochrane Library, and EBSCOhost, were searched for randomized controlled trials (RCTs) related to acupuncture treatment for CSVD-VCI. The quality of the included trials was evaluated, and a meta-analysis was conducted using the Review Manager 5.4 software. RESULTS: Ten articles on RCTs were included, involving 761 patients, i.e., 381 in the acupuncture group and 380 in the control group. The meta-analysis results indicated that the use of acupuncture alone and acupuncture alongside other therapies for CSVD-VCI could improve the overall clinical response rate [odds ratio = 3.51, 95% confidence interval (CI) = (2.05, 6.00), P < 0.00001], increase the patients' Montreal Cognitive Assessment scores [mean difference (MD) = 3.33, 95%CI (2.98, 3.68), P < 0.00001], Mini-Mental State Examination scores [MD = 2.78, 95%CI (2.51, 3.06), P < 0.00001], and activities of daily living scores [MD = 6.30, 95%CI (4.22, 8.37), P < 0.00001], and shorten the latency of auditory evoked potential P300 [MD = -14.67, 95%CI (-19.54, -9.80), P < 0.00001]. CONCLUSION: Acupuncture alone and acupuncture alongside other therapies are superior to non-acupuncture-based therapies in the treatment of CSVD-VCI. However, due to the small number of relevant available articles and their general low quality, this conclusion may be biased. More clinical RCTs with a larger sample size and higher quality are needed to support this theory.

Strain and Interference Synergistically Modulated Optical and Electrical Properties in ReS2/Graphene Heterojunction Bubbles.

Two-dimensional (2D) material bubbles, as a straightforward method to induce strain, represent a potentially powerful platform for the modulation of different properties of 2D materials and the exploration of their strain-related applications. Here, we prepare ReS2/graphene heterojunction bubbles (ReS2/gr heterobubbles) and investigate their strain and interference synergistically modulated optical and electrical properties. We perform Raman and photoluminescence (PL) spectra to verify the continuously varying strain and the microcavity induced optical interference in ReS2/gr heterobubbles. Kelvin probe force microscopy (KPFM) is carried out to explore the photogenerated carrier transfer behavior in both strained ReS2/gr heterobubbles and ReS2/gr interfaces, as well as the oscillation of surface potential caused by optical interference under illumination conditions. Moreover, the switching of in-plane crystal orientation and the modulation of optical anisotropy of ReS2/gr heterobubbles are observed by azimuth-dependent reflectance difference microscopy (ADRDM), which can be attributed to the action of both strain effect and interference. Our study proves that the optical and electrical properties can be effectively modulated by the synergistical effect of strain and interference in a 2D material bubble.

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study.

BACKGROUND: Immunotherapies have shown clinical activity in patients with advanced biliary tract cancer, for which outcomes remain poor despite standard of care treatment with gemcitabine and cisplatin. We aimed to evaluate gemcitabine and cisplatin plus durvalumab with or without tremelimumab as first-line treatment in patients with advanced biliary tract cancer. METHODS: This open-label, single-centre, phase 2 study was conducted at Seoul National University Hospital. Eligible patients were treatment-naïve adults aged 18 years or older with histologically proven unresectable or recurrent biliary tract cancer, at least one measurable lesion based on the Response Evaluation Criteria in Solid Tumors (version 1.1), an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 12 weeks or longer, and adequate healthy organ and bone marrow function. Initially, all patients received one 3-week cycle of gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on day 1 and 8 followed by gemcitabine and cisplatin plus durvalumab (1120 mg) and tremelimumab (75 mg) on day 1 of each cycle, starting with the second cycle (chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group). Following protocol amendment, patients were recruited to receive gemcitabine and cisplatin plus durvalumab, starting on day 1 of the first cycle (chemotherapy plus durvalumab group) or gemcitabine and cisplatin plus durvalumab and tremelimumab also from day 1 of the first cycle (chemotherapy plus durvalumab and tremelimumab group) in parallel and allocated using a random block method. Assessors and patients were not masked to the treatment group. The primary endpoint was objective response rate, assessed in the efficacy population (ie, patients who were treated at least until the first tumour response assessment). This study is registered with ClinicalTrials.gov, NCT03046862 (active). FINDINGS: Between March 2, 2017, and Feb 13, 2020, 128 patients were enrolled (32 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 49 in the chemotherapy plus durvalumab group, and 47 in the chemotherapy plus durvalumab and tremelimumab group). Four patients (two in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group and two in the chemotherapy plus durvalumab group) were excluded and 124 were evaluable for tumour response. The median duration of follow-up was 48·2 months (IQR 41·5-49·4) for the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 26·6 months (19·0-27·9) for the chemotherapy plus durvalumab group, and 24·2 months (20·7-31·7) for the chemotherapy plus durvalumab and tremelimumab group. 82 (66%) of 124 patients achieved an objective response (15 [50%] of 30 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 34 [72%] of 47 in the chemotherapy plus durvalumab group, and 33 [70%] of 47 in the chemotherapy plus durvalumab and tremelimumab group). The most common grade 3 and 4 adverse events were decreased neutrophil count (67 [53%] of 126), anaemia (50 [40%]), and decreased platelet count (24 [19%]), with no unexpected safety events. No adverse events leading to discontinuation or death occurred. INTERPRETATION: Gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety in patients with biliary tract cancer. Gemcitabine and cisplatin plus durvalumab are being evaluated in the phase 3, TOPAZ-1 study (NCT03875235) as first-line treatment in patients with advanced biliary tract cancer. FUNDING: AstraZeneca; National Research Foundation of Korea (Grant No. 2021R1A2C2007430).

Overexpression of HMGB3 and its prognostic value in breast cancer.

Background: High mobility group protein B3 (HMGB3) is abundantly expressed in a number of malignancies, contributing to tumor cell growth and predicting poor outcomes. More research on the connection between HMGB3 and breast cancer is needed. The prognostic significance of HMGB3 in breast cancer was examined and validated in this study. Methods: Using The Cancer Genome Atlas (TCGA) database RNA sequencing and clinical data, we investigated the associations between HMGB3 expression and tumor mutations, prognosis, and immune infiltration in breast cancer. The Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), breast cancer gene-expression miner (bc-GenExMiner), UALCAN, OncoLnc, cBio Cancer Genomics Portal (cBioPortal), and LinkedOmics databases were applied to examine the levels of expression, mutation, coexpression, and immune correlation of HMGB3 in breast cancer. cBioPortal and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used for coexpression and enrichment analyses, respectively. Experimental tests and a separate cohort of breast cancer patients in our center were used for validation. To determine independent risk factors affecting breast carcinoma prognosis, multivariate Cox regression analysis was performed. The Kaplan-Meier method was applied to analyze the connection between HMGB3 expression and overall survival time in breast cancer. Results: Pan-cancer investigation using the GEPIA and UALCAN databases revealed a high level of HMGB3 expression in different malignancies, including breast cancer. HMGB3 might be a potential diagnostic biomarker, according to the receiver operating characteristic (ROC) curve (AUC=0.932). And immunohistochemistry confirmed higher HMGB3 protein expression in breast cancer tissues in clinical samples. Experimental tests also showed that breast cancer cells have higher expression of HMGB3, and knockdown of HMGB3 can promote the proliferation of breast cancer cells and increase sensitivity to chemotherapy. Human epidermal growth factor receptor 2 (HER2), Nottingham Prognostic Index (NPI), basal-like status, nodal status (N+), triple-negative status, and Scarff-Bloom-Richardson (SBR) grade all showed positive correlations with HMGB3 expression. Conversely, HMGB3 expression was negatively associated with the expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer. Breast cancer patients with high HMGB3 expression had poor overall survival, which was validated by an analysis of a separate cohort of breast cancer patients in our center. Cox regression analysis identified high HMGB3 expression as an independently associated risk factor for breast carcinoma. The amount of immunological infiltration was substantially linked with the high expression of HMGB3. The chromosome centromeric region, ATPase activity, and the cell cycle are critical areas where HMGB3 is involved, according to enrichment analysis. Therefore, we suspected that HMGB3 might be a potential biomarker for detecting and treating breast carcinoma. Conclusion: Breast cancer tissues had higher HMGB3 expression than normal breast tissues. HMGB3 overexpression may serve as an indicator for poor breast cancer outcomes.

STAT3 as a target for sensitizing prostate cancer cells to irradiation.

Radioresistance of prostate cancer (PCa) is a major factor leading to local failure of radiotherapy. STAT3 is an oncogenic protein that was recently found to be activated in PCa tumors. This study aimed to investigate the radiosensitization effect of targeting STAT3 in PCa tumors. Here, the radiosensitization effect of STAT3 blockade was investigated by clonogenic assay, flow cytometry and western blot analysis in human PCa cells in vitro and in vivo. We demonstrated that STAT3 blockade with a STAT3 inhibitor or siRNA increased the radiosensitivity of PCa cells and that radiation together with STAT3 blockade induced more apoptosis and double-strand breaks (DSBs) than radiation alone in LNCaP cells. In addition, radiation induced STAT3 activation and survivin expression in PCa cells, which was inhibited by STAT3 blockade. Transfection with survivin cDNA attenuated the radiosensitization effect of STAT3 blockade. These effects were further confirmed by in vivo studies, which showed that the STAT3 inhibitor enhanced the treatment efficacy of radiation on LNCaP xenografts with decreased STAT3 activation and survivin expression. These findings suggest that STAT3 blockade radiosensitizes PCa cells through regulation of survivin. Thus, our study has revealed STAT3 as a potential sensitizer for irradiation in PCa cells. Its clinical application as an adjuvant in radiotherapy of PCa should be explored in the future.

Isolation and identification of 17ß-estradiol degrading bacteria and its degradation pathway.

The widespread presence of 17ß-estradiol (E2) in the environment is an emerging problem because it poses a potential threat to human health and aquatic organisms. In this study, a strain of E2 degrading bacteria was isolated from activated sludge. 16s rRNA analysis combined with physiological and biochemical detection confirmed that the bacterium was Ochrobactrum sp. strain FJ1. At an initial E2 concentration of 15 mg L-1, strain FJ1 degraded 98 ± 1% of E2 after 10 days. Furthermore, when methanol was added as an additional carbon source, the biomass of strain FJ1 increased by 35 ± 1%, and E2 degradation efficiency was slightly inhibited. Compared with E2 alone when glucose, sodium acetate, and methanol were added as additional carbon sources, biomass decreased by 20 ± 1, 13 ± 1 and 35 ± 1%, respectively. Analysis of the degradation products of E2 by LC/Q-TOF-MS confirmed that the major degradation products of E2 were estrone (E1) and 4,16-OH-E1, which was further degraded by strain FJ1 to several other unknown compounds. Based on SEM and FTIR analysis, the morphology of the bacteria became thicker and the thickness of the cell walls decreased under initial E2 stress, and thereafter E2 was transported into the bacteria primarily via several proteins on the cell surface. Considering the ability and efficiency of Ochrobactrum sp. strain FJ1 to degrade high E2 content, the strain could provide a new bioremediation technology for the effective biodegradation of E2. Finally, a potential bioremediation pathway of E2 by Ochrobactrum sp. strain FJ1 was proposed.

The Psychological Effect of Forming WeChat Groups Between Medical Staff and Patients With COVID-19.

Background: This study was conducted in order to explore the effect of psychological intervention based on the use of WeChat with coronavirus disease 2019 (COVID-19) patients. Methods: A total of 65 patients with COVID-19, from two wards, were divided into an experimental group and a control group with the ward as the basic unit. Communication concerning routine treatment and nursing was established between the medical staff and patients in the experimental group via WeChat groups. Within 48 h of admission, at 7 days, and on discharge, all 65 patients completed two self-evaluation questionnaires: the Positive and Negative Affect Schedule (PANAS) and the Hospital Anxiety and Depression Scale (HADS). Hospital stay statistics and a satisfaction survey on discharge were also collated for both groups of patients. Results: The PANAS scores of the experimental group were 26.61 ± 7.99 points on admission, 20.81 ± 5.48 points at 7 days, and 19.58 ± 6.61 points on discharge (P < 0.05). The scores of HADS in the experimental group were 27.74 ± 9.35 points on admission, 12.19 ± 1.92 points at 7 days, and 11.71 ± 3.64 points on discharge (P < 0.05). The differences in the PANS and HADS scores between the experimental and control groups at 7 days and on discharge were statistically significant. The discharge satisfaction ratings of the two groups of patients were 99.87 ± 0.34 and 98.68 ± 1.09 points, the difference being statistically significant (t = 5.827, P < 0.05). Conclusion: Establishing WeChat groups between medical staff and patients with COVID-19 and building a bridge for better communication improved patients' positive mentality and their compliance with doctors, shortened their hospital stay, and promoted their recovery.

Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide.

PURPOSE: MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy. PATIENTS AND METHODS: MEDI3726 was administered at 0.015-0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood. RESULTS: Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3-1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%). CONCLUSIONS: Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.

Prognostic models for 1-year survival of NPC after radiotherapy in different ages.

PURPOSE: Previous studies have shown that approximately 10% of nasopharyngeal cancer (NPC) patients die within a year of disease onset, and that age is an independent predictor. However, no predictive model has been developed. We aimed to establish novel prognostic models to predict the 1-year cancer-specific survival (CSS) of young, middle-aged, and older patients with NPC after radiotherapy. METHODS: The data of 2822 NPC patients who underwent radiotherapy between 2004 and 2015 were reviewed from the surveillance, epidemiology, and end results database. We divided them into young, middle-aged, and older people groups according to age (< 44 years, 45-59 years, and ≥ 60 years, respectively). Multivariate analyses were performed, and prognostic models were constructed. RESULTS: Multivariate analyses indicated that age, ethnicity, histological subtype, T, and M stage were independent predictors of 1-year CSS in the older people group. In contrast, ethnicity and age were not found to have predictive value in the young and middle-aged groups, respectively. Accordingly, three prognostic models with excellent predictive values were established for the three groups (C-indices: 0.791 [95% CI 0.722-0.859], 0.763 [95% CI 0.721-0.806] and 0.723 [95% CI 0.683-0.763], respectively). These predictive values are higher than those of the eighth edition American joint committee cancer tumor-node-metastasis (TNM) classification system. CONCLUSION: Three prognostic models for predicting the 1-year CSS of young, middle-aged, and older NPC patients after radiotherapy showed better predictive power than the TNM classification system. These models may guide treatment strategies and clinical decision-making in different cohorts.

Nuclear Her2 contributes to paclitaxel resistance in breast cancer cells.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

HOXA-AS3 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells via the miR-455-5p/PD-L1 Axis.

Hepatocellular carcinoma (HCC) is the most prevalent type of hepatic carcinoma. Long noncoding RNAs (lncRNAs) are considered crucial regulators of gene expression; however, their functions in HCC are not well understood. Thus, the present study is aimed at elucidating the functions of the lncRNA HOXA-AS3 in HCC. The functions of the HOXA-AS3/miR-455-5p/programmed death-ligand 1 (PD-L1) axis were investigated in vitro via qRT-PCR and dual-luciferase reporter assays. The effect of HOXA-AS3 expression on tumor growth and metastasis was assessed using a mouse xenograft model. High HOXA-AS3 expression was observed in the HCC cell lines. Furthermore, overexpression of HOXA-AS3 in HCC cells enhanced proliferation, migration, and invasion, regulated the cell cycle, and retarded apoptosis. We also identified an miR-455-5p binding site in HOXA-AS3. By sponging miR-455-5p, HOXA-AS3 increased the expression of PD-L1. Additionally, both the inhibition of PD-L1 and overexpression of miR-455-5p reversed the effects on cell proliferation and invasion triggered by the overexpression of HOXA-AS3. In conclusion, HOXA-AS3 modulated the functions of HCC cells through the miR-455-5p/PD-L1 axis. Therefore, HOXA-AS3 may be a novel therapeutic target for HCC.