LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

The body mass index and the risk of ectopic pregnancy: a 5-year retrospective case-control study.

PURPOSE: Acknowledging the associated risk factors may have a positive impact on reducing the incidence of ectopic pregnancy (EP). In recent years, body mass index (BMI) has been mentioned in research. However, few studies are available and controversial on the relationship between EP and BMI. METHODS: We retrospectively studied the EP women as a case group and the deliveries as a control group in the central hospital of Wuhan during 2017 ~ 2021. χ2 test of variables associated with ectopic pregnancy was performed to find differences. Univariate and multivariate binary logistic regression analysis was conducted to analyze the association of the variables of age, parity, history of induced abortion, history of ectopic pregnancy, history of spontaneous abortion, history of appendectomy surgery and BMI (< 18.5 kg/m2, 18.5 ~ 24.9 kg/m2, 25 kg/m2 ~ 29.9 kg/m2, ≥ 30 kg /m2) with EP. RESULTS: They were 659 EP and 1460 deliveries. The variables of age, parity, history of induced abortion, history of ectopic pregnancy and BMI were different significantly(P < 0.05). Multivariate analysis showed that the variables of age > 35 years old [(OR (Odds Ratio), 5.415; 95%CI (Confidence Interval), 4.006 ~ 7.320, P < 0.001], history of ectopic pregnancy (OR, 3.944; 95%CI, 2.405 ~ 6.467; P < 0.001), history of induced abortion(OR, 3.365; 95%CI, 2.724 ~ 4.158, P < 0.001) and low BMI (< 18.5 kg/m2) (OR, 1.929; 95%CI, 1.416 ~ 2.628, P < 0.001])increased the risk of EP. CONCLUSION: The history of ectopic pregnancy, history of induced abortion and age > 35 years old were the risk factors with EP. In addition to these traditional factors, we found low BMI (< 18.5 kg/m2) with women may increase the risk to EP.

Effect of black cloth ointment on hypertrophic scar formation: An investigation using integrated network pharmacology and animal assay.

BACKGROUND: Hypertrophic scars (HS) are a common disfiguring condition in daily clinical encounters which brings a lot of anxieties and concerns to patients, but the treatment options of HS are limited. Black cloth ointment (BCO), as a cosmetic ointment applicable to facial scars, has shown promising therapeutic effects for facial scarring. However, the molecular mechanisms underlying its therapeutic effects remain unclear. MATERIAL AND METHODS: Network pharmacology was first applied to analyze the major active components of BCO and the related signaling pathways. Subsequently, rabbit ear scar model was successfully established to determine the pharmacological effects of BCO and its active component ß-elemene on HS. Finally, the molecular mechanism of BCO and ß-elemene was analyzed by Western blot. RESULTS: Through the network pharmacology, it showed that ß-elemene was the main active ingredient of BCO, and it could significantly improve the pathological structure of HS and reduce collagen deposition. BCO and ß-elemene could increase the expression of ER stress-related markers and promote the increase of apoptotic proteins in the Western blot experiment and induce the apoptosis of myofibroblasts. CONCLUSIONS: Our findings indicate that the material basis for the scar-improving effects of the BCO is ß-elemene, and cellular apoptosis is the key mechanism through which the BCO and ß-elemene exert their effects.

Fucoxanthin Induces Ferroptosis in Cancer Cells via Downregulation of the Nrf2/HO-1/GPX4 Pathway.

This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.

Urinary exosomal prostate-specific antigen is a noninvasive biomarker to detect prostate cancer: Not only old wine in new bottles.

The study aimed at evaluating the performance of urinary exosomal prostate-specific antigen (UE-PSA) to predict the results of initial prostate biopsies and discriminate clinically significant prostate cancer (Gleason score ≥ 7, csPCa) from nonsignificant PCa (Gleason score < 7, nsPCa) plus benign patients. Two hundred seventy-two consecutive participants were admitted who underwent a prostate biopsy. The UE-PSA expression was detected by enzyme-linked immunosorbent assay (ELISA). The predictive power and clinical value of UE-PSA was assessed by receiver operating characteristic (ROC), decision curve analysis (DCA) and waterfall plots. UE-PSA was upregulated in PCa compared to benign patients (P < .001) and csPCa compared to nsPCa plus benign patients (P < .001). UE-PSA achieved an AUC of 0.953 (0.905-0.989) in distinguishing PCa from benign patients and an AUC of 0.879 (0.808-0.941) in predicting csPCa from nsPCa plus benign patients. These results were validated in an additional multicenter cohort. In addition, DCA showed that UE-PSA achieved the highest net benefit at almost any threshold probability compared to tPSA and %fPSA. As the waterfall plot showed, the UE-PSA assay could avoid 57.6% (155 cases) and 34.6% (93 cases) unnecessary biopsies while only missing 2.6% (7 cases) and 1.5% (4 cases) of the cases of csPCa at the cutoff value of 90% and 95% sensitivity, respectively. We validated that UE-PSA presented great diagnostic power and clinical utility to diagnose PCa and csPCa. UE-PSA could be a promising noninvasive biomarker to improve PCa detection.

HKDC1 upregulation promotes glycolysis and disease progression, and confers chemoresistance onto gastric cancer.

There is increasing evidence that hexokinase is involved in cell proliferation and migration. However, the function of the hexokinase domain containing protein-1 (HKDC1) in gastric cancer (GC) remains unclear. Immunohistochemistry analysis and big data mining were used to evaluate the correlation between HKDC1 expression and clinical features in GC. In addition, the biological function and molecular mechanism of HKDC1 in GC were studied by in vitro and in vivo assays. Our study indicated that HKDC1 expression was upregulated in GC tissues compared with adjacent nontumor tissues. High expression of HKDC1 was associated with worse prognosis. Functional experiments demonstrated that HKDC1 upregulation promoted glycolysis, cell proliferation, and tumorigenesis. In addition, HKDC1 could enhance GC invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). Abrogation of HKDC1 could effectively attenuate its oncogenic and metastatic function. Moreover, HKDC1 promoted GC proliferation and migration in vivo. HKDC1 overexpression conferred chemoresistance to cisplatin, oxaliplatin, and 5-fluorouracil (5-Fu) onto GC cells. Furthermore, nuclear factor kappa-B (NF-κB) inhibitor PS-341 could attenuate tumorigenesis, metastasis, and drug resistance ability induced by HKDC1 overexpression in GC cells. Our results highlight a critical role of HKDC1 in promoting glycolysis, tumorigenesis, and EMT of GC cells via activating the NF-κB pathway. In addition, HKDC1-mediated drug resistance was associated with DNA damage repair, which further activated NF-κB signaling. HKDC1 upregulation may be used as a potential indicator for choosing an effective chemotherapy regimen for GC patients undergoing chemotherapy.

Artificial intelligence for the diagnosis of clinically significant prostate cancer based on multimodal data: a multicenter study.

BACKGROUND: The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). METHODS: This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. RESULTS: The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. CONCLUSIONS: The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.

Necroptosis-related subtypes are associated with bronchiectasis in pulmonary non-tuberculous mycobacteria-infected patients: a perspective based on transcriptomic analysis.

The aim of this study was to explore the potential mechanisms responsible for the different manifestations of bronchiectasis in patients with pulmonary non-tuberculous mycobacteria (pNTM) infection. We found that the necroptosis level increased significantly after NTM infection. Further, the 31 pNTM-infected patients were classified into two subtypes based on necroptosis-related genes (NRGs) by unsupervised cluster analysis. After that, we compared the differences in clinical parameters, immune cell infiltration, and gene expression between the two subtypes. We observed that the high-necroptosis subtype possessed higher CT scores for bronchiectasis extent (P = 0.008) and severity (P = 0.023). And, more neutrophil infiltration in the high-necroptosis subtype was demonstrated both by the CIBERSORT algorithm and by blood neutrophil count (P = 0.001). Next, 688 differentially expressed genes (DEGs) between two subtypes were identified. To explore the portion in DEGs that might contribute to bronchiectasis, we intersected the DEGs with two gene modules. These two gene modules were identified as the most associated with CT scores for bronchiectasis extent and severity by weighted gene co-expression network analysis (WGCNA). Ninety-three intersection genes were obtained. Finally, 7 hub genes including ACSL1, ANXA3, DYSF, HK3, SLC11A1, STX11, and TLR4 were further screened out by machine learning algorithms and protein-protein interaction network analysis. These results suggested that the differential levels of necroptosis in pNTM patients might lead to differential extent and severity of bronchiectasis on radiographic imaging. This process might be associated with neutrophil infiltration and the involvement of seven hub genes.

How education level affects postoperative rehabilitation and follow-up: a single-center experience.

BACKGROUND: Radical prostatectomy remains the fundamental treatment for prostate cancer, and improving patients' compliance with postoperative follow-ups is essential for improving patients' quality of life. This study investigates the effect of education levels on patients' recovery and follow-up after radical prostatectomy. METHODS: Data from 1,112 patients undergoing radical prostatectomy between 2011 and 2020 were collected using medical records, and "pc-follow" systems were used to collect patients' baseline information, education level, pathological information, number of outpatient visits, the time interval between each visit, and PSA test data. RESULTS: Regarding postoperative outpatient data, there was no difference in the number of outpatient visits among the different education level groups in Shanghai (P = 0.063). A significant difference was found in the interval between outpatient visits among the groups (P < 0.001). Furthermore, significant differences were detected in the number and duration of outpatient clinic visits among the education level groups in all patients (P = 0.016, P = 0.0027). By contrast, no significant difference was found in the recovery time of urinary continence between all patients and those in Shanghai, grouped according to education level (P = 0.082, P = 0.68). For all patients and patients in the Shanghai area, the number of PSA follow-ups increased gradually with an increasing level of education (P < 0.001, P = 0.0029). CONCLUSIONS: Education level affected the number of postoperative clinic visits, compliance, and the number of PSA tests. However, no significant effect on the recovery of urinary continence was found. Further, clinicians must increase their focus on patients with low education levels to achieve equitable access to health services for all patients.

Molecular epidemiology and change trend of methicillin-resistant Staphylococcus aureus from invasive infections of a hospital in Hangzhou from 2012 to 2018.

The disease caused by methicillin-resistant Staphylococcus aureus (MRSA) is a global public health challenge that threatens society and patients seriously. Therefore, the molecular epidemiology and change trend of MRSA is essential for the control and treatment of diseases caused by the pathogen in their regions. To explore molecular epidemiology of MRSA in Hangzhou, we collected 162 MRSA isolates from 2012 to 2018, conducted the antimicrobial susceptibility and used polymerase chain reaction(PCR) to test the molecular typing including multilocus sequence typing (MLST), staphylococcal chromosome cassette mec (SCCmec), staphylococcal protein A (spa A) and Panton-Valentine leucocidin (PVL). All the strains was divided into community-associated MRSA (CA-MRSA) or hospital-associated MRSA (HA-MRSA). 162 MRSA isolates were divided into 16 STs and 30 spa types. The major ST type was ST5 (96/162, 59.3%) and the predominant spa type was t311 (83/162, 51.2%). Five SCCmec types were found and the most common SCCmec type was type II (101/162, 61.7%). ST5-II-t311 was the predominant MRSA clone. And the prevalence of ST5 MRSA gradually declined from 2014 to 2018 but the prevalence of ST59 MRSA significantly increased. At the same time, livestock-associated methicillin-resistant Staphylococcus aureus(LA-MRSA) ST398 and ST9 were detected. Twenty-eight isolates were PVL gene positive (28/162, 17.3%). The most prevalent PVL-positive clone was ST59-IVa-t437. Comparing with HA-MRSA, CA-MRSA had a lower probability of ST5 (9.1% vs 67.1%, P=0.000) but a higher probability of ST59 (63.6% vs 11.4%, P=0.000), not only that, it was more likely to carrying PVL-positive gene (36.4% vs 14.3%, P=0.028). In summary, the molecular types of MRSA were getting complex over time. ST5-II-t311 was the predominant clone of MRSA isolate with a downward incidence from 2014 to 2018. ST59 MRSA strains, which is thought community related strain are spreading into hospitals and has an upward incidence from 2014 to 2018.

The value of routine bone marrow examination in patients with extranodal NK/T-cell lymphoma staged with PET/CT.

BACKGROUND: Limited evidence supports the omission of routine bone marrow (BM) examination (biopsy and aspiration) in patients with nasal-type extranodal NK/T-cell lymphoma (ENKTCL). This study was aimed at assessing whether BM examination provides valuable information for positron emission tomography/computed tomography (PET/CT)-based staging in this patient population. PATIENTS AND METHODS: Patients newly diagnosed with ENKTCL who underwent initial staging with both PET/CT and BM examination between 2013 and 2020 were retrospectively identified in two Chinese institutions. Overall, 742 patients were included; the BM examination was positive in 67 patients. RESULTS: Compared with BM biopsy alone, the combination of BM biopsy and aspiration assessment did not afford any additional diagnostic value. No patient with a positive BM biopsy was found to have early-stage disease by PET/CT. BM biopsy or PET/CT led to upstaging from stage III to IV as a result of BM involvement in 21 patients. In 135 patients with distant organ involvement, BM involvement was associated with worse overall survival (OS) and progression-free survival (PFS) compared with the corresponding durations in patients without BM involvement (2-year OS: 35.9% vs. 60.4%, p < .001; PFS: 26% vs. 40.7%, p = .003). No difference in survival was noted between groups judged positive based on PET/CT and BM biopsy. CONCLUSION: Compared with aspiration, BM biopsy led to the detection of more BM lesions. Baseline PET/CT can be safely used to exclude BM involvement in early-stage disease. Overall, routine BM examination affords diagnostic or prognostic value over PET/CT in patients with advanced-stage nasal-type ENKTCL.

Circulating exosomal mRNA signatures for the early diagnosis of clear cell renal cell carcinoma.

BACKGROUND: There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. METHODS: Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. RESULTS: Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). CONCLUSIONS: We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

ß-Elemene induces apoptosis by activating the P53 pathway in human hypertrophic scar fibroblasts.

Hypertrophic scar (HS) is a condition characterized by excessive synthesis and deposition of collagen. There are many clinical methods to alleviate HS, but most of them are accompanied by many complications. To investigate the effects of ß-Elemene, extracted from the ginger family plant Wenyujin, on human hypertrophic scar fibroblast (hHSFs). Cultured hHSFs and human normal fibroblasts, observed the effect of ß-Elemene on apoptosis, extracellular matrix, and endoplasmic reticulum stress (ERS) by western blot, Real Time-Polymerase Chain Reaction (RT-PCR), and flow cytometry. Based on our findings, it is clear that ß-Elemene could inhibit the expression of α-smooth muscle actin (α-SMA), collagen I, and fibronectin, reduced collagen deposition. Further studies had found that ß-Elemene could increase the expression of ERS-related proteins CHOP and Calnexin in a dose-dependent manner, thereby promoting the aggregation of cleaved-caspase-3 and inducing hHSFs to undergo poptosis. This process may depend on the regulation of P53. The results of our study indicates that ß-Elemene induced hHSFs to undergo apoptosis though ERS pathway in a P53-dependent manner, which means that our research provided a new strategy for the development of drugs for the treatment of HS.

The prognostic value of weight loss during radiotherapy among patients with nasopharyngeal carcinoma: a large-scale cohort study.

BACKGROUND: We aim to investigate the prognostic value of weight loss during radiotherapy (RT) among patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 1149 NPC patients who received radical RT were retrospectively analyzed. Patients' weight were measured at initiation of RT (WPre-RT) and every week during RT (WRT1,2,3,4,5,6,7). Percentage of weight loss (PWL) at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT (RT-PWL1,2,3,4,5,6,7) were calculated using the following equation: (WPre-RT -WRT1,2,3,4,5,6,7)/WPre-RT × 100%. The optimal threshold of RT-PWL7 was determined by recursive partitioning analyses (RPAs). Our endpoints included disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). RESULTS: The median RT-PWLs were 0, 0, 1.5, 2.9, 4.1, 5.5, 6.6% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RT-PWL7 optimal threshold with respect to DFS was 5.3% based on RPAs. Therefore, a consistent threshold of 5% (<5% vs > ≥5%) was selected to classify NPC patients into low RT-PWL7 and high RT-PWL7 groups for survival analysis. Compared to high RT-PWL7 (≥5%), patients with low RT-PWL7 (< 5%) had significantly better ten-year DFS (61.2% vs 78.8%; P < 0.001), OS (70.1% vs 86.6%; P < 0.001), and DMFS (80.2% vs 88.5%; P = 0.007). However, no difference was observed between LRRFS groups (91.7% vs 94.3%; P = 0.173). In multivariate analysis, high RT-PWL7 was an independent risk factor for DFS (HR, 1.56; 95%CI, 1.19-2.03; P = 0.001), OS (HR, 1.54; 95%CI, 1.11-2.15; P = 0.011), and DMFS (HR, 1.47; 95%CI, 1.03-2.10; P = 0.033) in patients with NPC. In addition, treatment strategy, plasma Epstein-Barr virus DNA, and N stage were associated with weight loss. CONCLUSIONS: High RT-PWL7 was significantly associated with decreased DFS, OS, and DMFS for NPC patients. Clinicians should continuously inform patients on the health impact of minimizing RT-PWL7 under 5% during radiotherapy.

Vicagrel is hydrolyzed by Raf kinase inhibitor protein in human intestine.

As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP-catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of Km , Vmax , and CLint measured as 20.04 ± 1.99 µM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.

Circulating exosomal mRNA profiling identifies novel signatures for the detection of prostate cancer.

The landscape and characteristics of circulating exosomal messenger RNAs (emRNAs) are poorly understood, which hampered the accurate detection of circulating emRNAs. Through comparing RNA sequencing data of circulating exosomes with the corresponding data in tissues, we illustrated the different characteristics of emRNAs compared to tissue mRNAs. We then developed an improved strategy for emRNA detection based on the features of circulating emRNAs. Using the optimized detection strategy, we further validated prostate cancer (PCa) associated emRNAs discovered by emRNA-seq in a large cohort of patients and identified emRNA signatures for PCa screening and diagnosis using logistic regression analysis. The receiver operating characteristic curve (ROC) analysis showed that the circulating emRNA-based screening signature yielded an area under the ROC curve (AUC) of 0.948 in distinguishing PCa patients from healthy controls. The circulating emRNA-based diagnostic signature also showed a great performance in predicting prostate biopsy results (AUC: 0.851). In conclusion, our study developed an optimized emRNA detection strategy and identified novel emRNA signatures for the detection of PCa.

Impact of cumulative cisplatin dose in childhood nasopharyngeal carcinoma based on neoadjuvant chemotherapy response in the intensity-modulated radiotherapy era: a real-world study.

BACKGROUND: We aimed to comprehensively investigate the optimal cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) for locoregionally advanced nasopharyngeal carcinoma (CA-LANPC) with different tumor responses after neoadjuvant chemotherapy (NAC). METHODS: Patients with CA-LANPC who underwent NAC followed by cisplatin-based concurrent chemoradiotherapy were retrospectively analyzed. Evaluation of tumor response in patients was conducted by Response Evaluation Criteria for Solid Tumor (RECIST) 1.1 after two to four cycles NAC. Multivariate Cox proportional hazards models were used for prognosis. Recursive partitioning analysis (RPA) was conducted to classify participates and predict disease-free survival (DFS). RESULTS: One hundred and thirty-two patients with favorable response after NAC were included. The median CC-CCD was 163 mg/m2 (IQR, 145-194 mg/m2), and 160 mg/m2 was selected as the cutoff point to group patients into low and high CC-CCD groups (< 160 vs. ≥ 160 mg/m2). There was significant improvement in 5-year DFS (91.2% vs. 72.6%; P = 0.003) for patients receiving high CC-CCD compared to those receiving low CC-CCD. Multivariate analysis revealed that CC-CCD, T stage, and Epstein-Barr virus (EBV) DNA were independent prognostic factors for DFS (P < 0.05 for all). Patients were further categorized into two prognostic groups by RPA: the low-risk group (T1-3 disease with regardless of EBV DNA, and T4 disease with EBV DNA < 4000 copy/mL), and the high-risk group (T4 disease with EBV DNA ≥ 4000 copy/mL). Significant 5-year DFS improvement was observed for the high-risk group (P = 0.004) with high CC-CCD. However, DFS improvement was relatively insignificant in the low-risk group (P = 0.073). CONCLUSIONS: CC-CCD was a positive prognostic factor for responders after NAC in CA-LANPC. Furthermore, CC-CCD ≥ 160 mg/m2 could significantly improve DFS in the high-risk group with CA-LANPC, but the benefit of high CC-CCD in the low-risk group needs further study.

Multidrug Resistance-Associated Protein 3 Is Responsible for the Efflux Transport of Curcumin Glucuronide from Hepatocytes to the Blood.

Curcumin, a major polyphenol present in turmeric, is predominantly converted to curcumin-O-glucuronide (COG) in enterocytes and hepatocytes via glucuronidation. COG is a principal metabolite of curcumin in plasma and feces. It appears that the efflux transport of the glucuronide conjugates of many compounds is mediated largely by multidrug resistance-associated protein (MRP) 3, the gene product of the ATP-binding cassette, subfamily C, member 3. However, it is currently unknown whether this was the case with COG. In this study, Mrp3 knockout (KO) and wild-type (WT) mice were used to evaluate the pharmacokinetics profiles of COG, the liver-to-plasma ratio of COG, and the COG-to-curcumin ratio in plasma, respectively. The ATP-dependent uptake of COG into recombinant human MRP3 inside-out membrane vesicles was measured for further identification, with estradiol-17ß-d-glucuronide used in parallel as the positive control. Results showed that plasma COG concentrations were extremely low in KO mice compared with WT mice, that the liver-to-plasma ratios of COG were 8-fold greater in KO mice than in WT mice, and that the ATP-dependent uptake of COG at 1 or 10 µM was 5.0- and 3.1-fold greater in the presence of ATP than in the presence of AMP, respectively. No significant differences in the Abcc2 and Abcg2 mRNA expression levels were seen between Mrp3 KO and WT mice. We conclude that Mrp3 is identified to be the main efflux transporter responsible for the transport of COG from hepatocytes into the blood. SIGNIFICANCE STATEMENT: This study was designed to determine whether multidrug resistance-associated protein (Mrp) 3 could be responsible for the efflux transport of curcumin-O-glucuronide (COG), a major metabolite of curcumin present in plasma and feces, from hepatocytes into the blood using Mrp3 knockout mice. In this study, COG was identified as a typical Mrp3 substrate. Results suggest that herb-drug interactions would occur in patients concomitantly taking curcumin and either an MRP3 substrate/inhibitor or a drug that is predominantly glucuronidated by UDP-glucuronosyltransferases.

Replicate systematic review and meta-analyses on robotic surgery: a quality appraisal and overlap investigation.

BACKGROUND: The number of publications of systematic reviews and meta-analyses (MAs) on robotic surgery have been increasing, including many investigating the same topic. Their quality and extent of overlap remains unclear. We assessed the quality of the MAs in this area and investigated the extent of their overlap. METHODS: Relevant studies were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases up to August 1, 2017. Reporting and methodological quality levels were assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Assessment of Multiple Systematic Reviews (AMSTAR) checklists. A thorough investigation of the extent of overlap was performed. RESULTS: In total, 90 MAs in 5 surgical subspecialties were included after full-text review. The mean reporting and methodological quality scores were 22.5 (83.2%) and 7.6 (69.2%), respectively. Authors from university-affiliated institutions and the presence of statistician or epidemiologist coauthors were associated with better-reporting quality scores. The topics with the most overlapping MAs (all ≥ 6) were robot-assisted thyroidectomy, prostatectomy, gastrectomy, colectomy, and fundoplication. 36 (40%) of the included MAs cited previous MAs on the same topic. Among the 7 MAs comparing robot-assisted radical prostatectomy to the open procedure, most (6/7) drew the same conclusion. 50 to 86% of MAs on this topic included the same trials as primary studies. CONCLUSION: Conducting multiple overlapping MAs with identical conclusions on the same topic that are of suboptimal quality may be a waste of resource and effort. Authors from university-affiliated institutes and experts in epidemiology and statistics are more likely to conduct MAs that have better quality. More guidelines and registries are needed to avoid overlapping MAs.