[Prognostic value and imaging features of (18)F-FDG PET-CT in follicular lymphoma with different histopathology grade].

Follicular lymphoma (FL) is highly heterogeneous with different histopathologic grades. Its biological characteristics and clinical management are different. This study retrospectively analyzed (18)F-FDG PET-CT metabolic parameters, clinical features, and their relationship with prognosis in 161 FL patients with different histopathological grades (grade 1-2, grade 3A, grade 3B) at the Shanxi Cancer Hospital. There were 93 cases in the grade 1-2 group, 40 cases in the grade 3A group, and 28 cases in the grade 3B group. The expression of LDH, CD10, EZH2, c-Myc, and CD37 proteins was correlated with histological grade (grade 1-2, grade 3A, and grade 3B) (all P values<0.05) . The SUVmax, TLG, TBR, and TLR for the three groups were different (all P values<0.05) . The optimal thresholds of SUVmax, MTV, TLG, TBR, and TLR for predicting FL disease progression were 8.32, 201.31, 2 342.55, 6.56, and 3.52, respectively, and the rate of disease progression increased in patients with higher thresholds (all P value<0.05) . ß(2)-MG (>2.3 µg/L) , Follicular lymphoma international prognostic index-1 (FLIPI-1) score (3-5 points) , negative CD37 expression, positive c-Myc expression, and TLG (>2 342.55 g) were all independent risk factors for PFS in the FL patients (HR=3.609, 2.509, 0.255, 3.506, 13.531, all P value<0.05) . (18)F-FDG PET-CT is a powerful complement to FL histopathological grading and the combination of the two may better predict the prognosis of FL patients.

Achromobacter species (sp.) outbreak caused by hospital equipment containing contaminated water: risk factors for infection.

BACKGROUND: Nosocomial outbreaks of urinary tract infections caused by Achromobacter spp. have been rare in recent decades. AIM: To identify the origin of an Achromobacter sp. outbreak, conduct multi-modal infection control measures, and finally to stop the outbreak. To this end, an epidemiological outbreak investigation and risk factor analysis were performed. METHODS: Achromobacter sp. was detected in 22 patients in our urology wards and six environmental cultures of specimens obtained from the operating rooms. Strains isolated were submitted for antimicrobial susceptibility testing. An on-site epidemiological investigation, evaluation of patient medical records, and environmental sampling were performed to identify the source of the outbreak, and implementation of infection control intervention. A case-control study was performed to analyse the potential risk factors. FINDINGS: Environmental sampling showed that the source of the infection for 22 patients was an ISA-IIIA-type medical pressurizer containing contaminated water. A case-control analysis showed that the risk factors for infection were: diagnosis of kidney/ureteral stones, surgery, placement of a double-J stent, and history of hospitalization in the past three months. CONCLUSION: It was concluded that the outbreak occurred in patients who underwent internal lithotripsy and double-J stent placement, due to contact transmission with the contaminated sensor and connecting tubes of the ISA-IIIA-type medical pressurizer.

Construct validation of machine learning for accurately predicting the risk of postoperative surgical site infection following spine surgery.

BACKGROUND: This study aimed to evaluate the risk factors for machine learning (ML) algorithms in predicting postoperative surgical site infection (SSI) following spine surgery. METHODS: This prospective cohort study included 986 patients who underwent spine surgery at Taizhou People's Hospital Affiliated to Nanjing Medical University from January 2015 to October 2022. Supervised ML algorithms included support vector machine, logistic regression, random forest, XGboost, decision tree, k-nearest neighbour, and naïve Bayes (NB), which were tested and trained to develop a predicting model. The ML model performance was evaluated from the test dataset. We gradually analysed their accuracy, sensitivity, and specificity, as well as the positive predictive value, negative predictive value, and area under the curve. RESULTS: The rate of SSI was 9.33%. Using a backward stepwise approach, we identified that the remarkable risk factors predicting SSI in the multi-variate Cox regression analysis were age, body mass index, smoking, cerebrospinal fluid leakage, drain duration and pre-operative albumin level. Compared with other ML algorithms, the NB model had the highest performance in seven ML models, with an average area under the curve of 0.95, sensitivity of 0.78, specificity of 0.88, and accuracy of 0.87. CONCLUSIONS: The NB model in the ML algorithm had excellent calibration and accurately predicted the risk of SSI compared with the existing models, and might serve as an important tool for the early detection and treatment of SSI following spinal infection.

[Endovascular therapy accompanied by spontaneous portosystemic shunts for overt hepatic encephalopathy].

Objective: To preliminarily evaluate the safety and efficacy of shunt-related interventional therapy accompanied with spontaneous portosystemic shunts (SPSS) in patients with hepatic encephalopathy (HE). Methods: Case data on six patients who underwent interventional therapy accompanied by SPSS for HE from January 2017 to March 2021 were collected to evaluate the efficacy and postoperative complications. Results: All six patients underwent SPSS. Four patients had hepatitis B cirrhosis; one had alcoholic cirrhosis; and one had hepatic arterioportal fistula-induced portal hypertension. Child-Pugh liver function scores were C and B in three and three cases, respectively. The SPSS type was gastrorenal shunt in two cases; portal-thoracic-azygos venous in two cases; portal-umbilical-iliac venous in one case; and portal-splenic venous - inferior vena cava in one case. Two of them had previously had a transjugular intrahepatic portosystemic shunt (TIPS), and there were SPSS prior to TIPS. Five cases (5/6) successfully underwent shunt embolization, and one case (1/6) underwent stent implantation for flow restriction (portal-umbilical-iliac vein). The technical success rate was 100%. HE did not recur during hospitalization or the three-month follow-up period. However, one case had a recurrence of HE within a year after surgery and was treated symptomatically, while another experienced gastrointestinal bleeding a year after surgery.. Conclusion: SPSS embolization or flow restriction is effective and safe for improving HE patients' symptoms.

Synthesis, antiproliferative and 4D-QSAR studies of thiadiazole derivatives bearing acrylamide moiety as EGFR inhibitors.

As a target for clinical anti-cancer treatment, epidermal growth factor receptor (EGFR) exhibits its over-expression on various tumour cells and is associated with the development of a variety of human cancers. Herein, we described the synthesis, antiproliferative activity assay and 4D-QSAR studies of thiadiazole derivatives bearing acrylamide moiety as EGFR inhibitors. Compared with Gefitinib, some of the target compounds have excellent antiproliferative activities against EGFR-expressed A431 cell line. The robust and reliable 4D-QSAR was constructed using comparative distribution detection algorithm, ordered predictors selection and genetic algorithm method, and the following acceptable statistics are shown: r2 = 0.82, Q2LOO = 0.67, Q2LMO = 0.61, r2Pred = 0.78.

[Diosmetin regulates intestinal immune balance by inhibiting PI3K/AKT signaling to relieve 2, 4, 6-trinitrobenzene sulfonic acid-induced Crohn's disease-like colitis in mice].

OBJECTIVE: To investigate the therapeutic mechanism of diosmetin on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced Crohn's disease (CD)-like colitis in mice. METHODS: Wild-type C57BL/6 mice were randomized into control group, TNBS-induced CD-like colitis group (TNBS group) and 50 mg·kg-1·d-1 diosmetin-treated group (n=8). Disease activity (DAI) scores, body weight changes, histological scores, colon lengths and colon mucosal levels of TNF-α, IFN-γ, and IL-17A were measured to evaluate the severity of colitis. The changes of T lymphocyte subsets (Th1/Th2 and Th17/Treg) in the mesenteric lymph nodes were analyzed by flow cytometry. Network pharmacology and molecular docking were used to analyze the effect of diosmetin on PI3K/AKT pathway. RESULTS: Compared with TNBS group, diosmetin treatment significantly lowered DAI scores, histological scores, body weight loss and colon mucosal levels of TNF-α, IFN-γ, and IL-17A (P < 0.05) and increased the colon length of the rat models, but these improvements did not reach the control levels (P < 0.05). Diosmetin significantly lowered the percentages of Th1/Th17 cells in the mesenteric lymph nodes in TNBS-treated mice, which remained higher than the control levels (P < 0.05); The percentages of Th2/Treg cells were significantly higher in diosmetin group than in TNBS group (P < 0.05) and the control group (P < 0.05). Network pharmacologic analysis identified 46 intersection targets of diosmetin and CD, and among them AKT1, EGFR, SRC, ESR1, MMP9 and PTGS2 were the top 6 core targets. GO and KEGG analyses showed that the PI3K/AKT signaling pathway was closely related with the therapeutic effect of diosmetin on CD-like colitis. Molecular docking suggested strong binding of diosmetin to the key core targets. Diosmetin significantly reduced the levels of p-PI3K and p-AKT in the colon mucosa in TNBS-treated mice (P < 0.05), but their levels remained higher than those in the control group (P < 0.05). CONCLUSION: Diosmetin ameliorates TNBS-induced CDPlike colitis in mice possibly by regulating Th1/Th2 and Th17/Treg balance to improve intestinal immune disorder through inhibition of PI3K/AKT signaling.

[Treatment responses, outcomes, and prognostic factors associated with them in patients with secondary acute myeloid leukemia].

Objective: To evaluate treatment responses, outcomes, and prognostic factors in adults with secondary acute myeloid leukemia (sAML) . Methods: Between January 2008 and February 2021, date of consecutive cases of younger than 65 years of adults with sAML were assessed retrospectively. Clinical characteristics at diagnosis, treatment responses, recurrence, and survival were evaluated. Logistic regression and Cox proportional hazards model were employed to determine significant prognostic indicators for treatment response and survival. Results: 155 patients were recruited, including 38, 46, 57, 14 patients belonging to t-AML, and AML with unexplained cytopenia, post-MDS-AML, and post-MPN-AML, respectively. In the 152 evaluable patients, the rate of MLFS after the initial induction regimen was 47.4%, 57.9%, 54.3%, 40.0%, and 23.1% in the four groups (P=0.076) . The total rate of MLFS after the induction regimen was 63.8%, 73.3%, 69.6%, 58.2%, and 38.5% (P=0.084) , respectively. Multivariate analysis demonstrated that male gender (OR=0.4, 95% CI 0.2-0.9, P=0.038 and OR=0.3, 95% CI 0.1-0.8, P=0.015) , SWOG cytogenetic classification into unfavorable or intermediate (OR=0.1, 95% CI 0.1-0.6, P=0.014 and OR=0.1, 95% CI 0.1-0.3, P=0.004) and receiving low-intensity regimen as induction regimen (OR=0.1, 95% CI 0.1-0.3, P=0.003 and OR=0.1, 95%CI 0.1-0.2, P=0.001) were typical adverse factors impacting the first CR and the final CR; PLT<45 × 10(9)/L (OR=0.4, 95%CI 0.2-0.9, P=0.038) and LDH ≥258 U/L (OR=0.3, 95%CI 0.1-0.7, P=0.005) were independent factors for CR. Among the 94 patients with achieving MLFS, 46 cases had allogeneic hematopoietic stem cell transplantation. With a median follow-up period of 18.6 months, the probabilities of relapse-free survival (RFS) and overall survival (OS) at 3 years were 25.4% and 37.3% in patients with transplantation, and in patients with chemotherapy, the probabilities of RFS and OS at 3-year were 58.2% and 64.3%, respectively. At the time of achieving MLFS, multivariate analysis revealed that age ≥46 years (HR=3.4, 95%CI 1.6-7.2, P=0.002 and HR=2.5, 95%CI 1.1-6.0, P=0.037) , peripheral blasts ≥17.5% at diagnosis (HR=2.5, 95%CI 1.2-4.9, P=0.010 and HR=4.1, 95%CI 1.7-9.7, P=0.002) , monosomal karyotypes (HR=4.9, 95%CI 1.2-19.9, P=0.027 and HR=28.3, 95%CI 4.2-189.5, P=0.001) were typical adverse factors influencing RFS and OS. Furthermore, CR after induction chemotherapy (HR=0.4, 95%CI 0.2-0.8, P=0.015) and transplantation (HR=0.4, 95%CI 0.2-0.9, P=0.028) were substantially linked to longer RFS. Conclusion: Post-MDS-AML and post-MPN-AML had lower response rates and poorer prognoses than t-AML and AML with unexplained cytopenia. In adults with male gender, low platelet count, high LDH, and SWOG cytogenetic classification into unfavorable or intermediate at diagnosis, and receiving low-intensity regimen as the induction regimen predicted a low response rate. Age ≥46 years, a higher proportion of peripheral blasts and monosomal karyotype had a negative effect on the overall outcome. Transplantation and CR after induction chemotherapy were greatly linked to longer RFS.

[The efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitors in the treatment of Philadelphia-chromosomal-positive acute lymphoblastic leukemia].

Objective: The study aims to explore the efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitor (TKI) as an induction therapy for Philadelphia-chromosomal-positive acute lymphoblastic leukemia (Ph(+) ALL) . Methods: The data of the consecutive newly diagnosed patients with Ph(+) ALL were reviewed. The efficacy and safety of low-dose chemotherapy and conventional-dose chemotherapy combined with TKI were compared. Results: A total of 217 patients with a median age of 38 (10-69) years old were included in this study. 78 patients were in the low-dose chemotherapy group, and 139 patients were in the conventional-dose chemotherapy group. There were no significant differences in the 4-week complete remission (CR) rate (98.7% vs 97.0%, P=0.766) and overall CR rate (100% vs 100%, P=1.000) between the two groups. Multivariate analyses showed that the chemotherapy intensity was not related to the disease-free survival rate and overall survival rate. However, the lower incidence of infection (P=0.017) , the shorter duration of neutropenia (P=0.001) and PLT<20 × 10(9)/L (P=0.057) , and the lower red blood cell transfusion volume (P=0.002) were more common in the low-dose chemotherapy group than in the conventional-dose chemotherapy group. Conclusions: The low-dose chemotherapy is superior to the conventional-dose chemotherapy combined with TKI as induction therapy in Ph(+) ALL with similar efficacy but is safer.

[Variables associated with hematological remission and survival in patients with acute myeloid leukemia after induction failure and relapse].

Objective: This study aimed to explore variables associated with remission rate and survival in patients with acute myeloid leukemia (AML) after induction failure and relapse. Methods: Data of 373 consecutive patients with AML were analyzed after induction failure and relapse. Binary logistics and the Cox model regression were used to identify variables associated with remission rate and outcomes. Results: In patients with AML after induction failure and relapse, the total CR+CRi rates were 50.6% and 40.3%, respectively; among those who achieved CR/CRi, the 3-year RFS rates were 34.4% and 30.4%, respectively, and the 3-year overall survival rates were 40.1% and 31.6%, respectively. In the multivariate analyses, using CLAG or FLAG regimen as a re-induction chemotherapy regimen, age <39 years and SWOG low-risk were significantly associated with higher remission rates in patients with induction failure. Male, secondary AML, SWOG high-risk, the interval from the first remission to relapse within 12 months, and bone marrow blasts ≥20% at the time of relapse were significantly associated with lower remission rates in relapsed patients. Transplantation was significantly associated with prolonged relapse-free survival and overall survival in patients achieving hematologic remission; the SWOG low-risk group was significantly associated with longer overall survival in those with induction failure; and achieving CR (not CRi) or having female gender was associated with longer RFS or overall survival in relapsed patients. Conclusion: Reinduction chemotherapy regimen, age, gender, SWOG risk, secondary AML, the interval from the first remission to relapse, and bone marrow blast percentage at the time of relapse were significantly associated with remission rates in the patients with AML after induction failure and relapse. Transplantation, SWOG low-risk, achieving CR, or female gender were associated with longer survivals in those achieving remission.

Identification of Malus halliana R2R3-MYB gene family under iron deficiency stress and functional characteristics of MhR2R3-MYB4 in Arabidopsis thaliana.

Iron (Fe) is an essential element for plant growth and development. Fe deficiency can trigger leaf chlorosis and reduce fruit yield. Therefore, it is necessary to explore transcription factors in response to Fe deficiency stress. A total of 29 MhR2R3-MYB transcription factors were identified based on the transcriptome of Malus halliana under Fe deficiency stress. A comprehensive analysis of physical and chemical properties, gene structures, conserved motif composition, evolutionary relationship and chromosome distribution was performed. Subsequently, based on the transcriptome, 14 genes with the most significant expression under Fe deficiency stress were screened for qRT-PCR verification. Among them,the functional characteristics of MhR2R3-MYB4 (MD05G1089600) were further studied in Arabidopsis thaliana. Expression of 13 out of these 14 genes was upregulated, only one was downregulated. Maximum upregulation of MhR2R3-MYB4 under Fe deficiency was 36.39-fold and 58.21-fold compared with day 0 in leaves and roots, respectively. Overexpression of MhR2R3-MYB4 enhanced tolerance to Fe deficiency in A. thaliana and led to multiple biochemical changes: transgenic lines have higher chl a, chl b and Fe2+ content, higher enzyme activity (SOD, POD, CAT and FCR) and lower chlorosis than the wild type in Fe deficiency conditions. We suggest that MhR2R3-MYB4 plays an important part in Fe deficiency stress, which may contribute to improve Fe deficiency tolerance of apple in future.

[Association between polymorphism of CASP and NOX3 with risk of noise-induced hearing loss].

Objective: To explore the effect of gene polymorphism on workers suffering from noise induced hearing loss (NIHL) . Methods: In May 2019, a case-control study was conducted to select noise exposed workers in five factories in Zhejiang Province from 2017 to 2018. The average hearing threshold of binaural high frequency (3, 4, 6 kHz) was >25 dB (A) as the NIHL group, and the hearing threshold of any language frequency (0.5, 1, 2 kHz) was ≤25 dB (A) as the non NIHL group, with 307 people in each group. The general demographic data, occupational history, pure tone audiometry results and oral swab mucosal samples of noise exposed workers were collected, and the DNA of oral mucosal cells was extracted. The relationship between genetic risk score (GRS) and NIHL was analyzed, single nucleotide polymorphisms (SNP) were genotyped, the relationship between genotype and NIHL was analyzed by logistic regression, and the relationship between haplotype and NIHL was analyzed by R language. Results: After adjusting for gender, age, education and working years, the risk of NIHL among workers carrying cysteine-aspartic acid protease 3 gene (CASP3) rs1049216 recessive model GG genotype, rs6948 recessive model TT genotype, NADPH oxidase 3 gene (NOX3) rs12195525 additive model GT genotype and dominant model TT+GT genotype decreased (P<0.05) , the risk of disease was higher in workers with AA genotype carrying cysteine-aspartic acid protease 7 gene (CASP7) rs12415607 additive model (P<0.05) . There was a strong linkage disequilibrium (LD) relationship between rs1049216 and rs6948 (D'>0.8) . Haplotype AT and GG composed of rs1049216-rs6948 increased the risk of NIHL (P<0.05) . The risk of NIHL increased with the increase of GRS (OR=2.69, P<0.05) . Conclusion: Genotype polymorphisms at rs1049216 and rs6948 (CASP3) , rs12195525 (NOX3) , rs12415607 (CASP7) may be associated with susceptibility to NIHL.

[Comparison of single infusion of anti-BCMA versus combined infusion of anti-CD19 chimeric antigen receptor T cells for immune reconstruction in relapsed/refractory multiple myeloma].

Objective: We observed and compared the differences in immune reconstruction between single-infusion anti-B-cell maturation antigen (BCMA) , chimeric antigen receptor T cells (CAR-T) , and combined infusion of anti-CD19 CAR-T cells in the treatment of recurrent/refractory multiple myeloma (RRMM) . Methods: Sixty-one patients with RRMM who underwent CAR-T cell therapy in our hospital from June 2017 to December 2020 were selected. Among them, 26 patients received anti-BCMA target, and 35 patients received anti-BCMA combined with anti-CD19 target. Using flow cytometry, we determined T cell subsets (CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+)) , B cells (CD19(+)) , and NK cells (CD16(+) CD56(+)) at different time points before and after CAR-T treatment, and detected immunoglobulin IgG, IgA and IgM levels by immunoturbidimetry. We compared the reconstruction rules of lymphocyte subsets and immunoglobulins in the two groups. Results: CD8(+) T lymphocytes recovered most rapidly after the infusion of CAR-T cells, returning to pre-infusion levels at 3 months and 1 month after infusion, respectively[BCMA: 695 (357, 1264) /µl vs 424 (280, 646) /µl; BCMA+CD19: 546 (279, 1672) /µl vs 314 (214, 466) /µl]. NK cells returned to normal levels at 3 months after infusion in both groups[BCMA: 171 (120, 244) /µl, BCMA+CD19: 153 (101, 218) /µl (Normal reference range 150-1100/µl) ]; however, the NK cells were not maintained at stable levels in the BCMA CAR-T cells group. The recovery of CD4(+) T lymphocytes in both groups was slow and remained persistently low within 12 months after infusion, and no recovery was observed in most patients. The reversal of the ratio of CD4(+)/CD8(+) lasted for more than a year. The levels of CD19(+) B cells in both groups returned to baseline 3 months after infusion[BCMA: 62 (10, 72) /µl vs 57 (24, 78) /µl; BCMA+CD19: 40 (4, 94) /µl vs 29 (14, 46) /µl]. IgG returned to the pre-infusion level 12 months after infusion in the group with anti-BCMA cells alone, but not in the group with combined infusion of CD19 CAR T cells[7.82 (6.03, 9.64) g/L vs 6.92 (4.62, 12.76) g/L]. IgA returned to pre-infusion levels at 9 and 12 months after infusion, respectively[BCMA: 0.46 (0.07, 0.51) g/L vs 0.22 (0.12, 4.01) g/L; BCMA+CD19: 0.46 (0.22, 0.98) g/L vs 0.27 (0.10, 0.53) g/L]. IgM in both groups returned to pre-infusion levels 6 months after infusion[BCMA: 0.43 (0.06, 0.60) g/L vs 0.20 (0.13, 0.37) g/L; BCMA+CD19: 0.53 (0.10, 0.80) g/L vs 0.16 (0.11, 0.28) g/L]. There was no significant difference in the indexes of lymphocyte subpopulation reconstruction and immunoglobulin recovery between the two groups at each time point. Conclusion: This study showed that in patients with RRMM treated with CAR-T cells, the appropriate target antigen can be selected without considering the difference of immune reconstruction between anti-BCMA CAR-T and combined anti-CD19 CAR-T therapy.

Synthesis and receptor dependent 4D-QSAR studies of 4,5-dihydro-1,3,4-oxadiazole derivatives targeting cannabinoid receptor.

Cannabinoid receptor has been shown to be overexpressed in various types of cancers, especially non-small cell lung cancer. As a result, it could be used as novel target for anticancer treatments. Because receptor-dependent 4D-QSAR generates conformational ensemble profiles of compounds by molecular dynamics simulations at the binding site of the enzyme, this work describes the synthesis, biological activity evaluation and 4D-QSAR studies of 4,5-dihydro-1,3,4-oxadiazole derivatives targeting cannabinoid receptor. Compared with WIN55,212-2, compound 5 f showed the best antiproliferative activity. The receptor-dependent 4D-QSAR model was generated by multiple linear regression method using QSARINS. Leave-n-out cross-validation and chemical applicability domain were performed to analyse the independent test set and to verify the robustness of the model. The best 4D-QSAR model showed the following statistics: r2 = 0.8487, Q2LOO = 0.7667, Q2LNO = 0.7524, and r2Pred = 0.8358.