Gestational Exposure to PM2.5 and Specific Constituents, Meconium Metabolites, and Neonatal Neurobehavioral Development: A Cohort Study.

Exposure to fine particulate matter (PM2.5) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.

Three times spontaneous remission of severe aplastic anemia following granulocyte transfusion from related donors: a case report and literature review.

Aplastic anemia (AA) is a bone marrow failure disease caused by abnormal activation of T lymphocytes, resulting in the apoptosis of hematopoietic cells and bone marrow failure. Currently, hematopoietic stem cell transplantation (HSCT), immunosuppressive - therapy (IST), and supportive care (e.g. transfusion adjuvant therapy, hematopoietic growth factors, and prevention of infection) are the main treatments of AA. Granulocyte transfusion has recently been accepted as an useful adjuvant therapy of HSCT and intensive IST. This article reported a severe AA patient who failed to respond to IST, but achieved spontaneous remission three times after granulocyte transfusions from related donors. Such cases have rarely been reported. Existence of human leukocyte antigen (HLA) cross between the patient and his relatives may influence the T cell-mediated immunity, which might explain this patient's recovery.

[Validity of Caprini risk assessment model in identifying high venous thromboembolism risk patients among hospitalized medical patients].

OBJECTIVE: To test the validity of Caprini risk assessment model in identifying high venous thromboembolism (VTE) risk patients among hospitalized medical patients. METHODS: A retrospective case-control study was performed among hospitalized medical patients admitted into West China Hospital, Sichuan University from January 2010 and December 2011. A total of 218 patients with definite VTE during hospitalization were recruited. And 394 controls were randomly selected from the patients without VTE admitted into the same departments within the same period. The risks of both cases and controls were retrospectively assessed with the Caprini risk assessment model. RESULTS: The average Caprini cumulative risk score in cases was significant higher than that in controls (4.9 ± 2.6 vs 3.2 ± 2.0, P = 0.000). There was no significant difference in the risk of VTE between the patients at a low risk by Caprini model and those at a moderate risk (OR = 1.26, 95%CI: 0.62-2.56). Compared with a low risk, those with a high risk were associated with 2.00-fold increased risk of VTE (95%CI: 1.10-3.61), a highest risk was associated with 5.76-fold increased risk of VTE (95%CI: 3.24-10.24) (both P < 0.05) . When further stratifying the highest risk level with cumulative risk score ≥ 5 into 5-6, 7-8, and ≥ 9 risk level, the patients with score 5-6 were associated with 4.15-fold increased risk of VTE (95%CI: 2.28-7.56), those with score 7-8 11.13-fold increased risk of VTE (95%CI: 4.88-25.36) and those with score ≥ 9 21.00-fold increased risk of VTE (95%CI: 6.34-69.52) compared with low risk counterparts. CONCLUSION: Caprini risk assessment model can effectively and quantitatively assess the risk of VTE among hospitalized medical patients based on their individual VTE risk factors.

Preemptive inotuzumab ozogamicin eradicated measurable residual disease in Ph-negative acute lymphoblastic leukemia relapsed post CD19 CART therapy.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Identifying factors affecting willingness to participate in floating population health volunteer services by Chinese volunteers based on the theory of the planned behavior expansion model.

China has the world's largest internal migrant population, called the floating population. Compared to local residents, the floating population utilizes different health services and relies heavily on health volunteer services for supplementary services. In this study, the theory of planned behavior model was used to study the willingness of volunteers to participate in floating population health volunteer services. We examined the effects of several factors on willingness to participate and found that attitude and subjective norm, but not perceived behavioral control, have significant predictive effects on willingness to participate in health volunteer services. Furthermore, altruistic values, social incentives, and personality traits not only have significant predictive effects on volunteer participation but also indirectly affect willingness through attitude and subjective norms. These findings help us understand what factors affect volunteers' willingness to provide health services to the floating population and have important implications for mobilizing volunteers for floating population health services.

[Comparison of Therapeutic Efficacy between Hypomenthylating Agents Combined with Venetoclax and Half Dose Priming Regimen in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia].

OBJECTIVE: To compare the clinical efficacy and safety of hypomenthylating agents (HMA) combined with Venetoclax (VEN) and half dose priming regimen (CAG-like) in the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy. METHODS: The clinical data of 43 newly diagnosed elderly patients with AML who were not suitable for intensive chemotherapy in our hospital from April 2019 to October 2020 were retrospectively analyzed. Among them, 16 cases received HMA-VEN regimen and 27 cases received HMA-CAG-like regimen. The remission rate, early mortality and survival were compared between the two groups. And, the patients were grouped according to HCT-CI score. The effects of two different regimens in different groups on the efficacy and survival of patients were compared, and the prognosis of patients was further analyzed. RESULTS: After one course of treatment, the total remission rate of HMA-VEN group and HMA-CAG-like group was 81.3% (13/16) and 51.9% (14/27), respectively, and the difference between the two groups was statistically significant (χ2=4.650, P=0.045). The median overall survival (OS) time of HMA-VEN group had not yet reached, while that of HMA-CAG-like group was 11.2 months, and the HMA-VEN group had a longer OS (P=0.055). There was no tumor lysis syndrome occurred in both groups. The main adverse reactions were digestive tract reaction, bone marrow suppression and infection. The amount of agranulocytosis infection, pulmonary infection and platelet infusion in HMA-VEN group were significantly lower than those in HMA-CAG-like group (P<0.05), while the time of agranulocytosis and amount of erythrocyte infusion were similar (P>0.05). In HMA-Ven group 1 case died early, while in HMA-CAG-like group 8 cases died early due to pulmonary infection, respiratory failure, cerebral hemorrhage, and alveolar hemorrhage, the mortality in HMA-CAG-like group was significantly higher than that in HMA-VEN group (P=0.043). Among 43 patients, there was a significant difference in OS between HCT score 0-2 group and ≥3 group (P=0.033). In HMA-CAG-like group, patients with HCT score ≥3 had a worse prognosis (P=0.01), while in HMA-VEN group patients showed no statistically significant difference in prognosis (P=0.681). In HCT score 0-2 group, 9 cases receiving HMA-VEN regimen and 22 cases receiving HMA-CAG-like regimen showed no statistical difference in OS (P=0.281). In HCT score ≥3 group, 7 cases receiving HMA-VEN regimen had a longer OS than 5 cases receiving HMA-CAG-like regimen (P=0.015). CONCLUSION: Venetoclax combined with HMA can achieve higher response rate, lower early mortality, and longer OS, especially in those with more comorbidities and poor tolerability.

circ_0005379 inhibits the progression of oral squamous cell carcinoma by regulating the miR-17-5p/acyl-CoA oxidase 1 axis.

OBJECTIVES: To investigate the effects of circ_0005379 on the proliferation, apoptosis, migration, and invasion of oral squamous cell carcinoma (OSCC) cells and its mechanism. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of circ_0005379 and miR-17-5p in OSCC tissues and SCC15 cell lines. Western blot was used to detect the expression levels of acyl-CoA oxidase 1 (ACOX1). The circ_0005379 overexpression vector was transfected into SCC15 cells. Methyl thiazolyl tetrazolium blue staining, flow cytometry, Transwell, and Western blot were used to detect the effects of circ_0005379 overexpression on the proliferation, apoptosis, migration, and invasion of SCC15 cells and the expression of E-cadherin, ß-catenin, and Snail proteins. Dual luciferase reporter assay and RNA immunoprecipitation were used to examine the regulation of circ_0005379, miR-17-5p, miR-17-5p, and ACOX1 in SCC15 cells. A nude mouse xenograft model of SCC15 cells stably overexpressing circ_0005379 was established, and the effect of circ_0005379 overexpression on the growth of xenografts in nude mice was observed. RESULTS: Compared with adjacent cancer tissues, the expression levels of circ_0005379 and ACOX1 proteins in OSCC tissues were decreased (P<0.05), and the expression level of miR-17-5p was increased (P<0.05). Compared with HOK-16A cells, the expression levels of circ_0005379 and ACOX1 proteins in SCC15 cell lines were decreased (P<0.05), and the expression level of miR-17-5p was increased (P<0.05). After overexpressing circ_0005379, the activity and number of migrating and invading SCC15 cells and the expression levels of ß-catenin and Snail proteins were decreased (P<0.05); however, the apoptosis rate and expression level of E-cadherin protein were increased (P<0.05). In SCC15 cells, circ_0005379 targeted the negative regulation of miR-17-5p expression, and miR-17-5p targeted the negative regulation of ACOX1 expression. Overexpressing miR-17-5p or silencing ACOX1 could reverse the effects of circ_0005379 overexpression on the proliferation, apoptosis, migration, and invasion of OSCC cell lines. The tumor volume and weight of nude mice overexpressing circ_0005379 were decreased (P<0.05), the expression levels of circ_0005379 and ACOX1 protein in tumor tissues were increased (P<0.05), and the expression level of miR-17-5p was decreased (P<0.05). CONCLUSIONS: circ_0005379 may inhibit the proliferation, migration, and invasion of OSCC cells by downregulating the expression of miR-17-5p and upregulating ACOX1, which promote apoptosis and inhibit tumor growth in vivo. circ_0005379 may be a potential target for OSCC treatment.

A Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia.

OBJECTIVE: To explore the role of chidamide, decitabine plus priming regimen in the salvage treatment of relapsed/refractory acute myeloid leukemia. METHODS: A clinical trial was conducted in relapsed/refractory acute myeloid leukemia patients using chidamide, decitabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor, termed CDIAG, a double epigenetic priming regimen. RESULTS: Thirty-five patients were recruited. Three patients received 2 treatment cycles. In 32 evaluable patients and 35 treatment courses, the completed remission rate (CRR) was 42.9%. The median OS time was 11.7 months. The median OS times of responders were 18.4 months, while those of nonresponders were 7.4 months (P = 0.015). The presence of RUNX1 mutations was associated with a high CRR but a short 2-year OS (P = 0.023) and PFS (P = 0.018) due to relapse after treatment. The presence of IDH mutations had no effect on the remission rate (80.0% vs. 73.3%), but showed a better OS (2-year OS rate: 100.0% vs. 28.9%). Grade 3/4 nonhematological adverse events included pneumonia, hematosepsis, febrile neutropenia, skin and soft tissue infection and others. CONCLUSION: The double epigenetic priming regimen (CDIAG regimen) showed considerably good antileukemia activity in these patients. Adverse events were acceptable according to previous experience. The study was registered as a clinical trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier:NCT03985007.

Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

Few studies have described chimeric antigen receptor-modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report.

BACKGROUND: Extramedullary relapse is an important cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). This type of relapse is commonly observed in the central nervous system, while it is rare in the testicles and skin. Chimeric antigen receptor-modified T cell (CAR-T) therapy targeting CD19 has shown to be a beneficial treatment approach for relapsed/refractory B cell acute lymphoblasticleukemia (r/r B-ALL). Yet, few studies have reported data regarding the treatment of extramedullary B-ALL relapse, especially both in skin and testicle, with CAR-T therapy. CASE PRESENTATION: Here we reported a single case of a patient with relapsed B-ALL in skin and testicle who was successfully treated by the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy. A 29-year-old man with relapsed B-ALL in skin and testicle was enrolled in clinal trial involving the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy (ClinicalTrials.gov number, NCT03919240). The patient had toxicity consistent with the grade 1 cytokine release syndrome. CONCLUSIONS: ssCART-19 therapy may be used to effectively eliminate infiltrating leukemia cells in the skin and testicle with mild toxicity, which could be a much safer approach to bridge allo-HSCT, thus further improving the patient's outcome. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03919240, Registered 18 April 2019, retrospectively registered.

[Effect of down-regulation of sex determining region Y-box 9 on epithelial mesenchymal transition and cloning of oral squamous carcinoma cells].

OBJECTIVE: To investigate the effect of sex determining region Y-box 9 (SOX9) on epithelial mesenchymal transition (EMT) and cloning of oral squamous cell carcinoma (OSCC). METHODS: siRNA control, SOX9 siRNA were transfected into BcaCD885 cells in OSCC. Simultaneously, cells that did not undergo transfection were used as the control. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to select SOX9 siRNA1 with enhanced interference effect. A cell cloning assay was used to determine the cell's clone formation ability. E-cadherin and Vimentin expressions were detected by immunofluorescence. The expressions of E-cadherin, matrix metalloprotease 2 (MMP-2), Vimentin and matrix metalloprotease 9 (MMP-9) were detected by Western blot. Cell invasion and migration were detected in the Transwell compartment. RESULTS: The levels of SOX9 mRNA and protein in SOX9 siRNA cells were significantly lower than those of the control (P<0.05). An increase in the number of SOX9 siRNA1 cell clonesled to the considerable decrease of the number of cell invasion and migration. In addition, levels of MMP-2 and MMP-9 proteins in cells decreased significantly compared with the control (P<0.05). The level of Vimentin expression in SOX9 siRNA1 cells decreased, and expression level of E-cadherin was elevated. Cell EMT was inhibited compared with the control, and the difference was statistically significant (P<0.05). CONCLUSIONS: Down-regulation of SOX9 inhibited EMT, clonogenic formation, cell invasion and OSCC migration.

Development of automated online gel permeation chromatography-gas chromatograph mass spectrometry for measuring multiresidual pesticides in agricultural products.

An automated online gel permeation chromatography-gas chromatograph mass spectrometer (GPC-GC/MS) was developed for the rapid determination of residual pesticides in agricultural products. Pesticides were extracted from homogenized food samples with acetonitrile and decontaminated via the matrix solid-phase dispersion (MSPD) technique, using a primary secondary amine as sorbent prior to GPC-GC/MS analysis. A slightly modified preparation method and automated GPC step proved useful in minimizing matrix interference. To evaluate the performance of the system, 97 target pesticides were spiked at a concentration of 0.1mg/kg into a range of food types, including potato, cabbage, carrot, apple, orange, cucumber, and rice. A low flow rate of 0.1 mL/min in GPC resulted in a 40-fold reduction in solvent consumption compared with conventional GPC column applications. The combination of MSPD technique and GPC-GC/MS for the analysis of the 97 pesticides can be accomplished within 90 min. Most pesticides were recovered in the range of 70-120%, with relative standard deviation generally less than 10%. The results demonstrate that the method can be successfully applied with acceptable recoveries to a broad range of target pesticides within a diverse range of food types.

[Secreted expression of porcine interferon beta in Pichia pastoris and its inhibition effect on the replication of Pseudorabies virus].

In order to develop recombinant porcine interferon beta with high bioactivity, the rare codes that encoded 3th, 7th and 164th amino acids of porcine interferon beta mature protein were mutant into bias codes of Pichia pastoris and then the modified gene was introduced to yeast secreted expression vector pPICZ alphaA which resulted in pPICZalphaA-PIB. The SacI linearized plasmid pPICZalphaA-PIB was transformed into Pichia pastoris X-33 by electroporation. The transformants were identified by PCR using PoIFN-beta and AOX1 specific primers. The expression of PoIFN-beta was induced with methanol. Several positive clones were obtained and the one namely B1 produced the highest level of PoIFN-beta. The B1 was further fermented in shake-flask in larger volume. The concentration of the secreted PoIFN-beta was about 60 microg/mL and its antiviral activity is about 2.5 x 10(5) U/mL, so the specific activity of porcine interferon beta produced by the Pichia pastoris is approximately 4.17 x 10(6) U/mg. The expressed supernatant was concentrated and identified by SDS-PAGE and Western blot. There are two major proteins with respective molecular mass of approximately 25 kDa and 28 kDa in the supernatant. The results of Western blot indicated that the two proteins were positively reacted and manifested well PoIFN-beta antigenicity. In contrast with the deduced theoretical molecular mass value of PoIFN-beta, the expressed two major proteins were larger which maybe due to the difference of glycosylation. The antiviral effect of recombinant porcine interferon beta (rPoIFN-beta) on Pseudorabies virus (PrV) was studied in the present experiment. The result indicated that rPoIFN-beta could effectively inhibit the replication of PrV in MDBK cells, especially during the early phage of the virus replication.

[Effect of combined pentoxifylline and albendazole against echinococcus multilocularis infection in mice].

OBJECTIVE: To observe the effect of pentoxifylline (PTX), albendazole (ABZ), and a combination of PTX and ABZ in mice infected with Echinococcus multilocularis (E.M). METHODS: The first part of the experiment was to observe the in vitro effect of PTX on the cultured E.M protoscolex. In the second part, mice were infected by abdominal inoculation of E.M and divided into groups given by ABZ 50 mg/kg-d, PTX 360 mg/kg-d, PTX 180mg/kgxd, and a combined regimen ABZ 50 mg/(kgxd)+PTX 180 mg/(kgxd). Another infected group and a uninfected group served as controls which received normal saline only. 100 days post-treatment, the mice were sacrificed for further observation. Indicators included wet weight of the cyst, cyst inhibition rate, level of serum cytokines TGF-beta determined by ELISA, IL-2 and IL-10 determined by radio-immunoassay (RIA). RESULTS: The inhibition rate on cysts of the combined ABZ and PTX was 88%, considerably higher than 58 % of the group ABZ. The serum TGF-beta and IL-10 decreased and IL-2 increased after treatment in comparison to the controls. CONCLUSION: The PTX and ABZ combination shows better effect on E.multilocularis infection than that of single ABZ. PTX might help increase immunity of the mice.