Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T.

CD19-targeted chimeric antigen receptor T lymphocytes (CAR-T) has demonstrated a high proportion of complete remission in the treatment of relapsed refractory acute B cell lymphoblastic leukemia (r/r B-ALL). It is of great clinical significance to explore which factors will impact long-term disease-free survival of patients with r/r B-ALL after CAR-T therapy without bridging bone marrow transplantation. Our study found that, in patients with r/r B-ALL without bridging transplantation, the patients' age; infusion dosage; whether they had undergone allo-stem cell transplantation before CAR-T therapy, using CD-19-targeted or CD19/CD22-dual-targeted CAR-T; whether there is fusion gene; tumor burden before therapy; and comorbidity had no significant relationship with their long-term disease-free survival. We found only that CAR-T persistence was highly correlated with patients' long-term disease-free survival. So, we further profiled CAR-T cells using single-cell sequencing and found that there is a specific T cell subset that may be associated with the long-term persistence of CAR-T. Finally, according to the single-cell sequencing results, we established cell production process named PrimeCAR, which shared common signaling pathways with the T cell subset identified. In the preliminary clinical study, prime CAR-Ts yield good persistence in peripheral blood of patients with B-ALL and lymphoma, without observing grade 2 or higher cytokine release syndrome.

Differentially expressed long noncoding RNAs and mRNAs in PC12 cells under lysophosphatidylcholine stimulation.

Lysophosphatidylcholine (LPC) was previously found to show neuroprotective effect on nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) induced signalings. Also, numerous studies reported the emerging roles of long noncoding RNAs (LncRNAs) involved in neurodegenerative disease. However, the biological mechanism of LPC and expression profile of lncRNAs has not been reported. Here, lncRNAs in PC12 cells under LPC and NGF treatment were analyzed using high throughput sequencing technology for the first time. We identified 564 annotated and 1077 novel lncRNAs in PC12 cells. Among them, 121 lncRNAs were differentially expressed in the PC12 cells under LPC stimulation. KEGG analysis showed that differentially expressed mRNAs co-expressed with lncRNAs mainly enriched in ribosome, oxidative phosphorylation, Parkinson's disease, Huntington's disease and Alzheimer's disease etc. LncRNA-mRNA network analysis showed that lncRNA ENSRNOT00000082515 had interactions with 626 different mRNAs suggesting that lncRNA ENSRNOT00000082515 probably play vital role. Finally, sequencing data were validated by qRT-PCR for ENSRNOT00000084874, ENSRNOT00000082515, LNC_001033 forward Fgf18, Vcam1, and Pck2.

Correction: Optimal designs of the side sensitive synthetic chart for the coefficient of variation based on the median run length and expected median run length.

[This corrects the article DOI: 10.1371/journal.pone.0255366.].

The trend in delayed childbearing and its potential consequences on pregnancy outcomes: a single center 9-years retrospective cohort study in Hubei, China.

BACKGROUND: Due to the advancement of modern societies, the proportion of women who delay childbearing until or beyond 30 years has dramatically increased in the last three decades and has been linked with adverse maternal-neonatal outcomes. OBJECTIVE: To determine the trend in delayed childbearing and its negative impact on pregnancy outcomes. MATERIAL AND METHODS: A tertiary hospital-based retrospective study was conducted in Wuhan University Renmin Hospital, Hubei Province, China, during the years 2011-2019. The joinpoint regression analysis was used to find a trend in the delayed childbearing and the multiple binary logistic regression model was used to estimate the association between maternal age and pregnancy outcomes. RESULTS: Between 2011 and 2019, the trend in advanced maternal age (AMA ≥35 years) increased by 75% [AAPC 7.5% (95% CI: - 10.3, 28.9)]. Based on maternal education and occupation, trend in AMA increased by 130% [AAPC 11.8% (95% CI: 1.1, 23.7)] in women of higher education level, and 112.5% [AAPC 10.1% (95% CI: 9.4, 10.9)] in women of professional services. After adjusting for confounding factors, AMA was significantly associated with increased risk of gestational hypertension (aOR 1.5; 95% CI: 1.2, 2.1), preeclampsia (aOR 1.6; 95% CI: 1.4, 1.9), sever preeclampsia (aOR 1.7; 95% CI: 1.1, 2.6), placenta previa (aOR 1.8; 95% CI: 1.5, 2.2), gestational diabetes mellitus (aOR 2.5; 95% CI: 2.3, 2.9), preterm births (aOR 1.6; 95% CI: 1.4, 1.7), perinatal mortality (aOR 1.8; 95% CI: 1.3, 2.3), and low birth weight (aOR 1.3; 95% CI: 1.2, 1.4) compared with women aged < 30 years. CONCLUSION: Our findings show a marked increase in delayed childbearing and its negative association with pregnancy outcomes.

Optimal designs of the side sensitive synthetic chart for the coefficient of variation based on the median run length and expected median run length.

The side sensitive synthetic chart was proposed to improve the performance of the synthetic chart to monitor shifts in the coefficient of variation (γ), by incorporating the side sensitivity feature where successive non-conforming samples must fall on the same side of the control limits. The existing side sensitive synthetic- γ chart is only evaluated in terms of the average run length (ARL) and expected average run length (EARL). However, the run length distribution is skewed to the right, hence the actual performance of the chart may be frequently different from what is shown by the ARL and EARL. This paper evaluates the entire run length distribution by studying the percentiles of the run length distribution. It is shown that false alarms frequently happen much earlier than the in-control ARL (ARL0), and small shifts are often detected earlier compared to the ARL1. Subsequently, this paper proposes an alternative design based on the median run length (MRL) and expected median run length (EMRL). The optimal design based on the MRL shows smaller out-of-control MRL (MRL1), which shows a quicker detection of the out-of-control condition, compared to the existing design, while the results from the optimal design based on the EMRL is similar to that of the existing designs. Comparisons with the synthetic-γ chart without side sensitivity shows that side sensitivity reduces the median number of samples required to detect a shift and reduces the variability in the run length. Finally, the proposed designs are implemented on an actual industrial example.

Intrinsic and chemically-induced daughter number variations in cancer cell lines.

Multipolar mitosis was observed in cancer cells under mechanical stress or drug treatment. However, a comprehensive understanding of its basic properties and significance to cancer cell biology is lacking. In the present study, live-cell imaging was employed to investigate the division and nucleation patterns in four different cell lines. Multi-daughter divisions were observed in the three cancer cell lines HepG2, HeLa and A549, but not in the transformed non-cancer cell line RPE1. Multi-daughter mother cells displayed multi-nucleation, enlarged cell area, and prolonged division time. Under acidic pH or treatment with the anti-cancer drug 5-fluorouracil (5-FU) or the phytochemical compound wogonin, multi-daughter mitoses were increased to different extents in all three cancer cell lines, reaching as high as 16% of all mitoses. While less than 0.4% of the bi-daughter mitosis were followed by cell fusion events under the various treatment conditions, 50% or more of the multi-daughter mitoses were followed by fusion events at neutral, acidic or alkaline pH. These findings revealed a "Daughter Number Variation" (DNV) process in the cancer cells, with multi-daughter divisions in Stage 1 and cell fusions leading to the formation of cells containing up to five nuclei in Stage 2. The Stage 2-fusions were inhibited by 5-FU in A549 and HeLa, and by wogonin in A549, HeLa and HepG2. The parallel relationship between DNV frequency and malignancy among the different cell lines suggests that the inclusion of anti-fusion agents exemplified by wogonin and 5-FU could be beneficial in combinatory cancer chemotherapies.

The Heterogeneous Effects of Participation in Shadow Education on Mental Health of High School Students in Taiwan.

The effect of shadow education or private supplementary education (PSE) on school achievement has been prolifically studied, but its impact on well-being remains understudied. This study examines the heterogeneous effect of PSE participation on school achievement and depression symptoms among high schoolers in Taiwan. The study uses panel data of the Taiwan Upper Secondary Database (TUSD) in the 2014 and 2015 academic years. We join the inverse-probability-of-treatment weighting (IPTW) approach and the seemingly unrelated regression (SUR) model to estimate the effects of PSE participation patterns on two correlated outcomes, comprehensive assessment of high school entrance examination and self-reported depression symptoms in the 11th grade. The latent class analysis identifies five PSE participation patterns: always-taker, early-adopter, dropout, late-adopter, and explorer, to predict the effect of PSE on the scores of entrance examination and later depression symptoms in high school (n = 7708, mean age = 15.33). The findings suggest that PSE participation in junior high is positively associated with academic achievement. However, PSE participation also increases depression symptoms, particularly in the case of always-takers. In other words, while always-takers increase their school achievement in transition into high school, their risks of suffering from depression are also higher than their peers.

Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway.

BACKGROUND: Pyroptosis belongs to a novel inflammatory programmed cell death pathway, with the possible prognosis of endometrial cancer related to the terminal protein GSDMD. Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis. METHODS: We performed immunohistochemical staining and western immunoblotting analysis to observe expression of NLRP3, caspase-1, and GSDMD in human and xenograft mice endometrial cancer tissue and cell lines. We investigated treatment with hydrogen could boost ROS accumulation in endometrial cancer cells by intracellular and mitochondrial sources. GSDMD shRNA lentivirus was used to transfect endometrial cancer cells to investigate the function of GSDMD protein in pyroptosis. Propidium iodide (PI) staining, TUNEL assay, measurement of lactate dehydrogenase (LDH) release and IL-1ß ELISA were used to analysis pyroptosis between hydrogen-supplemented or normal culture medium. We conducted in vivo human endometrial tumor xenograft mice model to observe anti-tumor effect in hydrogen supplementation. RESULTS: We observed overexpression of NLRP3, caspase-1, and GSDMD in human endometrial cancer and cell lines by IHC and western immunoblotting. Hydrogen pretreatment upregulated ROS and the expression of pyroptosis-related proteins, and increased the number of PI- and TUNEL-positive cells, as well as the release of LDH and IL-1ß, however, GSDMD depletion reduced their release. We further demonstrated that hydrogen supplementation in mice was sufficient for the anti-tumor effect to inhibit xenograft volume and weight of endometrial tumors, as mice subjected to hydrogen-rich water displayed decreased radiance. Tumor tissue sections in the HRW groups presented moderate-to-strong positive expression of NLRP3, caspase-1 and GSDMD. Hydrogen attenuated tumor volume and weight in a xenograft mouse model though the pyroptotic pathway. CONCLUSIONS: This study extended our original analysis of the ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis and revealed possible mechanism (s) for improvement of anti-tumor effects in the clinical management of endometrial cancer.

Silencing of long noncoding RNA XIST attenuated Alzheimer's disease-related BACE1 alteration through miR-124.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. However, its pathogenetic mechanism is still poorly understood. An increasing number of studies have evidenced the important role of long noncoding RNAs (lncRNAs) in AD. The aim of the current study was to investigate the effect and molecular mechanism of the lncRNA X-inactive specific transcript (XIST) in AD. Bilateral common carotid artery occlusion (2VO) was used to induce an AD model in mice. Hydrogen peroxide (H2 O2 ) was used to induce an AD model in N2a cells. The lncRNA XIST, miR-124, and BACE1 messenger RNA expression levels were detected by a real-time polymerase chain reaction. The BACE1 protein expression level was detected by western blot and immunofluorescence assay. The Aß1-42 expression level was detected using an enzyme-linked immunosorbent assay kit. The expression level of lncRNA XIST was significantly upregulated in AD models, both in vivo and in vitro. Silencing of lncRNA XIST negatively regulated miR-124 and positively regulated BACE1 expression in N2a cells, which is attenuated by cotransfection of anti-miR-124 oligodeoxyribonucleotide (AMO-124). Silencing of lncRNA XIST reversed the effect of H2 O2 on miR-124, BACE1, and Aß1-42 expression in N2a cells, which was reversed by cotransfection of AMO-124. Silencing of lncRNA XIST attenuated AD-related BACE1 alteration through miR-124. LncRNA XIST may be a new potential target for the treatment of AD.

Resolution of left ventricular thrombus by edoxaban after failed treatment with warfarin overdose: A case report.

RATIONALE: Although novel oral-anticoagulants are widely used in patients with atrial fibrillation (AF) for stroke prevention, there was only limited evidence for their use in left ventricular (LV) thrombus. PATIENT CONCERNS: A 41-year-old man who presented with acute onset of right-hand clumsiness and aphasia even under high international normalized ratio (INR: 7.64) from warfarin use. He was previously treated with warfarin for the LV thrombus and non-valvular AF. Brain magnetic resonance imaging (MRI) showed multiple acute infarction in the cortex of the bilateral frontal lobes, left parietal lobe, and bilateral central semiovale, which highly suggested embolic stroke. DIAGNOSIS: The repeated transthoracic echocardiogram still revealed LV thrombus (1.27 × 0.90 cm), which failed to respond to warfarin therapy. INTERVENTIONS: Due to acute infarctions occurred under supratherapeutic range of INR, we switched warfarin to edoxaban (dose: 60 mg/day) after INR decreased to less than 2. OUTCOMES: The thrombus disappeared after receiving edoxaban for 23 days, and no more recurrent stroke was noted for more than 6 months. LESSONS: This is the first case demonstrates that while facing ineffective treatment of warfarin for LV thrombus, edoxaban could be safely and effectively used under this situation.

Ptosis as the only manifestation of diabetic superior division oculomotor nerve palsy: A case report.

RATIONALE: Diabetic oculomotor nerve palsies, also called ischemic third nerve palsies, are the most common etiologic subset of oculomotor nerve palsy in adults. Diabetic oculomotor nerve palsies typically present with ptosis and diplopia, but pupillary function is often spared. The oculomotor nerve separates into superior division and inferior division, with the superior division innervating the superior rectus and levator palpebrae superioris. The diabetic oculomotor nerve palsy may affect isolated superior or inferior division of the oculomotor nerve, but diplopia usually exists. PATIENT CONCERNS: A 56-year-old female was admitted to our hospital for acute onset right upper lid ptosis. The patient denied diplopia or other new focal neurologic symptoms. The neurological examination revealed ptosis of the right upper eyelid only, and other neurological examination revealed negative findings. DIAGNOSES: The diagnosis of diabetes-associated oculomotor nerve palsy was made, with acute ptosis as its only manifestation. INTERVENTIONS: We controlled her blood sugar aggressively with insulin. OUTCOMES: After the hyperglycemia improved, the right side ptosis recovered partially within one week. LESSONS: From this case, we suggest that when evaluating patients with acute onset ptosis as the only manifestation, diabetic-vasculopathic neuropathy should be considered. This case also implies that the most interior portion of the third cranial nerve may consist of nerve fibers mainly innervating the levator palpebrae superioris.

Forehead carbuncle with intractable headache.

Although carbuncles are commonly seen and may heal on their own or respond well to treatment, in rare conditions, bacteria from carbuncles can spread into the bloodstream and migrate to other areas of the body. Herein, we report on an elderly female who suffered from forehead carbuncle with intractable headache, later confirmed as having subgaleal abscess. Physicians should pay special attention to elderly and immune-compromised patients with carbuncles located on the middle of the face, especially when accompanied by intractable headache, to avoid poor outcome.

Gender, sleep problems, and obesity in Taiwan: a propensity-score-matching approach.

Obesity has become a major health risk in industrialized countries, with disturbed sleep identified as a correlate. This study used data drawn from Taiwan's 2005 Social Development Trend Survey on Health and Safety and the propensity-score-matching method to shed light on gender-specific associations between sleep problems and obesity among 24,113 adults aged 20-64 years. The average increase in obesity prevalence among respondents with disrupted sleep was 1.85%, as compared to those who did not report disrupted sleep, with similar psycho-social attributes. Similarly, the prevalence of obesity among those who reported restless sleep was increased by an average of 1.40% compared to those who did not report restless sleep with similar psycho-social attributes. We also found gender-specific vulnerability to different types of sleep problems. Among men who reported disrupted sleep, we found a 3.12% increase in the prevalence of obesity. Among women exposed to restless sleep, the increase in obesity prevalence was 1.84%. The observed gender difference in the prevalence of increases in obesity may be attributed to gender-specific behavioral responses to poor sleep. With poor sleep, men may respond to hunger by overeating; women may respond by physical inactivity. Both can contribute to an elevated risk of obesity.

Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific and South East Asian regions, 2007-2008.

Long-term surveillance of antimicrobial resistance in Neisseria gonorrhoeae has been conducted in the World Health Organization (WHO) Western Pacific Region (WPR) to optimise antibiotic treatment of gonococcal disease since 1992. In 2007 and 2008, this Gonococcal Antimicrobial Surveillance Programme (GASP) was enhanced by the inclusion of data from the South East Asian Region (SEAR) and recruitment of additional centres within the WPR. Approximately 17,450 N. gonorrhoeae were examined for their susceptibility to one or more antibiotics used for the treatment of gonorrhoea by external quality controlled methods in 24 reporting centres in 20 countries and/or jurisdictions. A high proportion of penicillin and/or quinolone resistance was again detected amongst isolates tested in North Asia and the WHO SEAR, but much lower rates of penicillin resistance and little quinolone resistance was present in most of the Pacific Island countries. The proportion of gonococci reported as 'resistant', 'less susceptible' or 'non-susceptible' gonococci to the third-generation cephalosporin antibiotic ceftriaxone lay in a wide range, but no major changes were evident in cephalosporin minimal inhibitory concentration (MIC) patterns in 2007-2008. Altered cephalosporin susceptibility was associated with treatment failures following therapy with oral third-generation cephalosporins. There is a need for revision and clarification of some of the in vitro criteria that are currently used to categorise the clinical importance of gonococci with different ceftriaxone and oral cephalosporin MIC levels. The number of instances of spectinomycin resistance remained low. A high proportion of strains tested continued to exhibit a form of plasmid mediated high level resistance to tetracyclines. The continuing emergence and spread of antibiotic resistant gonococci in and from the WHO WPR and SEAR supports the need for gonococcal antimicrobial resistance surveillance programs such as GASP to be maintained and potentially expanded.

Peri-operative hyperglycemia: a consideration for general surgery?

BACKGROUND: Intraoperative hyperglycemia in cardiac and neurosurgical patients is significantly associated with morbidity. Little is known about the perioperative glycemic profile or its impact in other surgical populations or in nondiabetic patients. METHODS: A systematic review of blood glucose values during major general surgical procedures reported since 1980 was conducted. Data extracted included blood glucose measures, study sample size, gender distribution, age grouping, study purpose, surgical procedure, anesthetic details, and infusion regime. Excluded studies were those with subjects with diabetes insipidus, insulin-treated diabetes, renal or hepatic failure, adrenal gland tumors or dysfunction, pregnancy, and emergency or trauma surgery. RESULTS: Blood glucose levels rose significantly with the induction of anesthesia (P < .001) in nondiabetic patients. At incision, 2 hours, 4 hours, and 6 hours, 30%, 40%, 38%, and 40% of studies, respectively, reported hyperglycemia. CONCLUSIONS: Factors that confound or protect against significant rises in perioperative glycemic levels in nondiabetic patients were identified. The findings facilitate investigating the impact of hyperglycemia on general surgical outcomes.

The invisible family: a qualitative study of suicide survivors in Taiwan.

The purpose of this interpretive phenomenological study is to describe the commonality of the lived experience of suicide survivors and how it influences their family relationships in Taiwan from a sociocultural perspective. Thirteen suicide survivors have participated in this study. Study results reveal that some survivors blame themselves, some blame others, and some are blamed by their family as part of their need to find a reason for the death. Consequently, family members ignore each other and treat each other as if they are invisible. These Chinese suicide survivors, unlike Western survivors, maintain their strained family connections because of strong cultural influences. Therefore, health professionals should acknowledge the experiences of living with an invisible family when supporting Chinese suicide survivors.

Altered E-cadherin expression and p120 catenin localization in esophageal squamous cell carcinoma.

BACKGROUND: E-cadherin is a well-known tumor suppressor and its dysregulated expression correlates with tumor differentiation, metastasis and survival in esophageal squamous cell carcinoma (ESCC). p120 catenin is an Armadillo protein normally bound to E-cadherin in the cadherin-catenin complex at the adherens junction. Dysregulated expression and mislocalization of p120ctn affect the protective function of the complex. The objective of the present study was to evaluate the clinical significance of E-cadherin and p120ctn expression in ESCC. METHODS: Immunohistochemistry was performed to investigate the expression of E-cadherin and p120ctn proteins in 71 patients with ESCC. The relationships between protein expression and clinicopathological characteristics were analyzed. RESULTS: Reduced E-cadherin and p120ctn expressions were observed in 42.3% and 8.5% of ESCC cases, respectively. Reduction of membranous p120ctn was observed in 33.8% of cases. Membranous E-cadherin was preserved when p120ctn co-localized on the membrane of tumor cells (72.3%, P = 0.001). High level E-cadherin expression and membranous p120ctn preservation positively correlated with tumor differentiation (P = 0.001 and P = 0.008, respectively). p120ctn expression was also significantly related to lymph node metastasis (P = 0.003). Heterogeneous expression of both E-cadherin and p120ctn was observed in dysplasia. CONCLUSIONS: Altered E-cadherin expression and p120ctn localization were related to tumor differentiation, indicating their important roles in the pathogenesis of ESCC.

Construction of a stable expression vector for Leifsonia xyli subsp. cynodontis and its application in studying the effect of the bacterium as an endophytic bacterium in rice.

To study the possibility of utilizing genetically engineered Leifsonia xyli subsp. cynodontis (Lxc) as an endophytic bacterium in rice, we constructed an Escherichia coli-Lxc shuttle vector, pLGUS, containing a beta-glucuronidase reporter gene, which was stable both in vitro and in vivo. Lxc grows and expresses the beta-glucuronidase reporter gene in all parts of rice, except for seed. A 2-year field study using three rice varieties from China showed that Lxc inoculation did not have a negative effect on the growth and yield of any of these varieties. Therefore, Lxc has the potential to be used as a benign endophyte for the expression of foreign genes in rice.

Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma.

3p21 is an important locus harbouring critical tumour suppressor genes (TSG), which are implicated in the pathogenesis of multiple tumours, including oesophageal carcinoma. RASSF1A is a 3p21.3 candidate TSG frequently inactivated by promoter methylation in multiple tumours. We investigated RASSF1A promoter methylation and gene expression in Chinese oesophageal squamous cell carcinoma (ESCC) to compare it to data from Japanese patients. Methylation-specific PCR (MSP) showed that RASSF1A was partially methylated in 3/7 (43%) cell lines; 22/64 (34%) primary tumours and 3/64 (5%) corresponding non-tumour samples; and was not methylated in 2 immortalized normal oesophageal epithelial cell lines and 6 normal oesophageal epithelium samples. Bisulfite genome sequencing confirmed the MSP results. Promoter hypermethylation correlated well with RASSF1A mRNA down-regulation. Treatment of cell lines with 5-aza-2'-deoxycytidine activated RASSF1A mRNA expression along with promoter demethylation. RASSF1A hypermethylation in the Chinese cohort was much lower than in a published report of Japanese ESCC patients (52%) and cell lines (74%). Our own analysis of Japanese ESCC cell lines for direct comparison also detected a high frequency of RASSF1A hypermethylation (8/10; 80%) and high levels of hypermethylation at each CpG site. No significant association between RASSF1A hypermethylation and histological differentiation (p=0.953), tumour staging (p=0.117), or survival (p=0.7571) was found in Chinese ESCC, unlike the results of Japanese patients. The incidence of oesophageal cancer shows marked variation by geographic area and ethnic group; it is almost three times higher in China than in Japan, indicating possible different pathogenetic mechanisms. Our results show that RASSF1A hypermethylation in ESCC has epidemiological/ethnic differences, and suggest that Chinese ESCC may result from different pathogenetic mechanisms.