Aim To investigate the effects of m6A demethylase ALKBH5 on cardiomyocytes pyroptosis in mice with myocardial infarction(MI).Methods The MI model of left anterior descending coronary artery ligation surgery was established by knocking down ALKBH5 using adeno-associated virus,and the hypox-ia model of mouse cardiomyocytes(HL-1)was estab-lished by knocking down small interfering RNA.The effects of ALKBH5 on the pyroptosis of MI mice and hypoxic HL-1 cells were observed.Subsequently,mechanism studies were conducted at the cellular lev-el,and the binding of ALKBH5 and IGF2BP2 to NL-RP3 mRNA was detected through RNA pull down and RNA immunoprecipitation(RIP)experiments.The MeRIP-qPCR method was used to determine the effects of ALKBH5 on the mRNA m6A level of NLRP3.Acti-nomycin D for RNA stability experiments were conduc-ted to detect the effects of ALKBH5 and IGF2BP2 on the stability of NLRP3 mRNA.Results Knocking down ALKBH5 in vivo and in vitro both inhibited NL-RP3 inflammasome activation and alleviated pyroptosis in MI mice and hypoxic HL-1 cells.Mechanistically,the results showed that NLRP3 mRNA could bind to ALKBH5 protein in HL-1 cells;knocking down ALK-BH5 could increase the m6A level of NLRP3 and re-duce the stability of NLRP3 mRNA;subsequently,it was confirmed that NLRP3 mRNA and IGF2BP2 pro-tein bound to each other;knocking down IGF2BP2 in-creased the mRNA stability of NLRP3.The Rescue ex-periment showed that knocking down IGF2BP2 re-versed the decrease in NLRP3 mRNA expression caused by knocking down ALKBH5.Conclusions ALKBH5 mediated m6A modification of NLRP3 pro-motes cardiomyocytes pyroptosis in mice with myocardi-al infarction.

Aim To investigate the effects of m6A demethylase ALKBH5 on cardiomyocytes pyroptosis in mice with myocardial infarction(MI).Methods The MI model of left anterior descending coronary artery ligation surgery was established by knocking down ALKBH5 using adeno-associated virus,and the hypox-ia model of mouse cardiomyocytes(HL-1)was estab-lished by knocking down small interfering RNA.The effects of ALKBH5 on the pyroptosis of MI mice and hypoxic HL-1 cells were observed.Subsequently,mechanism studies were conducted at the cellular lev-el,and the binding of ALKBH5 and IGF2BP2 to NL-RP3 mRNA was detected through RNA pull down and RNA immunoprecipitation(RIP)experiments.The MeRIP-qPCR method was used to determine the effects of ALKBH5 on the mRNA m6A level of NLRP3.Acti-nomycin D for RNA stability experiments were conduc-ted to detect the effects of ALKBH5 and IGF2BP2 on the stability of NLRP3 mRNA.Results Knocking down ALKBH5 in vivo and in vitro both inhibited NL-RP3 inflammasome activation and alleviated pyroptosis in MI mice and hypoxic HL-1 cells.Mechanistically,the results showed that NLRP3 mRNA could bind to ALKBH5 protein in HL-1 cells;knocking down ALK-BH5 could increase the m6A level of NLRP3 and re-duce the stability of NLRP3 mRNA;subsequently,it was confirmed that NLRP3 mRNA and IGF2BP2 pro-tein bound to each other;knocking down IGF2BP2 in-creased the mRNA stability of NLRP3.The Rescue ex-periment showed that knocking down IGF2BP2 re-versed the decrease in NLRP3 mRNA expression caused by knocking down ALKBH5.Conclusions ALKBH5 mediated m6A modification of NLRP3 pro-motes cardiomyocytes pyroptosis in mice with myocardi-al infarction.

Objective: To compare the prognosis and perioperative situation of patients with stage Ⅱ endometrial cancer (EC) between radical hysterectomy/modified radical hysterectomy (RH/mRH) and simple hysterectomy (SH). Methods: A total of 47 patients diagnosed EC with stage Ⅱ [International Federation of Gynecology and Obstetrics (FIGO) 2009] by postoperative pathology, from January 2006 to January 2021 in Peking University People's Hospital, were analyzed retrospectively. The patients were (54.4±10.7) years old, and the median follow-up time was 65 months (ranged 9-138 months). They were divided into RH/mRH group (n=14) and SH group (n=33) according to the scope of operation. Then the prognosis of patients between the groups were compared, and the independent prognostic factors of stage Ⅱ EC were explored. Results: (1) The proportions of patients with hypertension in RH/mRH group and SH group were 2/14 and 45% (15/33), the amounts of intraoperative blood loss were (702±392) and (438±298) ml, and the incidence of postoperative complications were 7/14 and 15% (5/33), respectively. There were significant differences (all P<0.05). (2) The median follow-up time of RH/mRH group and SH group were 72 vs 62 months, respectively (P=0.515). According to Kaplan-Meier analysis and log-rank method, the results showed that there were no significant difference in 5-year progression-free survival (PFS) rate (94.3% vs 84.0%; P=0.501), and 5-year overall survival rate (92.3% vs 92.9%; P=0.957) between the two groups. Cox survival analysis indicated that age, pathological type, serum cancer antigen 125 (CA₁₂₅), and estrogen receptor (ER) status were associated with 5-year PFS rate (all P<0.05). But the scope of hysterectomy (RH/mRH and SH) did not affect the 5-year PFS rate of stage Ⅱ EC patients (P=0.508). And level of serum CA₁₂₅ and ER status were independent prognostic factors for 5-year PFS rate (all P<0.05). Conclusions: This study could not find any survival benefit from RH/mRH for stage Ⅱ EC, but increases the incidence of postoperative complications. Therefore, the necessity of extending the scope of hysterectomy is questionable.
Female ; Humans ; Adult ; Middle Aged ; Aged ; Disease-Free Survival ; Retrospective Studies ; Neoplasm Staging ; Prognosis ; Endometrial Neoplasms/pathology* ; Hysterectomy/methods* ; Postoperative Complications/epidemiology* ; Uterine Cervical Neoplasms/pathology*

Objective: To explore the effects of preoperative hysteroscopic guided biopsy and segmental diagnosis and curettage on the risk of abdominal dissemination and prognosis of non-endometrioid carcinoma. Methods: The clinical and pathological data of 97 patients who underwent surgical treatment and were pathologically confirmed as non-endometrioid carcinoma (including serous carcinoma, clear cell carcinoma, mixed adenocarcinoma, and undifferentiated carcinoma, etc.) from October 2008 to December 2021 in Peking University People's Hospital, were collected for retrospective analysis. According to preoperative diagnostic methods, they were divided into hysteroscopic group (n=44) and non-hysteroscopic group (n=53). The impact of hysteroscopy examination on peritoneal cytology and prognosis was analyzed. Results: (1) There were no statistical differences in age, body mass index, tumor size, pathological characteristics, and treatment methods between the hysteroscopic group and the non-hysteroscopic group (all P>0.05), but the proportion of stage Ⅰ-Ⅱ patients in the hysteroscopic group was significantly higher than that in the non-hysteroscopic group [68% (30/44) vs 47% (25/53); χ²=4.32, P=0.038]. (2) Among 97 patients, 25 (26%, 25/97) of them were cytologically positive for ascites. The hysteroscopic group had a lower positive rate of peritoneal cytology than that in the non-hysteroscopy group, which was significantly different [11% (5/44) vs 38% (20/53); χ²=8.74, P=0.003]. Stratification according to surgical and pathological stages showed that the positive rate of peritoneal cytology in the hysteroscopic group (3%, 1/30) was lower than that in the non-hysteroscopic group (12%, 3/25) in the 55 patients with stage Ⅰ-Ⅱ, and that in the hysteroscopic group (4/14) was also lower than that in the non-hysteroscopic group (61%, 17/28) in the 42 patients with stage Ⅲ-Ⅳ. There were no significant differences (all P>0.05). (3) The 5-year disease-free survival (DFS) rate of the hysteroscopic group and the non-hysteroscopic group were respectively 72.7% and 60.4%, and there was no significant difference between the two groups (P=0.186). After stratification according to staging, the 5-year DFS rate were respectively 90.0% and 72.0% (P=0.051) between the hysteroscopic and non-hysteroscopic groups of patients in stage Ⅰ-Ⅱ, and 35.7% and 50.0% (P=0.218) between the hysteroscopic and non-hysteroscopic groups of patients in stage Ⅲ-Ⅳ, in which there were not statistically significant differences. The 5-year overall survival (OS) rate were respectively 86.4% and 81.1% between the hysteroscopic group and the non-hysteroscopic group, with no significant difference between the two groups (P=0.388). The 5-year OS rate were respectively 93.3% and 96.0% in the hysteroscopic group and non-hysteroscopic group for patients with stage Ⅰ-Ⅱ(P=0.872), and 71.4% and 67.9% in the hysteroscopic group and non-hysteroscopic group in patients with stage Ⅲ-Ⅳ (P=0.999), with no statistical significance. Conclusions: Diagnostic hysteroscopy do not increase the rate of positive peritoneal cytology result at the time of surgery in this cohort, and no significant correlation between preoperative hysteroscopy examination and poor prognosis of non-endometrioid carcinoma is observed. Therefore, preoperative hysteroscopic guided biopsy and segmental diagnosis and curettage in non-endometrioid carcinoma maybe safe.
Female ; Pregnancy ; Humans ; Endometrial Neoplasms/pathology* ; Retrospective Studies ; Hysteroscopy/methods* ; Cytology ; Prognosis ; Carcinoma ; Neoplasm Staging

Objective: To summarize the management and short-term outcomes of neonates delivered by mothers infected with SARS-CoV-2 Omicron variant. Methods: A retrospective study was performed on 158 neonates born to mothers infected with SARS-CoV-2 Omicron variant admitted to the isolation ward of Children's Hospital of Fudan University from March 15^th, 2022 to May 30^th, 2022. The postnatal infection control measures for these neonates, and their clinical characteristics and short-term outcomes were analyzed. They were divided into maternal symptomatic group and maternal asymptomatic group according to whether their mothers had SARS-CoV-2 symptoms. The clinical outcomes were compared between the 2 groups using Rank sum test and Chi-square test. Results: All neonates were under strict infection control measures at birth and after birth. Of the 158 neonates, 75 (47.5%) were male. The gestational age was (38⁺³±1⁺³) weeks and the birth weight was (3 201±463)g. Of the neonates included, ten were preterm (6.3%) and the minimum gestational age was 30⁺¹ weeks. Six neonates (3.8%) had respiratory difficulty and 4 of them were premature and required mechanical ventilation. All 158 neonates were tested negative for SARS-COV-2 nucleic acid by daily nasal swabs for the first 7 days. A total of 156 mothers (2 cases of twin pregnancy) infected with SARS-CoV-2 Omicron variant, the time from confirmed SARS-CoV-2 infection to delivery was 7 (3, 12) days. Among them, 88 cases (56.4%) showed clinical symptoms, but none needed intensive care treatment. The peripheral white blood cell count of the neonates in maternal symptomatic group was significantly higher than that in maternal symptomatic group (23.0 (18.7, 28.0) × 10⁹ vs. 19.6 (15.4, 36.6) × 10⁹/L, Z=2.44, P<0.05). Conclusions: Neonates of mothers infected with SARS-CoV-2 Omicron variant during third trimester have benign short-term outcomes, without intrauterine infection through vertical transmission. Strict infection control measures at birth and after birth can effectively protect these neonates from SARS-CoV-2 infection.
Female ; Humans ; Infant ; Infant, Newborn ; Male ; Pregnancy ; COVID-19 ; Mothers ; Pregnancy Complications, Infectious/prevention & control* ; Retrospective Studies ; SARS-CoV-2

Objective: To compare the effects of three treatment options: emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery, on the pathological characteris- tics of surgically-resected specimens from patients with completely obstructive colorectal cancer. Methods: This was a retrospective cohort study analyzing clinicopathological data of patients with complete obstructive colorectal cancer who were admitted to the General Surgery Department of Beijing Chaoyang Hospital, Capital Medical University, between May 2012 and August 2020. The inclusion criteria were diagnosed with complete colorectal obstruction, pathologically confirmed as adenocarcinoma, resectable on imaging assessment, and without distant metastasis, combined with the patients' clinical manifestations and imaging examination findings. Patients with multiple colorectal cancers, refusal to undergo surgery, and concurrent peritonitis or intestinal perforation before stenting of the intestinal obstruction were excluded. Eighty-nine patients with completely obstructive colorectal cancer were enrolled in the study and were divided into emergency surgery group (n=30), stent-surgery group (n=34), and stent-neoadjuvant chemotherapy- surgery group (n=25) according to the treatment strategy. Differences in the pathological features (namely perineural infiltration, lymphovascular infiltration, tumor deposits, specimen intravascular necrosis, inflammatory infiltration, abscesses, mucus lake formation, foreign body giant cells, calcification, and tumor cell ratio) and biomolecular markers (namely cluster of differentiation (CD)34, Ki67, Bcl-2, matrix metalloproteinase-9, and hypoxia-inducible factor alpha) were recorded. Pathological evaluation was based on the presence or absence of qualitative evaluation of pathological features, such as peripheral nerve infiltration, vascular infiltration, and cancer nodules within the specimens. The evaluation criteria for the pathological features of the specimens were as follows: Semi-quantitative graded evaluation based on the proportion of tissue necrosis, inflammatory infiltrates, abscesses, mucus lake formation, foreign body giant cells, calcification, and tumor cells in the field of view within the specimen were classified as: grade 0: not seen within the specimen; grade 1: 0-25%; grade 2: 25%-50%; grade 3: 50%-75%; and grade 4: 75%-100%. The intensity of cellular immunity was classified as none (0 points), weak (1 point), moderate (2 points), and strong (3 points). The two evaluation scores were then multiplied to obtain a total score of 0-12. The immunohistochemical results were also evaluated comprehensively, and the results were defined as: negative (grade 0): 0 points; weakly positive (grade 1): 1-3 points; moderately positive (grade 2): 4-6 points; strongly positive (grade 3): 7-9 points; and very strong positive (grade 4): 10-12 points. Normally-distributed values were expressed as mean±standard deviation, and one-way analysis of variance was used to analyze the differences between the groups. Non-normally-distributed values were expressed as median (interquartile range: Q1, Q3). A nonparametric test (Kruskal-Wallis H test) was used for comparisons between groups. Results: The differences were not statistically significant when comparing the baseline data for age, gender, tumor site, American Society of Anesthesiologists score, tumor T-stage, N-stage, and degree of differentiation among the three groups (all P>0.05). The differences were not statistically significant when comparing the pathological characteristics of the resected tumor specimens, such as foreign body giant cells, inflammatory infiltration, and mucus lake formation among the three groups (all P>0.05). The rates of vascular infiltration were 56.6% (17/30), 41.2% (15/34), and 20.0% (5/25) in the emergency surgery, stent-surgery, and stent- neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences between the groups (χ²=7.142, P=0.028). Additionally, the rate of vascular infiltration was significantly lower in the stent-neoadjuvant chemotherapy-surgery group than that in the emergency surgery group (P=0.038). Peripheral nerve infiltration rates were 55.3% (16/30), 41.2% (14/34), and 16.0% (4/25), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (χ²=7.735, P=0.021). The infiltration peripheral nerve rates in the stent-neoadjuvant chemotherapy-surgery group were significantly lower than those in the emergency surgery group (P=0.032). The necrosis grade was 2 (1, 2), 2 (1, 3), and 2 (2, 3) in the emergency surgery, stent- surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (H=10.090, P=0.006). Post hoc comparison revealed that the necrosis grade was higher in the stent-surgery and stent-neoadjuvant chemotherapy-surgery groups compared with the emergency surgery group (both P<0.05). The abscess grade was 2 (1, 2), 3 (1, 3), and 2 (2, 3) in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (H=6.584, P=0.037). Post hoc comparison revealed that the abscess grade in the emergency surgery group was significantly lower than that in the stent-surgery group (P=0.037). The fibrosis grade was 2 (1, 3), 3 (2, 3), and 3 (2, 3), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (H=11.078, P=0.004). Post hoc analysis revealed that the fibrosis degree was higher in both the stent-surgery group and the stent- neoadjuvant chemotherapy-surgery group compared with the emergency surgery group (both, P<0.05). The tumor cell ratio grades were 4 (3, 4), 4 (3, 4), and 3 (2, 4), in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, with statistically significant differences (H=8.594, P=0.014). Post hoc analysis showed that the tumor cell ratio in the stent-neoadjuvant chemotherapy-surgery group was significantly lower than that in the emergency surgery group (P=0.012). The CD34 grades were 2 (2, 3), 3 (2, 4), and 3 (2, 3) in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups, respectively, and the difference was statistically significant (H=9.786, P=0.007). Post hoc analysis showed that the CD34 grades in the emergency surgery, stent-surgery, and stent-neoadjuvant chemotherapy-surgery groups were 2 (2, 3), 3 (2, 4), and 3 (2,3), respectively. Post hoc analysis revealed that the CD34 concentration was higher in the stent-surgery group than that in the emergency surgery group (P=0.005). Conclusion: Stenting may increase the risk of distant metastases in obstructive colorectal cancer. The stent-neoadjuvant chemotherapy-surgery treatment model promotes tumor cell necrosis and fibrosis and reduces the proportion of tumor cells, vascular infiltration, and peripheral nerve infiltration, which may help decrease local tumor infiltration and distant metastasis in completely obstructive colorectal cancer after stent placement.
Humans ; Neoadjuvant Therapy/methods* ; Abscess ; Retrospective Studies ; Intestinal Obstruction/etiology* ; Stents ; Colorectal Neoplasms/therapy* ; Necrosis

Objective: To compare the effects of 3 treatment strategies (emergent surgery, self-expanding metallic stents, self-expanding metallic stents plus neoadjuvant chemotherapy) on postoperative anal function and quality of life in patients with complete obstructive left hemicolon cancer. Methods: A retrospective cohort study was conducted. Clinical data of patients with complete obstructive left hemicolon cancer admitted to General Surgery Department of Beijing Chaoyang Hospital between January 2017 and October 2019 were retrospectively collected. Patient inclusion criteria: (1) complete obstructive left hemicolon cancer was confirmed through clinical manifestation and abdominal computed tomography; (2) adenocarcinoma was confirmed by postoperative pathology; (3) emergent radical resection of primary tumor was performed with temporary stoma, or radical resection of primary tumor and primary anastomosis was performed without stoma, 7 to 14 days after completion of insertion of self-expanding metallic stents. Patients who did not receive stoma reversion after emergent operation were excluded. According to different therapies, patients were divided into three groups: emergent surgery (ES) group, self-expanding metallic stents (SEMS) group and self-expanding metallic stents plus neoadjuvant chemotherapy (SEMS+NAC) group. Wexner score for incotinence (higher score indicates the worse anal function), Vaizey score (>10 indicates fecal incontinence) and low anterior resection syndrome (LARS) scale (higher score indicates the worse anal function) were applied to evaluate anal function of patients among groups at postoperative 1-, 6- and 12-month. EORTC QLQ-C30 questionnaire was used to assess the quality of life. Risk factors of decreased anal function were identified by logistic regression analysis. Results: A total of 72 patients were enrolled, including 27 (37.5%) patients in ES group, 23 (31.9%) in SEMS group and 22 (30.6%) in SEME+NAC group. The baseline characteristics including age, gender, tumor location, comorbidities, total blood loss, operation time and postoperative complications, were comparable among groups, except that the proportion of laparoscopic surgery was significantly lower in ES group (4/27, 14.9%) than that in SEMS (15/23, 65.2%) and SEMS+NAC group (16/22, 72.7%) with significant difference (P<0.001). The follow-up ended up to October 2020, and the overall follow-up rate was 79.2% (57/72). No significant differences existed in the Wexner score of patients among groups at postoperative 1-, 6- and 12-month (all P>0.05). The Vaizey scores at postoperative 1-month in ES, SEMS and SEMS+NAC group were 7 (0-17), 3 (0-7) and 4 (0-8) respectively with significant difference (H=18.415, P=0.001), and the scores in SEMS and SEMS+NAC groups were significantly lower than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC group (P>0.05). Vaizey scores at postoperative 6- and 12-month among 3 groups were not significantly different (both P>0.05). The LARS scores at postoperative 1-month in ES, SEMS and SEMS+NAC groups were 20 (0-37), 15 (0-24) and 16 (0-28) respectively with significant difference (H=3.660, P=0.036), and the scores in SEMS and SEMS+NAC groups were significantly lower than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC groups (P>0.05). LARS scores at postoperative 6- and 12-month among 3 groups were not significantly different (both P>0.05). The QLQ-C30 score revealed that the social function of patients in SEMS group and SEMS+NAC group was significantly better than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC group (P>0.05). The logistic regression analysis revealed that only ES was an independent risk factor of decreased anal function (OR=2.264, 95% CI: 1.098-4.667, P=0.027). Conclusion: Compared to ES, SEMS may improve quality of life and short-term anal function of patients with complete obstructive left hemicolon cancer.
Humans ; Intestinal Obstruction ; Postoperative Complications ; Quality of Life ; Rectal Neoplasms ; Retrospective Studies ; Syndrome ; Treatment Outcome

Objective:Nivolumab is one of the most common programmed death 1 （PD-1） inhibitors used as an immune checkpoint inhibitor （ICI）. It brings significant therapeutic effects but often accompanied by serious drug toxicity. The pulmonary toxicities of nivolumab are not clear. This study aims to systematically explore the nivolumab-associated pulmonary toxicities and provide reference for clinical treatment. Methods:Data were extracted from US Food and Drug Administration （FDA） Adverse Event Reporting System （FAERS） database from January 1， 2016 to September 30， 2019. Two types of disproportionality analysis， information component （IC） and reporting odds ratio （ROR）， were applied in nivolumab-associated pulmonary adverse events （AEs） signal detection. Results:A total of 28 489 309 records were extracted from FAERS database and 8 181 records were associated with nivolumab. Analysis was conducted in 179 AEs and 86 signals were detected. Notably， potent signals were detected in radiation pneumonitis （IC₀₂₅： 3.99， ROR₀₂₅： 17.25）， pneumonitis （IC₀₂₅： 3.34， ROR₀₂₅： 10.64） and bronchial fistula （IC₀₂₅： 2.94， ROR₀₂₅： 8.78）. Nivolumab-associated pulmonary toxicities were more frequently reported in dyspnoea （IC₀₂₅： 0.50， ROR₀₂₅： 1.44）， pneumonia （IC₀₂₅： 0.08， ROR₀₂₅： 1.07） and pneumonitis （IC₀₂₅： 3.34， ROR₀₂₅： 10.64）. Results of IC and ROR methods were similar to each other. Most pulmonary toxicities were observed in patients with non-small cell lung cancer （N=3 711， 32.13%）， malignant melanoma （N=1 658， 14.36%） and renal cell carcinoma （N=731， 6.33%）. Conclusion:Significant pulmonary toxicities were detected in patients treated with nivolumab. Thus， it is highly important for clinicians to be vigilant about nivolumab-associated pulmonary AEs and be prepared to take immediate action for patient safety.