[Long-term follow-up of humanized and murine CD19 CAR-T-cell therapy for B-cell acute lymphoblastic leukemia].

Objective: Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods: Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results: The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions: The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.

[Analysis of vaginal microecology in 23 181 cases of the gynecological female outpatients].

Objective: To analyze the vaginal microecological status of vaginitis population and non-vaginitis population of gynecological female outpatients. Methods: A total of 30 265 women who visited the gynecological outpatient clinic of Beijing Obstetrics and Gynecology Hospital from December 2018 to December 2020 completed vaginal microecological examination. After removing the follow-up patients, 23 181 women were divided into group with symptoms and signs of vaginitis (6 697 cases) and group without symptoms and signs of vaginitis (16 484 cases), according to whether the women with symptoms and signs of vaginitis or not. And the vaginal microecological status of the two groups was compared and analyzed. Results: (1) The total detection rate of vaginitis in the initial women was 34.87% (8 083/23 181), of which 46.10% (3 087/6 697) in group with symptoms and signs of vaginitis and 30.31% (4 996/16 484) in group without symptoms and signs of vaginitis, nearly 1/3 of the gynecological outpatients without signs and symptoms of vaginitis had vaginitis. (2) Among the types of simple vaginitis, vulvovaginal candidiasis (VVC) was the most frequent in group with symptoms and signs of vaginitis (16.01%, 1 072/6 697), followed by aerobic vaginitis (AV; 12.83%, 859/6 697), with significant differences compared with group without symptoms and signs of vaginitis (all P<0.001). There were no statistical differences between the two groups of bacterial vaginosis (BV) and trichomonal vaginitis (TV), indicating that BV and TV were more likely to be neglected (all P>0.05). (3) The proportion of various combinations of vaginitis among 2 632 cases of mixed vaginitis were, in descending order: BV+AV, VVC+AV, BV+AV+VVC, AV+TV, AV+TV+BV, BV+VVC. (4) Microecological analysis of 15 098 cases diagnosed with non-vaginitis had normal flora (including those with normal flora and those with normal flora but decreased function) in 14 013 cases (92.81%, 14 013/15 098), abnormal flora in 429 cases (2.84%, 429/15 098) and the BV intermediate in 656 cases (4.34%, 656/15 098); this indicated that the vast majority of the microecological tests were normal in the vaginal microbiota of those without vaginitis. Conclusions: Microecological examination could diagnose multiple pathogenic infections at once, and is especially important as a guide for the definitive diagnosis of mixed vaginitis and vaginitis with atypical clinical symptoms. Vaginal infections such as BV and TV that are easily overlooked should be concerned.

[Infectious complications following chimeric antigen receptor T-cell therapy for a hematologic malignancy within 28 days].

Objective: To explore the incidence, clinical and microbiological characteristics and risk factors of infection in patients with acute lymphoblastic (ALL) , non-Hodgkin lymphoma (NHL) , and multiple myeloma (MM) within 28 days after CAR-T cell infusion. It provides data support for early identification of infection and the rational use of antibacterial drugs in these patients. Methods: We retrospectively analyzed the baseline data of 170 patients with ALL, NHL and MM who received chimeric antigen receptor-modified T (CAR-T) -cell treatment in the Department of Hematology of Wuhan Union Hospital from January 2016 to December 2020, and the clinical characteristics of infection within 28 days after infusion, including 72 patients with ALL, 56 patients with NHL, and 42 patients with MM; we used Poisson regression and Cox proportional hazard regression models to assess high-risk factors for infection before and after infusion, respectively. Results: Among 170 patients, 119 infections occurred in 99 patients within 28 days, with a cumulative infection rate of 58.2%. Seventy-eight patients had 98 bacterial infections and the cumulative incidence of bacterial infection was 45.9%. The infection density was 2.01, and the median time for the first infection was about 12 days after infusion. The adjusted baseline characteristic model showed that ALL patients, previous 30 days of infection history, refractory disease, absolute neutrophil count (ANC) <0.5×10(9)/L before infusion and ≥4 prior antitumor treatment regimens had a higher infection density within 28 days; grade 3 or 4 CRS was the only high-risk factor related to infection after infusion in the multivariate analysis. Conclusion: Infection is a common complication of CAR-T cell therapy in patients with hematologic malignancy. Bacterial infections occur in most patients regardless of the type of disease. ALL patients, previous 30 days of infection history, refractory disease, ANC<0.5×10(9)/L before infusion and grade 3 or 4 CRS are risk factors for infection. Chinese Clinical Trial Register:: ChiCTR-OIC-17011180, ChiCTR1800018143.

[Outcome of vaginal birth after cesarean section in women with advanced maternal age].

Objective: To explore the perinatal outcome of vaginal birth after cesarean (VBAC) in women with advanced age. Methods: Totally 2 587 women delivered after one or two prior cesarean sections (gestational age≥28 weeks) in the First Affiliated Hospital of Kunming Medical University from July 2013 to February 2017. 909 trial of labor after cesarean(TOLAC) cases of singleton pregnancy with one prior cesarean section were studied retrospectively. According to the age, of the 909 TOLAC cases, 237 were the advanced age group, and 672 cases were the low age group. The maternal and neonatal outcomes between the two groups were compared. Results: The percentage of TOLAC in women with advanced age was 32.4% (237/731), and VBAC rate was 88.2% (209/237). The percentage of TOLAC in younger women was 36.2% (672/1 856), and VBAC rate was 82.4% (554/672). The difference of the TOLAC rate between the two groups was not significant (P>0.05), and the VBAC rate of the advanced age group was higher than the low age group (P<0.05). In the comparison of the two groups, the proportion of bachelor degree or above(55.7%,132/237), the prepregnancy BMI (22.4±3.0) kg/m(2), pregnant interval time (68.5±38.3) months, the proportion of gestational hypertension (8.4%,20/237), the proportion of gestational diabetes(34.6%,82/237) and the rate of the neonatal ICU admission (18.1%,43/237) in the advanced age group were higher than those of the low age group (P<0.05), respectively. And there were no significant differences in the rate of postpartum hemorrhage, the rate of postpartum hemorrhage≥1 500 ml, the rate of postpartum transfusion, puerperal morbidity, neonatal birth weight, neonatal 5 min Apgar score<7 score, umbilical artery blood pH<7.0, neonatal tracheal intubation and respiratory distress syndrome (all P>0.05). In all TOLAC cases, the rate of uterine rupture was 0.11%(1/909) and there was no maternal and neonatal death. Conclusion: VBAC is a safe and feasible way of delivery for singleton pregnancy after one prior cesarean section in women with advanced age.

TNFAIP3 inhibits migration and invasion in nasopharyngeal carcinoma by suppressing epithelial mesenchymal transition.

TNF alpha induced protein 3 (TNFAIP3), a member of zinc finger protein family, is a gene whose expression level is promptly induced by the tumor necrosis factor. In this study, the clinical significance of TNFAIP3 was analyzed based on available samples in The Cancer Genome Atlas database. TNFAIP3 downregulation was associated with distant metastasis and worse patient prognosis. TNFAIP3-overexpressing and TNFAIP3-knockdown NPC cell line models were established through plasmid-mediated overexpression and small interfering RNA (siRNA), respectively. Cell migration and invasion capacities were evaluated by wound-healing and transwell assays. Functional studies indicated that TNFAIP3 knockdown promoted migration and invasion, whereas TNFAIP3 overexpression alleviated these functions. Western blot analysis was used to examine protein changes from TNFAIP3 overexpression and knockdown, in which TNFAIP3 promoted the protein expression of E-cadherin and suppressed vimentin expression. Our data suggested that TNFAIP3 inhibited migration and invasion by suppressing epithelial mesenchymal transition in NPC.

Changes in flowering functional group affect responses of community phenological sequences to temperature change.

Our ability to predict how temperature modifies phenology at the community scale is limited by our lack of understanding of responses by functional groups of flowering plants. These responses differ among species with different life histories. We performed a reciprocal transplant experiment along four elevation gradients (e.g., 3,200, 3,400, 3,600 and 3,800 m) to investigate the effects of warming (transferred downward) and cooling (transferred upward) on plant flowering functional groups (FFGs) and community phenological sequences (i.e., seven phenological events). Warming significantly decreased early-spring-flowering (ESF) plant coverage and increased mid-summer-flowering plant (MSF) coverage, while cooling had the opposite effect. All community phenological events were advanced by warming and delayed by cooling except for the date of complete leaf-coloring, which showed the opposite response. Warming and cooling could cause greater advance or delay in early-season phenological events of the community through increased coverage of MSF species, and warming could delay late-season phenological events of the community by increased coverage of ESF species. These results suggested that coverage change of FFGs in the community induced by temperature change could mediate the responses of the community phenological events to temperature change in the future. The response of phenological events to temperature change at the species level may not be sufficient to predict phenological responses at the community-level due to phenological compensation between species in the community.

Relatively stable response of fruiting stage to warming and cooling relative to other phenological events.

The timing of the fruit-set stage (i.e., start and end of fruit set) is crucial in a plant's life cycle, but its response to temperature change is still unclear. We investigated the timing of seven phenological events, including fruit-set dates during 3 yr for six alpine plants transplanted to warmer (approximately +3.5°C in soils) and cooler (approximately -3.5°C in soils) locations along an altitudinal gradient in the Tibetan area. We found that fruit-set dates remained relatively stable under both warming and cooling during the 3-yr transplant experiment. Three earlier phenological events (emergence of first leaf, first bud set, and first flowering) and two later phenological events (first leaf coloring and complete leaf coloring) were earlier by 4.8-8.2 d/°C and later by 3.2-7.1 d/°C in response to warming. Conversely, cooling delayed the three earlier events by 3.8-6.9 d/°C and advanced the two later events by 3.2-8.1 d/°C for all plant species. The timing of the first and/or last fruit-set dates, however, did not change significantly compared to earlier and later phenological events. Statistical analyses also showed that the dates of fruit set were not significantly correlated or had lower correlations with changes of soil temperature relative to the earlier and later phenological events. Alpine plants may thus acclimate to changes in temperature for their fruiting function by maintaining relatively stable timings of fruit set compared with other phenological events to maximize the success of seed maturation and dispersal in response to short-term warming or cooling.

[The outcome of trial of labor after cesarean section].

Objective: To explore the outcome of trial of labor after cesarean section(TOLAC). Methods: Totally 614 TOLAC were conducted in the First Affiliated Hospital of Kunming Medical University from July 2013 to June 2016. Among them, 586 cases of singleton pregnancy with one prior cesarean section(gestational age≥28 weeks)were studied retrospectively. The maternal and neonatal outcomes among the vaginal birth after cesarean(VBAC)group(481 cases), failed TOLAC group(105 cases)and the elective repeat cesarean section(ERCS)group(1 145 cases)were compared. Multiple logistic regression was used to determine the risk factors of admission to neonatal intensive care unit(NICU). Results: (1)The TOLAC rate was 29.62%(614/2 073)from July 2013 to June 2016, and the VBAC rate was 82.6%(507/614). The cesarean section rate was reduced by VBAC by 3.147%(507/16 112).(2)The comparison of adverse maternal outcomes: in the VBAC group, the postpartum hemorrhage volume was(431±299)ml, the rate of postpartum fever was 6.4%(31/481), the birth weight of the neonates was(3 085± 561)g, and the rate of large for gestational age was 2.9%(14/481). All were significantly lower than those in the failed TOLAC group and the ERCS group(P<0.05). There was no significant difference in other adverse maternal outcomes[the uterine rupture rate(0.2% ,1/481), the bladder injury rate(0), the proportion of postpartum hemorrhage volume≥1 500 ml(1.0%, 5/481), the blood transfusion rate(3.7%, 18/481)]and adverse perinatal outcomes[the rate of neonatal 5-minute Apgar score<7(0.4%, 21/481), the rate of umbilical arterial pH<7.0(0.6% , 3/481), the rate of the NICU admission and the perinatal mortality rate(12.3%, 59/481)]among the 3 groups(P>0.05). Multiple logistic regression showed no association between VBAC and admission to the NICU(OR=0.84, 95%CI: 0.58-1.21). The isolated risk factors for admission to the NICU were preterm birth(OR=16.71, 95% CI: 11.44-24.40), hypertensive disorder complicating pregnamcy(OR=3.89, 95% CI: 2.39-6.35), meconium stained amniotic fluid(OR=2.48, 95% CI: 1.62-3.80), small for gestational age(OR=2.00, 95% CI: 1.19-3.36)and diabetes mellitus(OR=1.69, 95% CI: 1.14-2.50). Conclusions: VBAC reduces cesarean section rate, with good outcomes in both mother and neonate. It is a safe and feasible way of labor in women with only one cesarean section history.

Maternal gestational diabetes mellitus and overweight and obesity in offspring: a study in Chinese children.

The purpose of this study was to investigate the effects of maternal gestational diabetes mellitus (GDM) and breast feeding on childhood overweight and obesity in a mainland Chinese population. The incidence of and factors associated with overweight and obesity were compared between children of mothers with (n=1068) and without (n=1756) GDM. The independent roles of the associated factors were examined by multiple logistic regression analysis. The incidence of overweight was higher (16.6 v. 12.6%, P=0.002) in the GDM group, but that of obesity was not different (10.7 v. 12.0%, P=0.315). At age 1-2 and 2-5 years, no difference in overweight (11.0 v. 12.0%, P=0.917, and 15.7 v. 14.6%, P=0.693, respectively) was found, while obesity (8.0 v. 13.6%, P=0.019, and 8.4 v. 13.4%, P=0.014, respectively) was less frequent in the GDM offspring. At age 5-10 years, increased overweight (22.2 v. 12.1%, P<0.001) and obesity (15.9 v. 9.0%, P=0.001) were found in the GDM group, which was associated with maternal obesity, being born large-for-gestational age, male gender and formula feeding. After adjusting for confounding factors, GDM remained an independent determinant of offspring overweight and obesity (aOR 2.28, 95% CI 1.61-3.22), suggesting that the effects of GDM were independent of breast feeding, as well as of maternal obesity and birth size.

Early third trimester maternal response to glucose challenge and pregnancy outcome in Chinese women-relationship between upper distribution level and recommended diagnostic criteria.

BACKGROUND/OBJECTIVES: The objective of this study was to examine the relationship between upper distribution levels of glucose values in the 75-g oral glucose tolerance test (OGTT) and recommended diagnostic criteria for gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. SUBJECTS/METHODS: The distribution of the OGTT 2-h values of 13,501 pregnant women, which were below the World Health Organization (WHO) threshold for overt diabetes mellitus (DM), and managed in one teaching hospital in China, was reviewed and related to maternal characteristics and pregnancy outcomes. RESULTS: For the entire group, the 90th and 95th percentile values of the OGTT 2-h glucose level, respectively, were close to the diagnostic cutoff values of the WHO and International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. For adverse maternal outcomes, glucose level above the 90th percentile value was associated with increased hypertensive disorders, whereas no difference was seen with cutoff using the 95th percentile value. For perinatal outcomes, the 90th percentile was associated with increased neonatal intensive care unit admission and hypoglycemia, whereas the 95th percentile showed in addition association with phototherapy for jaundice and 5th-minute Apgar score <7. Although no differences in the incidence of adverse pregnancy outcomes were found using the different cutoffs, the >95th percentile cutoff value would have missed out 33.3-56.7% of the cases of adverse outcomes that would otherwise have been attributed to GDM. CONCLUSIONS: Further studies are warranted to clarify which diagnostic criterion is most appropriate universally to identify adverse pregnancy outcomes attributed to GDM, and which could be mitigated with treatment specific for GDM.

Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis.

BACKGROUND: Because cerebral morphological abnormalities in major depressive disorder (MDD) may be modulated by antidepressant treatment, inclusion of medicated patients may have biased previous meta-analyses of voxel-based morphometry (VBM) studies. A meta-analysis of VBM studies on medication-free MDD patients should be able to distinguish the morphological features of the disease itself from those of treatment. METHOD: A systematic search was conducted for the relevant studies. Effect-size signed differential mapping was applied to analyse the grey matter differences between all medication-free MDD patients and healthy controls. Meta-regression was used to explore the effects of demographics and clinical characteristics. RESULTS: A total of 14 datasets comprising 400 medication-free MDD patients and 424 healthy controls met the inclusion criteria. The pooled meta-analysis and subgroup meta-analyses showed robustly reduced grey matter in prefrontal and limbic regions in MDD. Increased right thalamus volume was only seen in first-episode medication-naive patients, and increased grey matter in the bilateral anterior cingulate cortex only in medication wash-out patients. In meta-regression analyses the percentage of female patients in each study was negatively correlated with reduced grey matter in the right hippocampus. CONCLUSIONS: By excluding interference from medication effects, the present study identified grey matter reduction in the prefrontal-limbic network in MDD. The subgroup meta-analysis results suggest that an increased right thalamus volume might be a trait directly related to MDD, while an increased anterior cingulate cortex volume might be an effect of medication. The meta-regression results perhaps reveal the structural underpinning of the sex differences in epidemiological and clinical aspects of MDD.

Effect of intracerebral microinjection of naloxone on acupuncture- and morphine-analgesia in the rabbit.

Although there are unequivocal evidences indicating the participation of endogenous opiate-like substances in acupuncture analgesia, their exact sites of action remain to be elucidated. From the results of localization studies by injecting minute amount of narcotic antagonist naloxone into discrete brain areas and assessing its effect on acupuncture analgesia in rabbits it is concluded that nuclei accumbens, amygdala, habenula and periaquaductal grey are the strategic sites for endogenous opioids to exert their analgesic effect. These brain areas are also of extreme importance for the realization of morphine analgesia.