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Background: The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability., Patients and Methods: Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors., Results: BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29-58]) and non-HRRm (n = 1005; median 32 [IQR 20-55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41-58]), RAD51C (median 58 [IQR 48-66]), RAD51D (median 62 [IQR 54-69]), and PALB2 (median 64 [IQR 58-74]), and non-HRR genes NF1 (median 49 [IQR 25-60]) and RB1 (median 55 [IQR 30-71]). CCNE1-amplified and PIK3CA-mutated tumors had low GIS (CCNE1-amplified: median 24 [IQR 18-29]; PIK3CA-mutated: median 32 [IQR 14-52]) and were predominantly non-BRCAm., Conclusions: These analyses provide valuable insight into patterns of genomic instability and potential drivers of HRD, besides BRCAm, in ovarian cancer and will help guide future research into the potential clinical effectiveness of anti-cancer treatments in ovarian cancer, including PARP inhibitors as well as other precision oncology agents., Trial Registration: The SOLO1 trial was registered at ClinicalTrials.gov (NCT01844986) on April 30, 2013; the PAOLA-1 trial was registered at ClinicalTrials.gov (NCT02477644) on June 18, 2015 (retrospectively registered); Study 19 was registered at ClinicalTrials.gov (NCT00753545) on September 12, 2008 (retrospectively registered); the SOLO2 trial was registered at ClinicalTrials.gov (NCT01874353) on June 7, 2013; the OPINION trial was registered at ClinicalTrials.gov (NCT03402841) on January 3, 2018; the LIGHT trial was registered at ClinicalTrials.gov (NCT02983799) on November 4, 2016., Competing Interests: Declarations. Ethics approval and consent to participate: All trials and analyses were performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and were approved by the appropriate Institutional Review Boards. All patients provided written informed consent. Consent for publication: Not applicable. Competing interests: AB reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. IR-C reports grants to self from BMS, MSD, and Roche; grants to their institution from AstraZeneca, BMS, Merck Serono, MSD, Novartis, and Roche; consulting fees from AstraZeneca, Agenus, Advaxis, Amgen, BMS, Clovis, Deciphera, Genmab, GSK, Mersana, Merck Serono, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, and Tesaro; payment or honoraria to self for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Agenus, Advaxis, Amgen, AstraZeneca, BMS, Clovis, Deciphera, Genmab, GSK, Mersana, Merck Serono, MSD, Novartis, Pfizer, PharmaMar, Roche, and Tesaro; payment or honoraria to institution for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS, GSK, MSD, and Roche; and support for attending meetings and/or travel from AstraZeneca, GSK, and Roche. ER reports presentations for BMS, AstraZeneca, Clovis, Roche Diagnostic, GSK, and Roche; advisory boards for AstraZeneca, Roche, and GSK; and congress participation for BMS and AstraZeneca. KC reports grants to her institution from The Irish Cancer Society Clinician Research Leadership Award 2021, MSD Ireland, and ImmunoGen; consulting fees from GSK Ireland and Nextcure; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, GSK Ireland, MJH Life Sciences, and MSD Ireland; payment for expert testimony from St Vincent’s Health; support for attending meetings from MSD Ireland, Pfizer, and Roche Ireland; participation on a data safety monitoring board or advisory board for AstraZeneca, Eisai, GSK Ireland, and Merck; voluntary board member for Arc Cancer Support Centers; and voluntary advisory role for National Cancer Control Programme Ireland and National Center for Pharmacoeconomics Ireland. FS reports participating on scientific advisory boards for AstraZeneca, Zentalis, and GlaxoSmithKline; and receiving grant/research support to their institution from Repare Therapeutics, AstraZeneca, and InstilBio. CA reports receiving advisory board fees from AbbVie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech; participation on an advisory board for Blueprint Medicine; participation on the board of directors for GOG Foundation and NRG Oncology; clinical trial funding to her institution from AstraZeneca for this study; and clinical trial funding to her institution from AbbVie, AstraZeneca, Clovis, and Genentech. AL reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. AP reports honoraria for advisory or speaker activities and/or congress travel support from Roche, AstraZeneca, Tesaro, GSK, MSD, and Clovis; and participation on a data safety monitoring board from MSD. SL reports support for the present manuscript from AstraZeneca; grants or contracts to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare, GSK, and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GSK, Eisai, and Shattuck Labs; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Eisai; and participation on a data safety monitoring board or advisory board from AstraZeneca. EP-L reports lecture fees, fees for serving on a speakers' bureau, and travel support from AstraZeneca, GSK, Roche, and Tesaro; lecture fees from Clovis Oncology and Pfizer; expert testimony fees from AstraZeneca; support for attending meetings and/or travel from AstraZeneca and GSK; fees from AstraZeneca, Incyte, and Roche for participating on a data safety monitoring board or advisory board; and employment by ARCAGY Research. BY reports consulting or advisory roles for Amgen, AstraZeneca, Bayer, BMS, Clovis, ECS Progastrin, GSK, MSD, Myriad, Novartis, and Roche; and travel support from AstraZeneca, Bayer, MSD, and Roche. JL reports receiving research grants from AstraZeneca and Merck/MSD; lecture fees from Clovis Oncology, AstraZeneca, Neopharm, GSK, and MSD/Merck; and advisory board fees from AstraZeneca, GSK, Artios Pharma, Clovis Oncology, ImmunoGen, Mersana, Bristol Myers Squibb, Nuvation, Ellipses Pharma, VBL Therapeutics, Eisai, Sutro Bio, and Immagene, outside of the submitted work. UM reports participation in scientific advisory boards for Allarity, NextCure, Trillium, Agenus, ImmunoGen, Profound Bio, Eisai, Novartis, Boehringer Ingelheim, the Ovarian Cancer Research Alliance, MorphoSys, and CureLab; participation in a data safety monitoring board for Alkermes and Symphogen; consulting for Merck, GSK, and AstraZeneca; participation in a speakers' bureau from Med Learning Group; and funding from the Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE grant (P50CA240243), the Breast Cancer Research Fund, and the Dana-Farber/Harvard Cancer Center grant (2P30CA006516-57). CG reports clinical trial funding for this study to his institution from AstraZeneca; clinical research grants to his institution from Aprea, AstraZeneca, BergenBio, Clovis, GlaxoSmithKline, Medannexin, MSD, Novartis, Nucana, and Tesaro; personal consulting fees from AstraZeneca, GlaxoSmithKline, MSD, and Tesaro; honoraria for lectures/presentations from AstraZeneca, Chugai, Clovis Oncology, GlaxoSmithKline, MSD, Nucana, Roche, Takeda, and Tesaro; honoraria for lectures/presentations/preparing educational materials from Cor2Ed; advisory board attendance for AstraZeneca, Chugai, GlaxoSmithKline, MSD, Nucana, Roche, and Tesaro; and being a committee member on the Scottish Medicines Consortium. KMT reports salary and stock options from Myriad Genetics, Inc. ZL reports full-time employment with AstraZeneca and AstraZeneca stock ownership. DRH reports full-time employment with AstraZeneca and AstraZeneca stock ownership. CEE reports full-time employment with AstraZeneca and AstraZeneca stock ownership. SD reports full-time employment with AstraZeneca and AstraZeneca stock ownership. CE reports full-time employment with AstraZeneca and AstraZeneca stock ownership. PL-S reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. EAH reports full-time employment with AstraZeneca and AstraZeneca stock ownership. JSB reports full-time employment with AstraZeneca at the time of study and AstraZeneca stock ownership., (© 2024. The Author(s).)

Background: Academic pressure and frustration stimulation are significant stressors in college students, and response to the prolonged stimuli would cause adverse mental and physical outcomes. However, more is needed to know about the stress response and its predictors among undergraduate nursing students retaking failed course under the background of the abolition of the Final Supplementary Examination in China. This study aimed to investigate the stress response and its predictive factors of nursing student repeaters who are retaking at least one failed course., Methods: A cross-sectional study was conducted, utilizing convenience sampling to recruit 120 nursing student repeaters from four 4-year undergraduate medical universities in China between September 2020 and May 2021. Data collection instruments included a general information questionnaire, a stress response questionnaire, the Connor-Davidson resilience scale, a self-control scale, and a academic self-efficacy questionnaire. The data were analyzed using descriptive statistics, Pearson correlation coefficients, t-tests, analysis of variance (ANOVA), and multiple linear regression., Results: The average scores of the total stress response, emotional response, physical response, and behavioral response were 58.07 ± 26.72, 86.97 ± 17.12, 57.69 ± 9.75, 67.16 ± 9.22, respectively. Stress response was predicted by psychological resilience, self-control ability, academic self-efficacy and the number of retaking courses., Conclusions: The stress response among nursing student repeaters is relatively active. Higher psychological resilience, self-control ability, and academic self-efficacy predict lower levels of stress response. In order to help nursing students with failing and repeating course release their psychological stress and maintain well-being, nursing educators could adopt self-control promotion strategies and emphasize the cultivation of psychological resilience and academic self-efficacy as parts of health promotion programs for this particular student group., (© 2024. The Author(s).)

Background: Regorafenib, a multi-targeted kinase inhibitor, has been used in the treatment of Hepatocellular carcinoma (HCC). The purpose of this study is to investigate the mechanism of Regorafenib in HCC., Methods: Regorafenib's impact on the sensitivity of HCC cells was assessed using CCK8. Differential gene expression analysis was performed by conducting mRNA sequencing after treatment with Regorafenib. The m6A methylation status of CHOP and differential expression of m6A methylation-related proteins were assessed by RIP and Western Blot. To explore the molecular mechanisms involved in the therapeutic effects of Regorafenib in HCC and the impact of METTL14 and CHOP on Regorafenib treatment, we employed shRNA/overexpression approaches to transfect METTL14 and CHOP genes, as well as conducted in vivo experiments., Results: Treatment with Regorafenib led to a notable decrease in viability and proliferation of SK-Hep-1 and HCC-LM3 cells. The expression level of CHOP was upregulated after Regorafenib intervention, and CHOP underwent m6A methylation. Among the m6A methylation-related proteins, METTL14 exhibited the most significant downregulation. Mechanistic studies revealed that Regorafenib regulated the cell cycle arrest in HCC through METTL14-mediated modulation of CHOP, and the METTL14/CHOP axis affected the sensitivity of HCC to Regorafenib. In vivo, CHOP enhanced the anticancer effect of Regorafenib., Conclusion: The inhibition of HCC development by Regorafenib is attributed to its modulation of m6A expression of CHOP, mediated by METTL14, and the METTL14/CHOP axis enhances the sensitivity of HCC to Regorafenib. These findings provide insights into the treatment of HCC and the issue of drug resistance to Regorafenib., (© 2024. The Author(s).)

Objective: To evaluate the early and mid-term outcomes of open repair in patients with thoracoabdominal aortic aneurysm (TAAA) after thoracic endovascular aortic repair (TEVAR)., Methods: This was a retrospective single center study. Data were retrospectively collected and analyzed for consecutive patients undergoing open TAAA repair (TAAAR) after TEVAR from November 2016 to June 2021. Indications for TAAAR included aneurysm progression due to endoleak, persisted false lumen perfusion, proximal/distal disease progression, and aorta rupture. The risk factor of operative mortality was analyzed by multivariable logistic regression model and the survival was evaluated by Kaplan-Meier., Results: Sixty-three patients who met the inclusion criteria for the study were identified. The mean age at TAAAR was 41 ± 12 years and 43 (68.3%) were male. Marfan syndrome (MFS) was presented in 39 patients (61.9%). 60 (95.2%) patients presented with post-dissection aneurysm and 3 (4.8%) patients with degenerative aneurysm. The extent of TAAA was Crawford I in 9 (14.3%), II in 22 (34.9%), III in 23 (36.5%), and IV in 9 (14.3%). Emergent TAAAR was done in 10 (15.9%) patients, and deep hypothermic circulatory arrest was used in 22 (34.6%). Endograft was explanted in 31 (49.2%). Operative mortality was 11 (17.5%). Stroke, paraplegia, and acute kidney failure occurred in 5 (7.9%), 7 (11.1%), and 6 (9.5%) patients, respectively. Pulmonary complications occurred in 19 (30.2%) patients. The estimated survival was 74.8 ± 4.9% at 5 years. Late reoperations were performed in 2 patients at 2.5 years and 1.3 years, respectively., Conclusions: In this series of TAAA after TEVAR, TAAAR was related with a high risk of operative mortality and morbidity and the midterm outcomes represented a durable treatment and were respectable., (© 2024. The Author(s).)

Background: Early studies indicated that the androgen receptor (AR) could promote renal cell carcinoma (RCC) development and metastasis, but its linkage to RCC progression under hypoxia, remains unclear., Results: Here we found AR expression in RCC cells decreased in response to hypoxia, which might then lead to increase the cancer stem cells (CSC) phenotype through the lncTCFL5-2-modulated YBX1/SOX2 signals. The consequences of such hypoxia-modulated AR/lncTCFL5-2/YBX1/SOX2 signals ablity to alter the CSC phenotype might render RCC cells more resistant to targeted therapy with Sunitinib. Mechanism dissection revealed that AR might alter the lncTCFL5-2/YBX1/SOX2 signaling through transcriptional suppression of the lncTCFL5-2 expression via the AR-response-elements (AREs) on the lncTCFL5-2 promoter. The lncTCFL5-2 interacts with YBX1 to increase its stability, which in turn increases SOX2 expression at a transcriptional level via the YBX1-response-elements (YBX1Es) on the SOX2 promoter. The in vivo mouse model with orthotopic xenografts of RCC cells also validates the in vitro data, and a human RCC sample survey demonstrated the clinical significance of the AR/lncTCFL5-2/YBX1/SOX2 signaling axis for the RCC prognosis, likely as a result of regulating CSC phenotypes., Conclusions: Together, these findings suggest that hypoxia may increase the RCC CSC phenotype via altering the AR/lncTCFL5-2/YBX1/SOX2 signaling axis and a potential therapy to target this newly identified signal perhaps may help improve the targeted therapy with Sunitinib to better suppress RCC progression., (© 2022. The Author(s).)

Background: Radiation therapy (RT) with androgen deprivation therapy (ADT) is an effective therapy to suppress the locally advanced prostate cancer (PCa). However, we unexpectedly found that RT could also induce the androgen receptor splice variant 7 (ARv7) expression to decrease the radiosensitivity., Methods: The study was designed to target ARv7 expression with Quercetin or ARv7-shRNA that leads to enhancing and increasing the radiation sensitivity to better suppress the PCa that involved the modulation of the circNHS/miR-512-5p/XRCC5 signaling., Results: Mechanism studies revealed that RT-induced ARv7 may function via altering the circNHS/miR-512-5p/XRCC5 signaling to decrease the radiosensitivity. Results from preclinical studies using multiple in vitro cell lines and in vivo mouse models concluded that combining RT with the small molecule of Quercetin to target full-length AR and ARv7 could lead to better efficacy to suppress PCa progression., Conclusion: Together, these results suggest that ARv7 may play key roles to alter the PCa radiosensitivity, and targeting this newly identified ARv7 mediated circNHS/miR-512-5p/XRCC5 signaling with Quercetin may help physicians to develop a novel RT to better suppress the progression of PCa., (© 2022. The Author(s).)

Background: This study was designed to compare early outcomes associated with coronary artery bypass grafting for multi-vessel disease conducted using either minimally invasive or conventional off-pump techniques., Methods: From January 2017 through January 2021, 582 patients with multi-vessel lesion coronary artery disease underwent either minimally invasive cardiac surgery coronary artery bypass grafting (MICS CABG) or conventional off-pump coronary artery bypass grafting (OPCABG) treatment by our team at Anzhen Hospital. Patients in the MICS CABG group were propensity score-matched with those in the OPCABG at a 1:1 ratio (MICS CABG = 172; OPCABG = 172), using epidemiological data, preoperative clinical characteristics, and SYNTAX score as covariates. Perioperative outcomes and 6-month computed tomography angiography findings were compared between these groups., Results: No significant differences between groups were observed with respect to 30-day postoperative mortality, myocardial infarction, and stroke incidence. Surgical data indicated that the MICS CABG procedure was able to cover all three main arterial territories with a relatively low need for circulatory assistance. The MICS CABG procedure was associated with a longer operative duration, but was also associated with higher postoperative hemoglobin and activities of daily living index values as well as a shorter duration of postoperative hospitalization (P < 0.05). No differences in 6-month graft patency were observed between groups., Conclusions: MICS CABG is a safe, less invasive alternative to OPCABG when performing complete revascularization provided patients are properly selected, yielding similar in-hospital outcomes and 6-month graft patency rates together with an earlier return of physical function., (© 2022. The Author(s).)

Background: Human papillomavirus (HPV) infection is the main cause of cervical cancer. Characteristics of HPV infections, including the HPV genotype and duration of infection, determine a patient's risk of high-grade lesions. Risk quantification of cervical lesions caused by different HPV genotypes is an important component of evaluation of cervical lesion. Data and evidence are necessary to gain a deeper understanding of the pathogenicity of different HPV genotypes. The present study investigated the clinical characteristics of patients infected with single human papillomavirus (HPV) 53., Methods: This retrospective study analyzed the clinical data of patients who underwent cervical colposcopy guided biopsy between October 2015 and January 2021. The clinical outcomes and the follow-up results of the patients with single HPV53 infection were described., Results: 82.3% of the initial histological results of all 419 patients with single HPV53 infection showed negative (Neg). The number of patients with cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, vaginal intraepithelial neoplasia (VaIN)1, CIN1 + VaIN1, CIN1 + VaIN2, and CIN2 + VaIN2 was 45, 10, 2, 9, 6, 1, and 1, respectively. Cancer was not detected in any patient. When the cytology was negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL), we observed a significant difference in the distribution of histological results (P < 0.05). 95 patients underwent follow-up with cytology according to the exclusion criteria. No progression of high-grade lesions was observed during the follow-up period of 3-34 months., Conclusions: The lesion caused by HPV53 infection progressed slowly. The pathogenicity of a single HPV53 infection was low., (© 2021. The Author(s).)

Background: Lead is a nonessential heavy metal, which can inhibit heme synthesis and has significant cytotoxic effects. Nevertheless, its effect on the electrical properties of red blood cells (RBCs) remains unclear. Consequently, this study aimed to investigate the electrical properties and the electrophysiological mechanism of lead exposure in mouse blood using Electrical Impedance Spectroscopy (EIS) in 0.01-100 MHz frequency range. Data characteristic of the impedance spectrum, Bodes plot, Nyquist plot and Nichols plot, and Constant Phase Element (CPE) equivalent circuit model were used to explicitly analyze the differences in amplitude-frequency, phase-frequency, and the frequency characteristics of blood in electrical impedance properties., Results: Compared with the healthy blood in control mice, the changes in blood exposed to lead were as follows: (i) the hematocrit decreased; (ii) the amplitude-frequency and phase-frequency characteristics of electrical impedance decreased; (iii) the characteristic frequencies (f 0 ) were significantly increased; (iv) the electrical impedance of plasma, erythrocyte membrane, and hemoglobin decreased, while the conductivity increased. (v) The pseudo-capacitance of cell membrane (CPE&#95;Tm) and the intracellular pseudo-capacitance (CPE-Ti) were decreased., Conclusions: Therefore, EIS can be used as an effective method to monitor blood and RBC abnormalities caused by lead exposure. The electrical properties of the cells can be applied as an important observation in the evaluation of the toxic effects of heavy metals., (© 2021. The Author(s).)

Background: The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data., Methods: Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman's rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation., Results: Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells., Conclusions: Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.

Background: Nasopharyngeal carcinoma (NPC) is one of the most common malignancy in head and neck. With the development of treatments, the prognosis has improved these years, but metastasis is still the main cause of treatment failure. The endoplasmic reticulum (ER) resident protein 44 is a UPR-induced ER protein of the protein disulphide isomerase (PDI) family. This study investigated the role of ERp44 in NPC progression., Methods: Firstly, immunohistochemistry, western blot and qRT-PCR were used to investigate the expression of ERp44 in NPC samples and cell lines. We analyzed 44 NPC samples for ERp44 expression and investigated the association between its expression level with clinicopathologic parameters. Then we took CCK8, Transwell migration assay and used the zebrafish model to access the role of ERp44 on the malignant phenotype in NPC cells. Secondly, we used co-IP to gain the proteins that interact with ERp44 and took proteomic analysis. Furthermore, we successfully constructed the mutant variants of ERp44 and found the interaction domain with ATP citrate lyase(ACLY). Lastly, we subcutaneously injected NPC cells into nude mice and took immunohistochemistry to exam the expression of ACLY and ERp44. Then we used western blot to detect the expression level of epithelial-mesenchymal transition (EMT) markers., Results: In the present study, we found ERp44 was elevated in NPC tissues and correlated with clinical stages and survive state of the patients. In vitro, the downregulation of ERp44 in NPC cells (CNE2, 5-8F) could suppress cells proliferation and migration. After that, we recognized that ACLY might be a potential target that could interact with ERp44. We further constructed the mutant variants of ERp44 and found the interaction domain with ACLY. The promotion of ERp44 on cell migration could be inhibited when ACLY was knocked down. More importantly, we also observed that the interaction of ERp44 with ACLY, especially the thioredoxin region in ERp44 play a vital role in regulating EMT. Lastly, we found ERp44 was positively correlated with the expression of ACLY and could promote NPC cells growth in nude mice., Conclusion: Our data indicated that ERp44 participates in promoting NPC progression through the interaction with ACLY and regulation of EMT.

Background: Early studies indicated that ASC-J9®, an androgen receptor (AR) degradation enhancer, could suppress the prostate cancer (PCa) progression. Here we found ASC-J9® could also suppress the PCa progression via an AR-independent mechanism, which might involve modulating the tumor suppressor ATF3 expression., Methods: The lentiviral system was used to modify gene expression in C4-2, CWR22Rv1 and PC-3 cells. Western blot and Immunohistochemistry were used to detect protein expression. MTT and Transwell assays were used to test the proliferation and invasion ability., Results: ASC-J9® can suppress PCa cell proliferation and invasion in both PCa C4-2 and CWR22Rv1 cells via altering the ATF3 expression. Further mechanistic studies reveal that ASC-J9® can increase the ATF3 expression via decreasing Glutamate-cysteine ligase catalytic (GCLC) subunit expression, which can then lead to decrease the PTK2 expression. Human clinical studies further linked the ATF3 expression to the PCa progression. Preclinical studies using in vivo mouse model also proved ASC-J9® could suppress AR-independent PCa cell invasion, which could be reversed after suppressing ATF3., Conclusions: ASC-J9® can function via altering ATF3/PTK2 signaling to suppress the PCa progression in an AR-independent manner.

Cell membrane- covered drug-delivery nanoplatforms have been garnering attention because of their enhanced bio-interfacing capabilities that originate from source cells. In this top-down technique, nanoparticles (NPs) are covered by various membrane coatings, including membranes from specialized cells or hybrid membranes that combine the capacities of different types of cell membranes. Here, hybrid membrane-coated doxorubicin (Dox)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (DPLGA@[RAW-4T1] NPs) were fabricated by fusing membrane components derived from RAW264.7(RAW) and 4T1 cells (4T1). These NPs were used to treat lung metastases originating from breast cancer. This study indicates that the coupling of NPs with a hybrid membrane derived from macrophage and cancer cells has several advantages, such as the tendency to accumulate at sites of inflammation, ability to target specific metastasis, homogenous tumor targeting abilities in vitro, and markedly enhanced multi-target capability in a lung metastasis model in vivo. The DPLGA@[RAW-4T1] NPs exhibited excellent chemotherapeutic potential with approximately 88.9% anti-metastasis efficacy following treatment of breast cancer-derived lung metastases. These NPs were robust and displayed the multi-targeting abilities of hybrid membranes. This study provides a promising biomimetic nanoplatform for effective treatment of breast cancer metastasis.

Background: Kidney renal clear cell carcinoma (KIRC) is the most common type of kidney cancer in adults, and it is responsible for approximately 90-95% of cases. Although extensive evidence has suggested that many immune- and inflammation-related genes could serve as effective biomarkers in KIRC, the potential associations among immune-, inflammation- and KIRC-related genes has not been sufficiently understood., Methods: Here, we integrated multiple levels of data to construct an immune-, inflammation- or KIRC-directed neighbour network (IIKDN network) and a KIRC-related gene-directed network (KIRCD network)., Results: Our analysis suggested that immune- and inflammation-related genes in the network have special topological characteristics and expression patterns related to KIRC. We further identified five core clusters that showed a tighter network structure and stronger correlation of expression from the KIRCD network. Specifically, multiple-level molecular characteristics were systematically portrayed, including somatic mutation, copy-number variant and DNA methylation for the genes in five core clusters. We discovered that the genes showed strong correlation with respect to the expression and methylation levels in these five core clusters. These five core clusters could become special prognostic biomarkers for KIRC, and functional analysis showed that they were associated with activation of the immune and inflammation systems and cancer progression., Conclusions: Our findings highlighted the novel role of the immune and inflammation genes in KIRC.

Background: This study investigated early and midterm outcomes after valve-sparing aortic root replacement (VSSR procedure with De Paulis Valsalva graft) for acute aortic dissection or ascending aortic aneurysm in a single Chinese hospital center., Methods: Between September 2005 to July 2013, 38 patients (84.2% male; mean age, 45.5 ± 12.4) underwent VSSR procedure with De Paulis valsalva graft for acute aortic dissection or ascending aortic aneurysm and were followed up clinically and echocardiographically., Results: Among the 38 cases studied, intensive care unit stay duration was 34.5 (interquartile range, 16-34.6) days; hospital stay duration was 11.7 ± 7.9 days; operation time was 6.8 ± 1.9 h; and cross-clamping time was 154.4 ± 42.0 min. There was one intraoperative conversion to Bentall procedure; one re-operation for bleeding; one operative death and one case who developed complications. Mean follow-up was 39.7 ± 21.7 months (range, 12-108 months; cumulative rate, 1483 patients-months; follow-up rate, 94%). At 5 and 10 years, overall freedom from valve replacement was 94% and 87%; freedom from aortic regurgitation grade II or higher was 94% and 91%; and freedom from reoperation was 94% and 90% years, respectively., Conclusions: The reimplantation type of valve-sparing procedure appears to be facilitated by the use of the De Paulis valsalva graft with satisfactory perioperative and midterm results.

Background: Numerous oral anticancer chemotherapies are available. Non-adherence or over-adherence to these chemotherapies can lead to lowered efficacy and increased risk of adverse events. The objective of this study was to identify patients' adherence profiles using a qualitative-quantitative method., Methods: A capecitabine treatment was initiated for 38 patients with advanced breast or colorectal cancer. At inclusion, information on patients' beliefs was reported using a questionnaire. Later, Information on patients' relation to treatment was obtained from a sub-group during an interview with a sociologist. Questionnaires were analyzed using Multiple Classification Analysis to cluster patients. Treatment adherence was evaluated by an electronic medication event monitoring systems (MEMS caps) and then correlated with patient clusters. Interviews were analyzed to complete and explain results., Results: 38 patients were enrolled between 2008 and 2011 and completed the questionnaire. Twenty had adherence measured with MEMS caps all along treatment. Between 4 and 6 months after inclusion, 16 patients were interviewed. Patient profile B (retired, with a regular life, surrounded by a relative's attention to drug adherence, with a low educational level) was statistically associated with adequate adherence (p = 0.049). A tendency for lower adherence was observed among more highly educated patients with an irregular, active life (NS). All patients taking capecitabine demonstrated a risk of over-adherence, potentiating side effects., Conclusions: These encouraging primary results suggest that further studies should be undertaken and that educational programs tailored to patient profiles should be evaluated to enhance adherence for those who need it and to empower all patients to manage treatment side effects.

Background: The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance and its activation is aberrant in several types of cancer including mesothelioma. Protein kinase CK2 affects several cell signaling pathways through the mechanism of phosphorylation., Methods: Protein and mRNA levels of CK2α and Gli1 were tested by quantitative RT-PCR and immunohistochemistry staining in mesothelioma samples and cell lines. Down-regulated Gli1 expression and transcriptional activity were demonstrated by RT-PCR, Western blot and luciferase reporter assay., Results: In this study, we show that CK2α is over-expressed and a positive regulator of Hegdehog/Gli1 signaling in human malignant pleural mesothelioma. First of all, we found that the mRNA levels of CK2α and Gli1 were broadly elevated and correlated (n = 52, r = 0.401, P < 0.05), compared with LP9 (a normal mesothelial cell line). We then investigated their expression at the protein level, and found that all the 7 mesothelioma cell lines tested showed positive staining in CK2α and Gli1 immunohistochemistry. Correlation analysis by Pearson test for CK2α and Gli1 expression in the 75 mesothelioma tumors and the 7 mesothelioma cell lines showed that the two protein expression was significantly correlated (n = 82, r = 0.554, P < 0.01). Furthermore, we demonstrated that Gli1 expression and transcriptional activity were down-regulated after CK2α was silenced in two mesothelioma cell lines (H28 and H2052). CK2α siRNA also down-regulated the expression of Hh target genes in these cell lines. Moreover, treatment with a small-molecule CK2α inhibitor CX-4945 led to dose-dependent inhibition of Gli1 expression and transcriptional activity. Conversely, forced over-expression of CK2α resulted in an increase in Gli1 transcriptional activity in H28 cells., Conclusions: Thus, we report for the first time that over-expressed CK2α positively regulate Hh/Gli1 signaling in human mesothelioma.

Background: This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma., Methods: Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks., Results: For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen's d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen's d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS., Conclusions: Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed., Trial Registration: ClinicalTrials.gov Identifier: NCT00891618.

Background: Oxaliplatin-based regimens induce a potential risk of hypersensitivity reaction (HSR), with incidence varying from 10% to 25% and lack of clearly identified risk factors. The present study aimed to assess incidence and risk factors in HSR., Methods: All patients treated with oxaliplatin in the Medical Oncology Department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) from October 2004 to January 2011 were enrolled. Incidence and severity of HSR were analyzed retrospectively and the potential clinicopathological covariates were tested on univariate and multivariate analysis., Results: A total of 1,221 doses of oxaliplatin were administered for 191 patients, 8.9% of whom experienced an HSR. Seventeen HSRs were observed, with 1.6% grade 3 and no grade 4 events. The first reaction appeared after a median of 3 oxaliplatin infusions. Using univariate analysis, HSR was associated with younger age (mean age, 56.2 years; p = 0.04), female gender (p = 0.01) and prior exposure to platinum salts (p = 0.02). No increased risk was associated with mean dose or with presence of atopic background. Multivariate analysis confirmed that women were at higher risk of oxaliplatin HSR than men (p < 0.05). Reintroduction of oxaliplatin was effective in 64.7% of hypersensitive patients using an appropriate premedication strategy. Patients who experienced a grade 3 HSR were not rechallenged., Conclusion: The risk of developing oxaliplatin HSR should not be underestimated (8.9% of patients). The medical team's vigilance should be increased with women, younger patients and patients with prior exposure to platinum salts.

Background: In spite of increasing efforts to enhance patient safety, medication errors in hospitalised patients are still relatively common, but with potentially severe consequences. This study aimed to assess antineoplastic medication errors in both affected patients and intercepted cases in terms of frequency, severity for patients, and costs., Methods: A 1-year prospective study was conducted in order to identify the medication errors that occurred during chemotherapy treatment of cancer patients at a French university hospital. The severity and potential consequences of intercepted errors were independently assessed by two physicians. A cost analysis was performed using a simulation of potential hospital stays, with estimations based on the costs of diagnosis-related groups., Results: Among the 6, 607 antineoplastic prescriptions, 341 (5.2%) contained at least one error, corresponding to a total of 449 medication errors. However, most errors (n = 436) were intercepted before medication was administered to the patients. Prescription errors represented 91% of errors, followed by pharmaceutical (8%) and administration errors (1%). According to an independent estimation, 13.4% of avoided errors would have resulted in temporary injury and 2.6% in permanent damage, while 2.6% would have compromised the vital prognosis of the patient, with four to eight deaths thus being avoided. Overall, 13 medication errors reached the patient without causing damage, although two patients required enhanced monitoring. If the intercepted errors had not been discovered, they would have resulted in 216 additional days of hospitalisation and cost an estimated annual total of 92,907€, comprising 69,248€ (74%) in hospital stays and 23,658€ (26%) in additional drugs., Conclusion: Our findings point to the very small number of chemotherapy errors that actually reach patients, although problems in the chemotherapy ordering process are frequent, with the potential for being dangerous and costly.

Background: In the absence of effective drugs, controlling SARS relies on the rapid identification of cases and appropriate management of the close contacts, or effective vaccines for SARS. Therefore, developing specific and sensitive laboratory tests for SARS as well as effective vaccines are necessary for national authorities., Results: Genes encoding truncated nucleocapsid (N) and spike (S) proteins of SARSCoV were cloned into the expression vector pQE30 and fusionally expressed in Escherichia coli M15. The fusion protein was analyzed for reactivity with SARS patients' sera and with anti-sera against the two human coronaviruses HCoV 229E and HCoV OC43 by ELISA, IFA and immunoblot assays. Furthermore, to evaluate the antigen-specific humoral antibody and T-cell responses in mice, the fusion protein was injected into 6-week-old BALB/c mice and a neutralization test as well as a T-cell analysis was performed. To evaluate the antiviral efficacy of immunization, BALB/c mice were challenged intranasally with SARSCoV at day 33 post injection and viral loads were determined by fluorescent quantitative RT-PCR. Serological results showed that the diagnostic sensitivity and specificity of the truncated S-N fusion protein derived the SARS virus were > 99% (457/460) and 100.00% (650/650), respectively. Furthermore there was no cross-reactivity with other two human coronaviruses. High titers of antibodies to SRASCoV appeared in the immunized mice and the neutralization test showed that antibodies to the fusion protein could inhibit SARSCoV. The T cell proliferation showed that the fusion protein could induce an antigen-specific T-cell response. Fluorescent quantitative RT-PCR showed that BALB/c mice challenged intranasally with SARSCoV at day 33 post injection were completely protected from virus replication., Conclusion: The truncated S-N fusion protein is a suitable immunodiagnostic antigen and vaccine candidate.