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In the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS.Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/mIn total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P.00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P.00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified.In this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.

microRNAs (miRNA) are promising predictors in colorectal cancer (CRC). We investigated whether miRNAs could predict adenoma recurrence in patients with advanced colorectal adenoma (ACRA) after polypectomy. miRNA expression profiling was performed by miRNA microarray to identify recurrence-related miRNAs. Candidate miRNAs extracted from formalin-fixed paraffin-embedded blocks of patients with ACRA were measured using real-time PCR. Logistic regression analysis was conducted to investigate whether validated miRNA expression profiles were independent from other known adenoma recurrence risk factors. The prognostic values of six miRNAs and three independent risk factors were assessed by the area under the receiver operating characteristic (ROC) curve analysis. The expressions of six candidate miRNAs were significantly decreased from levels in normal colorectal tissue compared with ARCA with adenoma recurrence (RACRA) in this retrospective cohort. However, only miRNA (miR)-194 emerged as a practical predictor. The sensitivity and specificity of miR-194 as a predictor were 71.0% and 78.0%, respectively, at a cutoff value of 0.1311 in the retrospective cohort. Sensitivity and specificity were 76.1% and 77.2%, respectively, in the prospective cohort using the same cutoff value. Low expression levels of miR-194, adenoma size ≥2 cm, and ≥3 adenomas were independent risk factors for adenoma recurrence. Moreover, low expression of miR-194 was a better predictor of adenoma recurrence than the adenoma size and numbers according to ROC curve analysis. miR-194 may be an independent predictor for adenoma recurrence in patients with ACRA after polypectomy. Cancer Prev Res; 7(6); 607–16. ©2014 AACR.

PDF - 114K, Differential miRs expression levels between NRACRA tissues and RACRA tissues in miR microarray.

PDF - 114K, Differential miRs expression levels between normal colorectal tissues (Normal) and NRACRA tissues in miR microarray.

PDF - 111K, Characteristics of study population and advanced colorectal adenoma.

Background Preventive colostomy is required for colorectal surgery, and the incidence of complications associated with ileostomy and colostomy remains controversial. This study aimed to compare the incidence of postoperative complications between ileostomy and colostomy procedures. Methods Data analysis was conducted on 30 studies, and meta-analysis and trial sequential analysis (TSA) were performed on five studies. The basic indicators, such as stoma prolapse, leak, wound infection, ileus, and a series of other indicators, were compared. Results No statistically significant differences were observed with complications other than stoma prolapse. Meta-analysis and TSA showed that the incidence of ileostomy prolapse was lower than that of colostomy prolapse, and the difference was statistically significant. Apart from the four complications listed above, the general data analysis showed differences in incidence between the two groups. The incidence of skin irritation, parastomal hernia, dehydration, pneumonia, and urinary tract infections was higher with ileostomy than with colostomy. In contrast, the incidence of parastomal fistula, stenosis, hemorrhage, and enterocutaneous fistula was higher with colostomy than with ileostomy. Conclusions There were differences in the incidence of ileostomy and colostomy complications in the selected studies, with a low incidence of ileostomy prolapse. PROSPERO registration number: CRD42022303133

Micro-aerobic conditions enhanced the stability of the PN/A system, which was associated with the high diversity and network complexity. Micro-aerobic conditions provided a more complex niche for both aerobic and anaerobic bacteria.

Background More effective targeted therapy and new combination regimens are needed for Acute myeloid leukemia (AML), owing to the unsatisfactory long-term prognosis of the disease. Here, we investigated the synergistic effect and the mechanism of a histone deacetylase inhibitor, Chidamide in combination with Cladribine, a purine nucleoside antimetabolite analog in the disease. Methods Cell counting kit-8 assays and Chou-Talalay’s combination index were used to examine the synergistic effect of Chidamide and Cladribine on AML cell lines (U937, THP-1, and MV4-11) and primary AML cells. PI and Annexin-V/PI assays were used to detect the cell cycle effect and apoptosis effect, respectively. Global transcriptome analysis, RT-qPCR, c-MYC Knockdown, western blotting, co-immunoprecipitation, and chromatin immunoprecipitation assays were employed to explore the molecule mechanisms. Results The combination of Chidamide with Cladribine showed a significant increase in cell proliferation arrest, the G0/G1 phase arrest, and apoptosis compared to the single drug control in AML cell lines along with upregulated p21Waf1/Cip1 expression and downregulated CDK2/Cyclin E2 complex, and elevated cleaved caspase-9, caspase-3, and PARP. The combination significantly suppresses the c-MYC expression in AML cells, and c-MYC knockdown significantly increased the sensitivity of U937 cells to the combination compared to single drug control. Moreover, we observed HDAC2 interacts with c-Myc in AML cells, and we further identified that c-Myc binds to the promoter region of RCC1 that also could be suppressed by the combination through c-Myc-dependent. Consistently, a positive correlation of RCC1 with c-MYC was observed in the AML patient cohort. Also, RCC1 and HDAC2 high expression are associated with poor survival in AML patients. Finally, we also observed the combination significantly suppresses cell growth and induces the apoptosis of primary cells in AML patients with AML1-ETO fusion, c-KIT mutation, MLL-AF6 fusion, FLT3-ITD mutation, and in a CMML-BP patient with complex karyotype. Conclusions Our results demonstrated the synergistic effect of Chidamide with Cladribine on cell growth arrest, cell cycle arrest, and apoptosis in AML and primary cells with genetic defects by targeting HDAC2/c-Myc/RCC1 signaling in AML. Our data provide experimental evidence for the undergoing clinical trial (Clinical Trial ID: NCT05330364) of Chidamide plus Cladribine as a new potential regimen in AML.

Background: Diabetic cardiomyopathy (DCM) is a serious complication of Obesity with type 2 diabetes. Bariatric surgery can effectively improve DCM; however, the underlying mechanisms remain elusive. Our objective was to investigate the effect and potential mechanisms of duode-nal-jejunal bypass (DJB) on oxidative stress in the heart. Methods: DJB was performed on DCM rats, and high glucose (HG) and palmitate (PA) were used to simulate DCM in H9C2 cells in vitro. AMPK agonists and inhibitors were used to verify the role of the AMPK pathway. Serum from different groups of rats was used to verify that the im-provement in DCM after DJB surgery was not strictly owing to improvement in blood glucose levels and connect the experiments in vivo and in vitro. Results: DJB surgery effectively improved oxidative stress and increased expression of the AMPK pathway, p-eNOS/eNOS, NRF2, HO-1, and SOD2 in terms of protein and mRNA in the heart of DCM rats. Compared to H9C2 cells in the HG+PA environment alone, the addition of either AMPK agonists or serum from DJB rats increased the expression of the AMPK pathway, p-eNOS/eNOS, NRF2, HO-1, and SOD2 in terms of protein and mRNA and decreased the content of ROS, but this improvement was almost eliminated by the addition of AMPK inhibitors. Conclusions: Therefore, DJB surgery can improve oxidative stress in the heart of DCM rats, which may be achieved by activating the AMPK pathway, thereby increasing the phosphorylation level of eNOS, increasing NO and reducing ROS production, and improving the antioxidant system and not solely the improvement of blood glucose.

IntroductionThis study aims to evaluate the efficacy and safety of the novel combination of Aza and HIA as the frontline induction therapy in newly diagnosed AML patients eligible for intensive chemotherapy (IC) (registered on ClinicalTrials.gov, number NCT04248595).MethodsAza (75mg/m2/d on days1-5 subcutaneous) is administered in combination with HIA [HHT 2mg/m2/d on days 4-8 intravenous over 3 hours, idarubicin 6mg/m2/d on days 4-6 intravenous, and cytarabine 100mg/m2/d on days 4-10 intravenous]. The primary endpoint was complete remission (CR) or CR with incomplete blood count recovery (CRi). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), and adverse events (AEs).ResultsA total of 20 AML patients (aged 18-70 years) were enrolled between Jan 2020 and Sep 2022. 95% (19/20) of patients achieved CR/CRi, and 89.5% (17/19) had undetectable MRD, in which 94.7% (18/19) reached CR/CRi, and 88.9% (16/18) obtained MRD negative after the 1st cycle of induction therapy. Median OS and RFS were both not reached during the follow-up. The estimated 2-year OS and RFS were 87.5% (95%CI, 58.6% to 96.7%) and 87.1% (95%CI, 57.3% to 96.6%), respectively. No patient discontinued the treatment for AEs.DiscussionThis study provides preliminary evidence for this novel combination therapy as the first-line induction therapy for young or older AML patients fit for IC.

Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression.

OBJECTIVE: To compare the surgical methods and complications in pediatric patients with neuroblastoma (NB) at International neuroblastoma staging system (INSS) stage 4 in the adrenal site. METHODS: Thirty-four patients, 21 males and 13 females, with NB at INSS stage 4 underwent radical surgery (RS) from May 2018 to May 2021, and were retrospectively included. Patients were divided into three groups, namely RS group (group A), tumor biopsy + chemotherapy + RS group (group B), and bone marrow biopsy + chemotherapy + RS group (group C) depending on the particular treatment protocol. The total survival rate, factors related to surgical resection, and surgical complications in each group were analyzed. Results: 5 cases were enrolled in group A, 9 cases in group B, and 20 cases in group C. The number of Encasement of Vessels (EVS) was higher in the (CR+MR) group compared to the IR group (P=0.039). The operative time was shorter when EVS was present (P=0.022). RS complications mainly included bleeding (73.5%), celiac leakage (70.6%) and intestinal obstruction (26.5%). A total of 29 cases (85.3%) were graded by CDC as grade II, 2 cases as grade IIIa, 1 case as grade IIIb, 1 case as grade IVa and 1 case as grade IVb.By comparing patients who developed grade II and grade III complications or higher, it was observed that neuron-specific enolase (NSE) (PCONCLUSION: In this study, it is concluded that pre-operative biopsy in patients with NB at INSS stage 4 located in the adrenal glands allows for a clear diagnosis, and that subsequent RS does not increase the risk of surgical complications. Moreover, EVS is proved an important factor for surgical resection and surgical complications.

Background and study aims The aim of the study was to evaluate short- and long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in China because no study has yet been conducted to confirm its effectiveness in EGC in China. Patients and methods A total of 570 EGC samples from 537 patients were collected for evaluation of en bloc, complete, and curative resection using ESD. Data from 302 patients with at least 3 years of active follow-up were collected for analysis of recurrence of EGC and occurrence of metachronous GC (MGC). Short- and long-outcomes of mixed-type and pure differentiated EGC were also compared. Results En bloc resection rates of 96.0 %, 98.7 %, and 95.2 %, complete resection rates of 91.2 %, 96.6 % and 90.8 %, and curative resection rates of 83.0 %, 96.2 % and 88.2 % were achieved in all EGCs included in the study, those with absolute indication, and those with expanded indication, respectively. As a long-term outcome, recurrence was observed in 1.3 % of patients, 3-year and 5-year recurrence rates being 0.7 % and 1.2 %, respectively. Thirteen patients (4.3 %) exhibited MGCs during follow-up, all of which were resected in a second ESD. Conclusions The effectiveness of ESD for EGC in China was confirmed, with satisfactory short- and long-term outcomes. With scheduled follow-up, the outcomes for mixed-type EGC can be similar to those for pure differentiated EGC after complete resection without development of lymphovascular invasion.

Liquid biopsy has been experimented with to identify the mutation of lymphoma based on next-generation sequencing (NGS). We applied NGS analysis to circulating tumor DNA (ctDNA) in 20 lymphoma patients. Then, we compared treatment outcomes, and clinical characteristics among these patients, then investigated mutational profiling. Two independent cohorts of 241 patients with mature B cell lymphoma in Mature B-cell malignancies data set (MBN) data set and 50 diffuse large B-cell lymphoma (DLBCL) patients in DLBCL data set, were used to examine the association between gene mutations and prognosis. We found ctDNA positive group had significantly more relapsed/PD (7/12, 58.3%) and less CR/PR patients (1/12, 8.3%) compared to negative group (0, 0%) (5/8, 62.5%) (p 0.001). Somatic alterations were identified in 12 of 20 patients and the total 11 mutations were: Ataxia telangiectasia mutated (ATM), TP53, BCL2, BTG2, CD28, EP300, IDH2, IRF8, JAK3, NOTCH1, and NRAS. ATM (S2168L) was found in SLL and TLBL for the first time. BTG2 (c.292_293del), CD28 (P119T), IRF8 (E74D) and NOTCH1 (c.4348 G A) were newly detected in DLBCL, angioimmunoblastic T-cell lymphoma, primary central nervous system lymphoma, and BCL for the first time respectively. We also disclosed an unreported mutation EP300 (c.1058_1059insC) in DLBCL. Our cases implied ctDNA detection consistent with the FISH of tissue samples to some extent, speculating new molecular subtypes of DLBCL, finding some potential drug-resistant mutations, and suggesting disease recurrence. Moreover, in MBN and DLBCL datasets, patients with TP53 mutation had a significantly shorter OS (all p 0.05) in both circulating free DNA and tumor tissue. The mutations (no SNP) of NOTCH1 (all p 0.05) significantly contributed to worse OS in the two cohorts.

Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.

Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.

Imbalance issue is a major yet unsolved bottleneck for the current object detection models. In this work, we observe two crucial yet never discussed imbalance issues. The first imbalance lies in the large number of low-quality RPN proposals, which makes the R-CNN module (i.e., post-classification layers) become highly biased towards the negative proposals in the early training stage. The second imbalance stems from the unbalanced ground-truth numbers across different testing images, resulting in the imbalance of the number of potentially existing positive proposals in testing phase. To tackle these two imbalance issues, we incorporates two innovations into Faster R-CNN: 1) an R-CNN Gradient Annealing (RGA) strategy to enhance the impact of positive proposals in the early training stage. 2) a set of Parallel R-CNN Modules (PRM) with different positive/negative sampling ratios during training on one same backbone. Our RGA and PRM can totally bring 2.0% improvements on AP on COCO minival. Experiments on CrowdHuman further validates the effectiveness of our innovations across various kinds of object detection tasks.

For solving large sparse linear complementarity problems effectively, by utilizing the parametric method, the acceleration strategy and the relaxation technique to the modulus-based matrix splitting (MMS) iteration method, we develop the accelerated relaxation MMS (ARMMS) iteration method, which generalizes the generalized accelerated MMS (GAMMS) and the relaxation MMS (RMMS) ones proposed recently. Meanwhile, it is proved that the ARMMS iteration method is convergent under proper restrictions when the system matrix is a positive definite matrix or an $$H_{+}$$ -matrix. In addition, we also study the convergence properties of the ARM accelerated overrelaxation (ARMAOR) method. Numerical experiments show that the proposed iteration method is efficient, and it outperforms some existing ones with suitable choice of the parameter and matrix splitting.

BACKGROUND: The aim of the study is to compare the Lich-Gregoir vesico-ureteral reimplantation in laparoscopy and open surgery. METHODS: In this case control study, we enrolled pediatric patients who were diagnosed with unilateral duplex kidney and had underwent surgical treatment. The surgical treatments were either conventional open surgery or laparoscopic surgery. We collected the basic demographic data and extracted the operative-related statistics such as operation time, blood loss, length of hospital stay, pain level, and post-operative complications. The two groups were compared using Student’s t-test. RESULTS: A total of 90 subjects were enrolled. Of the enrolled subjects, 35 underwent open surgery and 55 underwent laparoscopic surgery. There were no observable difference in the basic demographics between two groups (P>0.05). The duration of operation in laparoscopic surgery group was significantly shorter than in the open surgery group (95.60±5.25 vs. 108.70±3.12 min, P=0.040). It was also noted that the amount of blood loss, length of hospital stay, drainage level, and the mean visual analog scale in laparoscopic group were significantly lower (P

The purpose of this study was to examine the role of endothelial progenitor cells (EPCs) in protection against ischemic-reperfusion injury (IRI) in a nephron-sparing surgery (NSS) rat model using erythropoietin (EPO) preconditioning. Fifty-four male Sprague-Dawley rats were randomly divided into 3 groups for right kidney nephrectomy treatment: sham group (exposure without clamp treatment), NSS group (3 days of peritoneal phosphate buffered saline [PBS] injection before renal blood vessels were clamped for 40 mins and NSS was performed), and EPO group (3 days of EPO abdomen injections prior to renal blood vessel clamping for 40 min before NSS was performed). After 12, 24, and 72 hours, inferior vena cava blood and renal tissues were harvested. The extent of renal injury was assessed, along with EPC number, cell proliferation, angiogenesis, and vascular growth factor expression. EPO preconditioning significantly improved renal function and histologic morphology, indicated by reduced blood urea nitrogen (BUN) ([33.12 ± 1.88] vs [16.03 ± 0.91], P .05) and serum creatinine (Scr) ([190.2 ± 20.23] vs [77.23 ± 5.82], P .05) levels and histologic injury scores ([3.20 ± 0.78] vs [1.70 ± 0.67], P .05). Angiogenesis in peritubular capillaries markedly increased in the EPO group. EPC numbers increased in the kidneys at 24 hours following reperfusion in the EPO group, compared to the NSS group. Furthermore, EPO preconditioning also increased SDF-1α and CXCR7 expression at 24 hours following reperfusion relative to the NSS group. These findings suggest that EPO pretreatment can reduce renal injury in rats caused by IRI. Mechanistically, this may be related to EPC mobilization and recruitment to injured renal tissues by SDF-1α and CXCR7.

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In phase 3 clinical studies, the addition of daratumumab to standard-of-care regimens consistently demonstrated a significant progression-free survival (PFS) benefit and improved depth of response, including minimal residual disease-negativity, in patients (pts) with newly diagnosed MM or RRMM. In the primary analysis of the phase 3 CASTOR study (median follow-up: 7.4 mo), D-Vd reduced the risk of disease progression or death by 61% (median PFS, not reached [NR] vs 7.2 mo; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28-0.53; P Methods: Eligible pts in LEPUS and CASTOR received ≥1 prior line of therapy and were randomized 2:1 in LEPUS and 1:1 in CASTOR to 8, 21-day cycles of V (1.3 mg/m2 SC) on Days 1, 4, 8, and 11, and d (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± D (16 mg/kg IV) given QW for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. The primary endpoint for both studies was PFS. Results: A total of 211 (D-Vd, n=141; Vd, n=70) pts in LEPUS and 498 (D-Vd, n=251; Vd, n=247) pts in CASTOR were randomized. The median (range) age was 61 (28-82) years for Chinese and 64 (30-88) years for global pts. In general, baseline characteristics were similar between Chinese and global pts and balanced between treatment arms, with the exception of median body weight (LEPUS: 67 kg; CASTOR: 76 kg). Chinese and global pts both received a median of 2 prior lines of therapy; 79% and 66% received prior V, 27% and 28% were refractory to lenalidomide, and 64% and 32% were refractory to their last prior line of therapy, respectively. After a median follow up of 8.2 months in LEPUS and 7.4 months in CASTOR, a consistent PFS benefit of D-Vd vs Vd was demonstrated in the pooled analysis set across age (60 mL/min) subgroups (Table 1). Median time to progression was also consistently prolonged with D-Vd vs Vd across pooled pt subgroups. Among response evaluable pts, D-Vd improved overall response rate, rate of very good partial response or better, and rate of complete response or better (Table 2) and prolonged median duration of response vs Vd in all pt subgroups. Additional data, including PFS2, from the pooled subgroups analysis will be presented at the meeting. The safety profile of D-Vd was generally consistent across pts in LEPUS and CASTOR. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Vd/Vd) occurring at a ≥5% frequency with D-Vd vs Vd in both Chinese and global pts included thrombocytopenia (51%/37%; 45%/33%), lymphopenia (44%/29%; 10%/3%), neutropenia (16%/6%; 13%/4%), and hypertension (12%/3%; 7%/1%). 49%/38% of Chinese and 42%/34% of global pts had ≥1 serious TEAEs. TEAEs leading to treatment discontinuation occurred in 4%/3% of Chinese and 7%/9% of global pts, and TEAEs leading to death occurred in 4%/10% of Chinese and 5%/6% of global pts. Rates of infusion-related reactions (IRRs) were similar for D-Vd across studies (LEPUS: 38%; CASTOR: 45%); most occurred during the first infusion and the majority were grade 1/2. Conclusions: D-Vd demonstrated a clinical benefit, including significantly improved PFS, in pooled Chinese and global pts with RRMM who received ≥1 prior line of therapy, regardless of age, cytogenetic risk status, or renal function. The safety profile of D-Vd was consistent across all pts, and no new safety concerns were identified. These results support the use of D-Vd in Chinese pts with RRMM. Disclosures Jin: The First Affiliated Hospital of Zhejiang University: Current Employment. Spencer:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cilag GmbH: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weisel:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Honoraria. Mateos:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka:Adaptive Technologies: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Gai:Janssen: Current Employment, Current equity holder in publicly-traded company. Liu:Janssen: Current Employment, Current equity holder in publicly-traded company. Yang:Janssen: Current Employment, Current equity holder in publicly-traded company.

Stem cell-based therapy has been suggested as a promising option for the treatment of renal ischemia-reperfusion injury (IRI). However, how to efficiently deliver stem cells remains a challenge. In the present study, we firstly proposed the utilization of kidney extracellular matrix hydrogel (ECMH) as an injectable scaffold for delivering adipose-derived mesenchymal stem cells (ad-MSCs) into ischemic kidneys. A modified strategy of decellularization and gelation was introduced to prepare the ECMH, by which the bioactive ingredients were retained as much as possible. Bioluminescence living imaging and immunofluorescence revealed that ECMH could significantly elevate the retention and survival rate of transplanted ad-MSCs in damaged kidneys and reduce their escape rate to other organs, which consequently resulted to the enhanced therapeutic effect of ad-MSCs on renal IRI. Further, in vitro evidence demonstrated that ECMH could remarkably reduce the oxidative stress and apoptosis, promote the proliferation, secretion, and epithelial differentiation of ad-MSCs, as well as facilitate cell migration while acting as a sustained-release scaffold. This study establishes an effective approach to enhance the therapeutic potential of ad-MSCs for renal IRI. Our findings suggest that ECMH derived from organs or tissues would be a promising injectable scaffold for stem cell-based therapy. STATEMENT OF SIGNIFICANCE: It remains a challenge to efficiently deliver stem cells to target tissues, which may limit the clinical application of stem cell-based therapy. In this study, we developed a modified strategy of decellularization and gelation to prepare the kidney extracellular matrix hydrogel (ECMH). In vivo and in vitro evidence indicated that the kidney ECMH could improve the retention and survival rate, as well as multiple biological functions of adipose-derived mesenchymal stem cells, thereby contributing to the histological and functional recovery of injured kidneys induced by ischemia-reperfusion. Our findings highlight the use of organs or tissues derived ECMH as a promising stem cell delivery scaffold for tissue repair.

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS’ function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

ZSM-5 zeolite was modified by Fenton's reagent, FeSO4 and H2O2 aqueous solutions using impregnation method, respectively. All these catalysts were characterized by XRD, ICP-OES, N2 adsorption-desorption, NH3-TPD, Py-FTIR and evaluated in propene oligomerization process. The results demonstrated that the framework of the parent ZSM-5 was well preserved after modification with Fenton's reagent, FeSO4 or H2O2 solutions. However, the SiO2/Al2O3 ratios for all the modified ZSM-5 samples increased due to the dealumination. Furthermore, Fe was detected in Fenton-ZSM-5 while no Fe was observed for FeSO4-ZSM-5 catalyst. The BET surface areas and total pore volumes of three modified catalysts significantly increased compared with the original ZSM-5 sample. Among them, the BET surface area of the Fenton-ZSM-5 increased by 17.86%. The increase of mesopores was probably caused by the removal of the residual organic template in the catalysts due to the generation of ·OH radicals by Fenton's reagent and H2O2. The Fenton-ZSM-5 catalyst formed new acid sites of Bronsted (B) and Lewis (L) with little change in the total calculated amount, which significantly changed the B/L ratio. Compared with the parent ZSM-5, the Fenton-ZSM-5 catalyst exhibited the best activity and stability for propene oligomerization reaction. The initial propene conversion and diesel selectivity were as high as 98.3% and 92.4%, respectively, and kept at >80% and >82% for about 24 h, respectively.

Waste C1 gases as alternatives to pure CO2 can potentially facilitate the practical application of microbial electrosynthesis (MES) for chemicals production and further decrease the total cost. Thi...

OBJECTIVE We aimed to investigate whether Chinese endoscopists without narrow-band imaging (NBI) experiences could achieve high accuracy in the real-time diagnosis of colorectal polyps using NBI International Colorectal Endoscopic (NICE) classification after web-based training. METHODS Altogether 15 endoscopists from five centers with no NBI experiences followed a short, web-based training program on the NICE classification and took web-based test. Their performances were compared with 15 matched experienced endoscopists with no NBI experience who received no NBI training. These 15 trained endoscopists then made real-time diagnoses of colorectal neoplasia. A logistic regression was used to assess potential predictors of diagnostic performance. RESULTS Compared with those who received no training, trained endoscopists achieved comparable overall accuracy (85.3% vs 83.1%, P = 0.408) and accuracy at a high-confidence level (87.0% vs 86.0%, P = 0.670), but had a higher confidence rate (86.1% vs 83.7%, P = 0.004) for the diagnosis of neoplasia. Real-time diagnostic accuracy, sensitivity and specificity were 94.3% (95% confidence interval [CI] 91.5%-96.2%), 96.2% (95% CI 93.4%-97.9%) and 85.3% (95% CI 74.8%-92.1%) at high-confidence level. The high-confidence level was the strongest predictor of real-time diagnostic accuracy (odds ratio 12.66, P

This paper presents a novel electromechanical brake (EMB) with automatic wear adjustment function, which has been ignored in most previous studies. With the aim of investigating the parameter characteristics of the EMB system and analyzing the proposed function, the mathematical models of the DC motor, motor friction, worm drive, ball screw and load are established in MATLAB/Simulink. The differences between the simulation and the experiment under step, triangular wave, square wave and sinusoidal input signals are discussed. The parameter characteristics of clamping force-motor current and clamping force-ball screw displacement are obtained, which also verifies that the established model is correct. The results demonstrate that the automatic wear adjustment function of the new EMB could guarantee that the brake stroke and response time remain consistent across each braking manoeuvre.

Objective: The present study aimed to investigate the function of lncRNA CASC15 (cancer susceptibility candidate 15) in hepatocellular carcinoma (HCC), as well as its regulatory roles in SOX4 expre...

Purpose: The early BCR-ABL1 reduction had the prognostic impact of the chronic-phase chronic myeloid leukemia (CML-CP) patients. This study was to find a more precise early prognosis index at 3 months in the patients with newly diagnosed CML-CP, especially for the patients with BCR-ABL1IS >10%. Methods: We retrospectively analyzed the data of 79 newly diagnosed CML-CP patients from October 2013 to April 2017. All patients took imatinib regularly and continuously and monitored BCR-ABL1 transcript level at baseline and 3, 6, 9, 12, 18 months after starting imatinib treatment. Results: Among the 44(55.7%) patients with BCR/ABL1IS ≤10% at 3 months after imatinib treatment, 12(27.3%) cases did not achieve major molecular response (MMR) at 12 months, and 7(14.9%) patients with the halving time BCR-ABL1 transcript ≤40 days failed to achieve MMR at 12 months. However, approximately twenty-six percent of the patients with BCR-ABL1IS >10% still obtained MMR. Moreover, the patients with BCR-ABL1IS ≤10% and halving time ≤40 days had a significantly better MMR than that of the patients with the BCR-ABL1IS ≤10% and halving time >40 days (88.6% versus 11.1%, P 10% and halving time >40 days rarely achieved MMR at 12 months. Conclusion: These data indicated that the halving time of BCR-ABL1 transcript was also an important prognostic factor as that of the BCR-ABL1IS. Combined observations of these two prognosis indexes are more accurate predictor for the long-term molecular response, especially for the CML-CP patients with BCR-ABL1IS >10%, and which is helpful for TKI switching as early as possible to improve patients' survival and reduce drug costs.

The C-X-C chemokine receptor 4 (CXCR4) has been reported to be involved in several cancer related processes. The current study was designed to investigate the role of CXCR4 in human kidney cancer and to unveil the underlying molecular mechanisms. The results showed the expression of CXCR4 to be significantly (P

Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) provides the majority of the catalytic site of the active P4H enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors. However, a pan-cancer analysis of P4HA1 has not been performed.Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 using the datasets of The Cancer Genome Atlas (TCGA) and Kaplan–Meier Plotter. Genomic and epigenetic alterations of P4HA1 and the correlation of P4HA1 with DNA methylation in different cancers were also analyzed across multiple databases. In addition, the purity-adjusted partial Spearman’s correlation test was utilized to evaluate the correlation between P4HA1 expression and immune cell infiltration. We also further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC).Results: We characterized the expression profiles and prognostic values of P4HA1 in multiple cancer types. P4HA1 expression was increased in clear cell renal cell carcinoma (RCC) compared to adjacent normal tissues, and P4HA1 positively correlated with the overall survival (OS) and disease-free survival (DFS) in papillary RCC. In addition, a positive correlation between P4HA1 expression and immune cell infiltration was observed in clear cell RCC. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability, and tumor mutation burden in chromophobe RCC. Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition of RCC cells.Conclusion: Overall, our study has suggested that P4HA1 might play a significant role in tumorigenesis in RCC and may be a prognostic biomarker and therapeutic target for several malignant tumors, including RCC.

Nitrogen removal of petrochemical wastewater through partial nitritation/anammox (PN/A) is appealing, but its feasibility and stability under toxic inhibition remain unclear. This study started a PN/A granular sludge system in a membrane bioreactor and fed it with diluted acrylic fiber wastewater. During long-term operation, the nitritation and anammox performance remained stable at a 30% volume ratio, and declined with increasing volume ratio, resulting in deteriorated nitrogen removal. Meanwhile, the short-term inhibition batch tests further showed that ammonia oxidation bacteria (AOB) in the flocs were suppressed while anammox bacteria (AnAOB) in the granules were not affected. Further analysis indicated suppression of AnAOB over the long-term operation, which was mainly caused by the disintegration of granules as demonstrated by sludge morphology. This selective inhibition is associated with variational sludge morphology, and the distribution of functional bacteria plays an important role in the feasibility and stability of PN/A treating acrylic fiber wastewater. As above, this study demonstrated the feasibility of PN/A for acrylic fiber wastewater treatment, but wastewater dilution or pre-treatment is still required for efficient nitrogen removal.