Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Chimeric antigen receptor (CAR) T-cell therapy has exhibited remarkable clinical efficacy in the treatment of relapsed/refractory multiple myeloma (R/RMM), and BCMA-targeted CAR-T cell therapy for R/RMM can achieve an effective rate of more than 90%, with more than 70% of patients obtaining complete response (CR).However, even among patients with CR, relapse and progression of the disease may still occur, and currently there are few reports on the effectiveness of a second CAR-T cell infusion with the same target after progression of disease. Aims: To preliminarily analyze the adverse reactions and clinical efficacy of receiving a second BCMA-targeted CAR-T cell infusion for R/RMM. Methods: The adverse reactions, clinical efficacy and factors affecting the clinical efficacy of a second (including a third) CAR-T cell infusion of R/RMM in the Department of Hematology of Shaanxi Provincial People’s Hospital performed from March 2021 to January 2022 were retrospectively analyzed, and the cut-off time of observation period was at the death of patient or February 26, 2023. Results: A total of 24 patients with R/RMM [males vs. females (13 vs. 11), median age of 57 years (44 years –70 years)] who received a second (including a third) BCMA-CAT-T cell infusion were included in this study, of which 70.8% (17/24) were type IgG, 16.7% (4/24) were type IgD, 4.2%(1/24) was type light-chain, and 8.3% (2/24) were type IgA. For the time from the first BCMA-CAT-T cell therapy, 45.8% (11/24) of the patients were more than 12 months and 54.2% (13/24) were less than 12 months. 54.2% (13/24) of the patients were converted the murine CAR-T to human CAR-T, and 45.8% of the patients received the same humanized infusion. 83.3% (20/24) of the patients received only one CAR-T cell infusion before, and 16.7% (4/24) of the patients received twice in the past. After the BCMA-CAR-T infusion, 58.3 % (14/24) of patients had cytokine release syndrome (CRS), of which 50% (12/24) had grade 1 CRS, 8.3% (2/24) had grade 2 CRS, and only 4.2% (1/24) had grade 1 central nervous system reaction. The median observation time was 5 months (range: 1-18 months). The overall response rate (ORR) was 83.3 % (20/24), among which，41.6% of the patients achieved complete response (CR), 16.7% (4/24) achieved very good partial response (VGPR), and 25% (6/24) achieved partial response (PR). 25% (6/24) of the patients died during the observation period, and the overall survival rate at 12 months was 51.8 %. Summary/Conclusion: The patients with R/RMM who had received BCMA-CAR-T infusion and afterwards showed progressive disease or relapse, could receive a second BCMA-CAR-T therapy. Keywords: CAR-T, Multiple myeloma

Background: In clinical hematology, diffuse large B-cell lymphoma (DLBCL) is notably heterogeneous and varies in prognosis. Serum albumin (SA) is considered a biomarker of prognostic value in a number of hematologic malignancies. However, current knowledge of the association between SA levels and survival is limited, especially in DLBCL patients aged >= 70 years. Thus, this study sought to assess the prognostic value of SA levels among this age group of patients. Methods: The data of DLBCL patients aged >= 70 years at the Shaanxi Provincial People's Hospital in China from 2010 to 2021 were retrospectively reviewed. The SA levels were measured using standard procedures. The Kaplan-Meier method was used to estimate survival time, and the Cox proportional hazards model for time-to-event data was used to identify potential risk factors. Results: The data of 96 participants were included in the study. The univariate analysis showed that B symptoms, Ann Arbor stage III or IV of the disease, high International Prognostic Index (IPI) scores, high NCCN-IPI scores, and low SA levels were prognostic factors for an undesirable overall survival (OS) rate. The multivariate analysis showed that a high SA level (hazard ratio: 0.43; 95% confidence interval: 0.2-0.88; P=0.022) was an independent prognostic factor of superior outcomes. Conclusions: An SA level >= 4.0 g/dL was identified as an independent biomarker of prognostic value for DLBCL patients aged >= 70 years.

Introduction It has been made great commercial success in hematological malignancies by chimeric antigen receptor (CAR) T cell therapy. However, high rate of adverse events (AEs) still remains an issue. Non-viral Genome Targeting CAR (gtCAR) delivery technology, which uses CRISPR-Cas9 to insert CAR DNA to TRAC locus specifically in human T cells, produces moderate CAR-T cells compared with conventional ones. Earlier results of SC-gtCAR19, an anti-CD19 gtCAR-T candidate from an investigator initiated Phase I clinical trial (ChiCTR2000031942) demonstrated a favorable benefit-risk profile in relapsed/refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL) patients. Reported here are updated long-term follow-up results. Objective The primary objective is to assess safety. Secondary objective is to evaluate efficacy. Level of CAR-T cell in blood was explored. Method This is a single center, open-label and single-arm trial. Patients or allogeneic donors underwent leukapheresis and their CD3+ T cells were selected and modified by non-viral vector to produce SC-gtCAR19. A standard lymphodepletion chemotherapy was performed. The median dose was 3.89×106CAR+ cells/kg (0.58-8.31×106/kg). AEs were graded according to CTCAE v5.0. Cytokine Release Syndrome (CRS) and neurological events (NEs) were graded by ASTCT consensus grading. Relapse defined as bone marrow (BM) blast or B-ALL related mutation gene positive from nonexistence regardless of specific value, and extramedullary disease (EMD) occurrence. Result As of May 1st 2022, twenty-two r/r B-ALL patients received SC-gtCAR19 (Table 1). The median age was 29 (13-61), and the median number of previous regimen was 5 (2-16). The median baseline BM blast after preconditioning was 44.1% (0.3-99%), particularly 73% of patents with high disease burden (>25% leukemic blast). Five patients (23%) once had stem cell transplantation (SCT), and 14 (64%) have B-ALL related chromosomal and molecular abnormalities. One patient has EMD. No patient has been treated by any other CD19 related therapy before enrollment. The most common AEs of any grade were anaemia (100%), pyrexia (91%), neutrophil count decreased (91%), and white blood cell count decreased (86%) (Table 2). CRS occurred in 20 patients (91%), and 4 of them (18%) with grade 3 CRS. The median time to CRS onset was 7 days (IQR 7-14), and the median duration of any grade CRS was 3 days (IQR 2-5). Three patents developed NEs, one was grade 2 and 2 were grade 3 (temporary seizure, related to infection and patient's cerebral infarction before enrollment). No fatal or life-threatening events happened. No Tocilizumab administered, four patients used vasopressors and 2 steroids for treatment of CRS. All patients were eligible for efficacy analysis. At Day 28, the overall response rate was 100%, with 9 (41%) patients achieving complete remission (CR), ten (45%) achieving complete remission with incomplete haematological recovery (CRi), and 3 (14%) with blast-free hypoplastic. Among them, twenty patients (91%) achieved minimum residual disease (MRD) negative CR, and those 2 patients with MRD positive CR were assessed undetectable BM MRD in Day 90. Patient with EMD, the nodal lesions in her breast disappeared at Day 60. At a median follow-up of 19.9 months (4.5-26.6), nineteen patients relapsed, within which 7 (36.8%) antigen escape relapse. The median duration of remission for 19 patients achieving CR/CRi was 8 months (2.5-NE). All patients received a consolidation treatment by Lenalidomide 3 months after infusion on condition of CR status until disease progression/death, and all of them did not receive SCT afterwards before relapse. As of the data cutoff, two patients (9%) had ongoing CR with median follow-up of 22.4 months. The median relapse-free survival for 19 patients was 8.9 months (2.9-NE) (Figure 1). The median OS was 24.2 months (3.7-NE) (Figure 2). CAR T cell level measured by cell copies percentage per peripheral blood mononuclear cells peaked at median 12 days (IQR 10-13) (Figure 3). The median peak percentage of copies was 53% (IQR 26.5-72.1%). Conclusion This study is the first clinical trial applied a gtCAR-T candidate for r/r B-ALL treatment. SC-gtCAR19 has a better risk-tolerance. Despite TCR gene knocked-out, gtCAR-T cell proliferation and its function both short and long term may not be influenced. We illustrate that this novel approach is feasible in terms of manufacture and clinical application. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction Multiple Myeloma (MM) is an incurable malignant hematological disease. Even though treated with systematic therapies, most patients reoccurred and developed into relapsed/refractory MM. The progression of MM has various manifestations, of which secondary plasma cell leukemia and extramedullary infiltration belong to late stage manifestations, with the worst clinical prognosis. Previous studies have shown that CAR-T therapy targeting BCMA can effectively improve the clinical prognosis of most R/R MM, but there is limited research on the clinical efficacy of CAR-T on R/R MM with extramedullary lesions. Objective To observe the adverse reactions, clinical efficacy, and duration of efficacy of humanized BCMA-CAR-T in R/R MM treatment with extramedullary lesions. Methods We retrospectively analyzed the data of R/R MM patients with extramedullary lesions who received autologous BCMA-CAR-T therapy in Shaanxi Provincial People's Hospital from March 2021 to May 2022 (Registration NO. CHiCTR2100043093), including the adverse reactions, efficacy of CAR-T therapy, and the duration of improvement. Follow-up analysis was up to July 25, 2022, or the date of patient death. Results We evaluated the therapy in a large cohort of 37 R/R MM patients with extramedullary invasion that comprised both males (n = 21) and females (n = 16), aged between 41 and 68 years old (median age = 58). The types of immunoglobulin included light chain 21.3% (8/37), IgG 37.8% (14/37), IgA 24.3% (9/37), and IgD 13.5% (5/37). Patients with ECOG score more than 2 accounted for 70.2% (26/37), of which 16.2% (6/37) of them were paraplegia with extramedullary infiltration. Patients with extramedullary involvement in a single site accounted for 51.3% (19/37), while 48.7% (18/37) of them involved ≥ 2 sites. The median number of previous treatment lines was 3 (2-7), with 54.1% (20/37) of patients received autologous hematopoietic stem transplantation, and 21.6% (8/37) received CAR-T infusion in the past. Cytokine Release Syndrome (CRS) occurred at the 4th hour after infusion and lasted for 4h to 16d (median time = 5d). The occurrence of CRS was 94.5% (34/37), with CRS ≤2 91.8% (34/37), CRS = 3 2.7%, and CRES = 1 8.1% (3/37). All the patients were treated for more than 1 month, with 70.2% (25/37) treated for more than 3 months and 27.0% (12/37) treated for more than 6 months. After 1 month of treatment, the Overall Response Rate (ORR) was up to 97.3% (36/37), including Complete Remission (CR), Very Good Partial Remission (VGPR), and Partial Remission (PR). Among them, CR was 18.9% and VGPR was 43.2%. After 3 months of treatment, ORR was 56% (14/25), CR was 20% (5/25), VGPR was 32% (8/25), while 8.0% (2/25) died due to serious infection (paraplegia with lung infection). After 6 months, ORR was 66.7% (8/12), with 58.3% CR (7/12). However, 33.3% (4/12) showed Disease Progression (PD), of which 16.7% (2/12) died. Conclusion Our study shows autologous humanized BCMA-CAR-T treatment of MM with extramedullary lesions is effective, but the duration of improvement is short. The long-term efficacy needs to be demonstrated by more clinical studies.

Abstract Introduction Multiple myeloma is a hematological malignancy that is prone to be companied by bone marrow destruction, renal impairment and extramedullary infiltration. Current treatments include proteasome inhibitor, immunomodulatory drug, hematopoietic stem cell transplantation, and monoclonal antibody targeted therapies. However, it is still clinically incurable. Chimeric antigen receptor (CAR) T-cell therapy is a new immune targeted therapeutic strategy. It is reported better clinical efficacy for relapsed/refractory multiple myeloma (r/r MM) treatment has been achieved by immunotherapies targeted B-cell maturation antigen (BCMA). Therefore, it is important to investigate the treatment of a novel human BCMA-specific CAR-T therapy for r/r MM. Objective The objective of this clinical study is to evaluate the safety and efficacy of the novel human BCMA-targeting CAR-T therapy in patients with r/r MM, especially patients who relapsed from prior CAR-T therapy. Method This work is a clinical study registered and investigated by our center. CD3+ T cells were negatively selected from patients' peripheral blood mononuclear cells, activated and modified by lentivirus to produce anti-BCMA CAR-T cells. The cells were administrated intravenously to patients after expanding for 7-13 days in vitro. 24 patients had enrolled in this study, with 13 males and 11 females. The median age was 53 years old (range,41-75), and patients with cytogenetically high risk factors accounting for 41.66% (10/24). 50% (12/24) was infiltrated with extramedullary lesions. 16.6% (4/24) of them had relapsed from other CAR-T therapies before this enrollment. 50% (12/24) had been previously conducted autologous hematopoietic stem cell transplantation (HSCT), whereas 4.16% (1/24) with allogeneic HSCT. Patients with the expression of BCMA in the plasma cells higher than 30%, accounted for 25% (6/24). 2-3 days after being administered the lymphodepleting chemotherapy regimen, CAR-T cells were infused intravenously. The indicators of patients' condition were detected, including inflammatory cytokine concentration, serum protein levels, CAR-T cell number copies, and the proportion of plasma cells by bone marrow biopsy. The improvement of patients, the occurrence of adverse reactions, the incidence and grade of cytokine release syndrome (CRS), was analyzed and evaluated. Result All patients received infusions of CAR-T positive cells at the average dose of 9.45×10 6/kg (5-17.5) and the median injection day is the 10th day (8th-13th day) after cell isolation. After infusion, 100% (24/24) of the patients had fever lasting for 48 hours, with 37.5% (9/24) of them showing low blood pressure and being treated with drug. Heart rate increase was found in 45.8% (11/24). Nausea, diarrhea and transient consciousness disorder occurred in 50% (12/24), 33.3% (8/24), and 12.5% (3/24) of them, respectively. 16.6% (4/24) was administrated with dexamethasone to relieve symptoms, with the total dose less than 20 mg, while nobody was treated with IL-6 receptor antagonist. CAR-T cells had expanded in all patients, reaching the peak at the 4th day after infusion (Figure). The levels of IL-6, IL-8 and IFN-γ in peripheral blood also increased significantly. The incidence of CRS is 100%, of which grade I, II and III is 62.5%, 33.3% and 4.2%, respectively. 2 patients showed grade I CRES, constituting 8.3% (2/24). All patients were assessed for the efficacy of CAR-T cells 2 weeks after infusion. ORR was 100%, with 4.2% (1/24) MR, 8.3% (2/24) PR, 62.5% (15/24) VGPR and 25% (6/24) CR. 18 patients were treated for more than 1 month, with 11.1% (2/18) PR, 44.4% (8/18) VGPR, 11.1% (2/18) CR, and 33.3% (6/18) sCR. 16 patients were infused before more than 2 months, with 25% (4/16) VGPR, 12.5% (2/16) CR, 50% (8/16) sCR, and 12.5% (2/16) PD. 6 patents were administrated more than 3 months ago, with 1 developing deep remission to sCR from VGPR. The others remain the same condition. Conclusion The novel human BCMA targeted CAR-T cell therapy of this study showed safety and efficacy in the treatment of r/r MM patients with extramedullary infiltration, high-risk cytogenetical factors as well as relapse with prior BCMA CAR exposures. Deep remission can be achieved. However, more observation need to be conducted. The CAR-T treatment of BCMA target still cannot prevent the disease progress of a small numbers of patients. The control after CAR-T therapy needs more investigation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

SRY-related high-mobility-group box 12 (SOX12) has currently emerged as a key cancer-related protein in multiple human cancer types. However, little is known about the relevance of SOX12 in multiple myeloma (MM). The current study aimed to investigate the potential role of SOX12 in MM. Our results demonstrated that SOX12 expression was markedly elevated in MM cell lines. A series of cellular assays demonstrated that SOX12 knockdown significantly reduced the proliferation and colony formation, and upregulated cell apoptosis of MM cells. By contrast, SOX12 overexpression promoted the proliferation, colony formation and decreased the apoptosis of MM cells, results that reveal its oncogenic effects. SOX12 regulated β-catenin expression and TCF/LEF transcriptional activity. Moreover, the SOX12-knockdown-mediated antitumor effect in MM cells was significantly reversed by transfecting a β-catenin expression vector. Notably, SOX12 inhibition retarded tumor growth in vivo of a MM-derived mouse xenograft model. In conclusion, our results suggest a potential oncogenic function for SOX12 in MM. Our findings reveal that SOX12 knockdown inhibits the growth of MM cells by downregulating the Wnt/β-catenin signaling pathway, results that imply SOX12 may represent a novel therapeutic target for MM treatment.

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft- versus -host disease (G v HD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

Introduction: It has been made great clinical progresses in hematological malignancies by chimeric antigen receptor (CAR) T cell therapy which utilizes virus vector for manufacture. However, there're still issues unresolved, for instance, sophisticated virus production process, deadly Cytokine Release Syndrome (CRS) side-effect, and high recurrence rate, which probably limit the availability of CAR-T therapy. Non-viral Genome Targeting CAR-T (nvGT CAR-T) may provide a feasible solution to those unmet needs mentioned above. We used CRISPR-Cas9 and non-viral vector to insert anti-CD19 CAR DNA to a specific genome locus in human T cells, which in theory, produces more moderate CAR-T cells compared with conventional CAR-T cells. The efficacy of anti-CD19 nvGT CAR-T cells had been demonstrated in our previous pre-clinical studies, and in this Phase I clinical trial (ChiCTR2000031942), its safety and efficacy in relapsed/refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL) patients were explored. Objective: The primary objective of this Phase I trial is to assess safety, including evaluation of adverse events (AEs) and AEs of special interest, such as CRS and neurotoxicity. Secondary objective is to evaluate efficacy as measured by the ratio of complete remission (CR). Method: Peripheral blood mononuclear cells were collected from patients or allogeneic donors, then CD3+ T cells were selected and modified by nvGT vector to produce anti-CD19 CAR-T, then administrated to patients with r/r B-ALL. Up to July 2020, twelve patients with r/r B-ALL had been enrolled in this study and 8 patients completed their treatments and entered follow-up period. For 8 patients with follow-up data, the median age was 33 years (range, 13 to 61), and the median number of previous regimens was 5 (range, 2 to 11). The median baseline percentage of bone marrow (BM) blast is 72% (range, 24.5% to 99%). Among those subjects, 2 patients once have been conducted autologous or allogeneic hematopoietic stem cell transplantation (Auto-HSCT or Allo-HSCT), and 2 patients experienced serious infection before CAR-T infusion. No patient has been treated by any other CAR-T therapy before enrollment. Baseline characteristics refer to Table 1. Administering a lymphodepleting chemotherapy regimen of cyclophosphamide 450-750 mg/m2 intravenously and fludarabine 25-45 mg/m2 intravenously on the fifth, fourth, and third day before infusion of anti-CD19 nvGT CAR-T, all patients received an infusion at dose of 0.55-8.21×106/kg (Table 1). Result: Until day 30 post CAR-T cell infusion, 8/8 (100%) cases achieved CR and 7/8 (87.5%) had minimal residual disease (MRD)-negative CR (Table 1). Anti-bacterial and anti-fungal were performed in patients SC-3, SC-4 and SC-5 after CAR-T cell infusion, which seems no influence on efficacy. Patient SC-7 was diagnosed as T-cell Acute Lymphoblastic Leukemia before Allo-HSCT but with recent recurrence of B-ALL, which was MRD-negative CR on day 21 post nvGT CAR-T therapy. Up to July 2020, all cases remain CR status. CRS occurred in all patients (100%) receiving anti-CD19 nvGT CAR-T cell, including 1 patient (12.5%) with grade 3 (Lee grading system1) CRS, two (25%) with grade 2 CRS, and 5 (62.5%) with grade 1 CRS. There were no cases of grade 4 or higher CRS (Table 1). The median time to onset CRS was 9 days (range, 1 to 12 days) and the median duration of CRS was 6 days (range, 2 to 9 days). None developed neurotoxicity. No fatal or life-threatening reactions happened and no Tocilizumab and Corticosteroids administered following CAR-T treatment. Data including body temperature (Figure 1), CAR-positive T cell percentage (Figure 2), Interleukin-6 (IL-6) and Interleukin-8 (IL-8) (Figure 3 and 4), C-reactive Protein (CRP) (Figure 5), Lactate Dehydrogenase (LDH) (Figure 6), and Procalcitonin (PCT) (Figure 7), are in accordance with the trend of CRS. Conclusion: This Phase I clinical trial primarily validates the efficacy of this novel CAR-T therapy, however, it still needs time to prove its durability. Surprisingly, we find that nvGT CAR-T therapy is seemingly superior than viral CAR-T therapy in terms of safety. All subjects which are high-risk patients with high tumor burden had low grade CRS, even a few patients sent home for observation post infusion with limited time of in-patient care. Furthermore, patients could tolerate a higher dose without severe adverse events, which probably bring a better dose-related efficacy. Disclosures No relevant conflicts of interest to declare.

Colorectal cancer (CRC) is one of the most common malignancies with high levels of invasiveness, drug resistance and mortality, but the internal mechanisms of CRC are largely unknown. MicroRNAs (miRs) have been reported to be involved in the development of CRC, and numerous studies have demonstrated that the abnormal expression of miR-33a-5p might be associated with CRC. However, the function and downstream mechanism of miR-33a-5p in colorectal cancer (CRC) remains unclear. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folic acid metabolism, interestingly was confirmed to be one of the target genes of miR-33a-5p in the present study. We first confirmed that miR-33a-5p in CRC tissues and cell lines were downregulated (P < 0.05), and that the proliferation, clone formation capacities, G1/S progression, and migration capacities of the two CRC cell lines HCT116 cells and HT29 were suppressed by miR-33a-5p overexpression in vitro (P < 0.05). Ctrl HCT116 and miR-33a-5p-overexpressing HCT116 were injected into nude mice. In vivo tumour formation was significantly suppressed by miR-33a-5p overexpression (P < 0.05) as well as the proliferation marker Ki67 (P < 0.05). Additionally, MTHFD2 protein expression was significantly enhanced in CRC tissues. From bioinformatics predictions and a luciferase report analysis, MTHFD2 was confirmed to be one of the target genes of miR-33a-5p. In contrast to the role of miR-33a-5p overexpression, MTHFD2 overexpression promoted the proliferation and migration of HCT116 and HT29 cells (P < 0.05), which confirmed that MTHFD2 was a functional target gene of miR-33a-5p. In conclusion, miR-33a-5p inhibits the growth and migration of CRC by targeting MTHFD2.

Background: The aim of this study was to investigate OCB among physicians in China and explore whether their job satisfaction mediates the association between doctor-patient relationship (DPR) and organizational citizenship behavior (OCB). Methods: This cross-sectional, questionnaire-based survey was conducted among 1400 physicians in Shaanxi, China in 2014. The subjects were selected using a multi-stage cluster sampling methodology. The self-administered questionnaires included OCB Scale, DDPRQ, and PJSQ. Hierarchical linear regression analysis was used to estimate the effects of job satisfaction on the association between DPR and OCB. Results: DPR negatively predicted four dimensions of OCB, including conscientiousness, sportsmanship, civic virtue, and altruism. DPR was negatively related to five job satisfaction dimensions, namely work satisfaction (WS), promotion satisfaction (PS), reward satisfaction (RS), supervision satisfaction (SS), and environment satisfaction (ES). WS was positively correlated with conscientiousness and civic virtue; PS and SS were positively related to all four OCB dimensions; RS was positively related with civic virtue and altruism, and ES was positively correlated with conscientiousness and civic virtue. WS and PS partially mediated the association between DPR and conscientiousness; PS and SS partially mediated the relation between DPR and sportsmanship; PS, SS, and ES mediated the association between DPR and civic virtue; and PS, RS and SS partially mediated the relation between DPR and altruism. Conclusion: Job satisfaction mediated the association between DPR and OCB among Chinese physicians. The poor DPR possibly reduce physicians’ job satisfaction, thereby causing a decline of OCB in hospitals. Therefore, DPR improvement and job satisfaction have a great potential to promote physicians’ job performance in China.

Current methods for diagnosing thyroid carcinoma are time consuming or expensive. Thus, alternative approaches are required. In the present study, microRNAs (miRNAs) with higher sensitivity and specificity were screened while distinguishing between differentiated thyroid carcinoma (DTC) and subtype papillary thyroid carcinoma (PTC). A total of 120 cases suspected of having thyroid carcinoma were selected and examined using clinical color Doppler ultrasound, and computed tomography scan at the same time. The tissue specimens were obtained with fine needle aspiration, multiphase biopsy and surgical resection. The expression of miR146b, miR221 and miR222 was detected uisng the RT-quantitative polymerase chain reaction method. The receiver operating characteristic curve was used to obtain the cut-off value. Pathological examination identified 8 cases of normal thyroid tissue; 9 cases of hyperplastic nodules; 12 cases of thyroid adenoma; and 91 cases of thyroid carcinoma, of which 59 cases were DTC, 15 cases were follicular carcinoma and 17 cases were undifferentiated carcinoma. In the thyroid carcinoma, the expression levels of miR146b, miR221 and miR222 were significantly higher than those of other tissues (P<0.05). The expression levels of these miRNAs in the differentiated type were also significantly higher than those in the undifferentiated type (P<0.05). A comparison of the differentiated subunit identified no statistically significant difference (P>0.05). Following diagnosis of DTC, the area under curve (AUC) of miR146b, miR221 and miR222 was 0.832, 0.806 and 0.745, respectively; the cut-off values were 1.346, 1.213 and 1.425, respectively; susceptibility was 72.8, 71.5 and 68.7%, respectively; and specificity was 62.3, 60.9 and 59.3%, respectively. The AUC of the combined miR-146b and -221 following diagnosis of PTC was 0.695; the cut-off values were 1.506 and 1.462, respectively; susceptibility was 78.9%; and specificity was 68.5%. The AUC of the combined miR-146b and -222 was 0.677; the cut-off values were 1.523 and 1.443, respectively; susceptibility was 76.3%; and specificity was 66.4%. The AUC of the combined miR-221 and -222 was 0.662; the cut-off values were 1.564 and 1.437, respectively; susceptibility was 74.9%; and specificity was 68.2%. In conclusion, miR146b, miR221 and miR222 may be used as susceptibility and specificity indices of DTC, although they cannot be used as susceptibility or specificity indices for distinguishing PTC. Combining the two indices together can improve diagnostic accuracy to a certain extent.