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BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Terapia Neoadjuvante , Piridinas , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Terapia Neoadjuvante/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto Jovem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , AdolescenteRESUMO
BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.
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Neoplasias Colorretais , Neoplasias Retais , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Imunoterapia , Instabilidade de Microssatélites , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Objective To construct a machine learning prediction model for postoperative liver injury in patients with non-liver surgery based on preoperative and intraoperative medication indicators.Methods A case-control study was conducted on 315 patients with liver injury after non-liver surgery selected from the databases developed by 3 large general hospitals from January 2014 to September 2022.With the positive/negative ratio of 1 ∶3,928 cases in corresponding period with non-liver surgery and without liver injury were randomly matched as negative control cases.These 1243 patients were randomly divided into the modeling group(n=869)and the validation group(n=374)in a ratio of 7∶3 using the R language setting code.Preoperative clinical indicators(basic information,medical history,relevant scale score,surgical information and results of laboratory tests)and intraoperative medication were used to construct the prediction model for liver injury after non-liver surgery based on 4 machine learning algorithms,k-nearest neighbor(KNN),support vector machine linear(SVM),logic regression(LR)and extreme gradient boosting(XGBoost).In the validation group,receiver operating characteristic(ROC)curve,precision-recall curve(P-R),decision curve analysis(DCA)curve,Kappa value,sensitivity,specificity,Brier score,and F1 score were applied to evaluate the efficacy of model.Results The model established by 4 machine learning algorithms to predict postoperative liver injury after non-liver surgery was optimal using the XGBoost algorithm.The area under the receiver operating characteristic curve(AUROC)was 0.916(95%CI:0.883~0.949),area under the precision-recall curve(AUPRC)was 0.841,Brier score was 0.097,and sensitivity and specificity was 78.95%and 87.10%,respectively.Conclusion The postoperative liver injury prediction model for non-liver surgery based on the XGBoost algorithm has effective prediction for the occurrence of postoperative liver injury.
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Air pollution is a serious global public health problem. Air pollutants, especially fine particulate matter (PM2.5), are associated with increased risks of various diseases. In recent years, studies have confirmed that PM2.5 is closely related to chronic kidney disease, secondary kidney disease, and end-stage renal disease. This review summarized the effects of PM2.5 and its components on kidney diseases, and the potential mechanism of kidney injury induced by PM2.5 exposure from the aspects of inflammatory injury and oxidative stress, renal hemodynamic changes, and DNA damage and methylation, aiming to provide an insight for further mechanism research and the prevention and control of air pollution-induced kidney damage.
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Objective:To study the risk factors for retinopathy of prematurity (ROP) in very low birth weight infants (VLBWIs).Methods:From October 2020 to December 2021, VLBWIs with gestational age(GA) ≤32 weeks admitted to the neonatal department of our hospital were retrospectively studied. According to the occurrence of ROP, they were assigned into ROP group and non-ROP group. The clinical data of the two groups were compared and the risk factors of ROP in VLBWI were analyzed.Results:A total of 251 VLBWIs were enrolled, including 60 cases (23.9%) in ROP group and 191 (76.1%) in non-ROP group. The GA and birth weight (BW) of ROP group were significantly lower than non-ROP group [28(26,30) w vs. 29(28,31) w, 1 035(840,1 285) g vs. 1 260(1 110,1 380) g, respectively, all P<0.001]. The ROP group had longer duration of oxygen therapy [42.0(26.0, 53.5) d vs. 24.0(18.0, 34.0) d], higher incidences of blood transfusion [2.5(1.0, 3.0) times vs. 2.0 (1.0, 2.0) times] and hyperglycemia (80.0% vs. 16.8%), higher average [(5.6±0.5) mmol/L vs. (5.1±0.5) mmol/L] and peak [10.4(7.8,13.2) mmol/L vs. 6.5(6.1,6.8) mmol/L] blood glucose levels in the first week than the non-ROP group (all P<0.001). Multivariate analysis showed that longer duration of oxygen therapy ( OR=1.047, 95% CI 1.008-1.087, P=0.018) and higher peak blood glucose level in the first week ( OR=1.268, 95% CI 1.092-1.474, P=0.002) were the independent risk factors for ROP. Conclusions:Longer duration of oxygen therapy and higher peak of blood glucose level in the first week are risk factors for ROP in VLBWIs.
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Objective:To study the risk factors of secondary hydrocephalus after severe intraventricular hemorrhage (IVH) in preterm infants for prevention and early identification of post-hemorrhagic hydrocephalus (PHH).Methods:From June 2013 to June 2021, preterm infants with severe IVH admitted to our hospital were retrospectively analyzed. They were assigned into PHH group and non-PHH group. Rank sum test or chi-square test was used for comparison between the two groups and multivariate logistic regression analysis was used to analyze the risk factors of PHH in preterm infants.Results:A total of 246 preterm infants with severe IVH were enrolled, including 68 cases (27.6%) in the PHH group and 178 cases (72.4%) in the non-PHH group. Multivariate logistic stepwise regression analysis showed that male gender ( OR=2.014, 95% CI 1.063-3.817), gestational age ≤30 week ( OR=2.240, 95% CI 1.210-4.146), 5-min Apgar score ≤5 ( OR=3.980, 95% CI 1.483-10.685), placental abruption ( OR=2.940, 95% CI 1.324-6.531) were independent risk factors for PHH in preterm infants and thrombocytopenia was the protective factor for PHH in preterm infants ( OR=0.305, 95% CI 0.147-0.632). The incidence of moderate thrombocytopenia in non-PHH group was significantly higher than PHH group ( P<0.05). No significant differences existed in the incidences of mild and severe thrombocytopenia between the two groups ( P>0.05). Conclusions:Male gender, gestational age ≤30 week, 5-min Apgar score ≤5, placental abruption are risk factors for PHH in premature infants with severe IVH and moderate thrombocytopenia has protective effects.
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Objective: Through the use of high-density polyethylene implants in adults with cleft lip and palate nasal deformities and abnormal functions, to evaluate the clinical effect of postoperative patients on improving nasal shape and symptoms. Methods: A retrospective study of 12 patients with nasal deformities after cleft lip and palate surgery in the Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine from January 2018 to January 2022 was completed, including 7 males and 5 females, with the age ranging from 18 to 29 years. All the patients underwent nasal deformity correction, and nasal septum correction was performed if necessary. High-density polyethylene implants (MEDPOR/Su-Por) were used intraoperatively. Follow-up for at least 6 months was performed to measure the relevant appearance indicators and subjective Visual Analog Scale (VAS) scores, and to compare the clinical effects before and after surgery. SPSS 22.0 software was used for statistical analysis. Results: Before and after surgery, the average VAS score of nasal obstruction decreased by (4.83±0.94) points; the average VAS score of appearance satisfaction increased by (3.92±1.08) points; the height of nasal columella was increased by (1.79±0.78)mm; the height of nasal tip was increased by (2.79±1.50)mm; the height of ipsilateral nostril was increased by (1.83±0.62)mm; the width of the ipsilateral nasal floor was reduced by (0.42±0.47)mm. All of above were statistically significant (all P<0.05). Conclusion: High-density polyethylene implants can effectively improve the shape and function of the nose in operations related to cleft lip and palate nasal deformity and abnormal functions, and are an ideal synthetic material.
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OBJECTIVES@#Diabetic kidney disease is one of the most serious complications of diabetes mellitus (DM), and it is a main cause for chronic kidney disease and end-stage kidney disease (ESRD). It is important to find out the factors that cause the progression of renal function. The study aims to explore the relationship between serum uric acid (SUA) trajectory and the progression of renal function in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 846 patients with T2DM, who were admitted to the Department of Nephrology and Endocrinology, the Third Xiangya Hospital of Central South University, from January 2009 to December 2021 and met the criteria of baseline estimated glomerular filtration rate (eGFR)≥60 mL/(min·1.73 m2), were selected as the research subjects. The SUA data of multiple measurements were collected and identified as different SUA trajectories by group-based trajectory modeling (GBTM). According to the SUA trajectories, the patients were divided into a low trajectory group (105 cases), a middle trajectory group (396 cases), a middle high trajectory group (278 cases), and a high trajectory group (67 cases). Cox regression analysis was used to examine the effect of SUA trajectory on the progression of renal function in patients with T2DM. Subgroup analysis was performed by sex, age, course of disease, body mass index (BMI) and hemoglobin A1c (HbA1c).@*RESULTS@#The median follow-up was 4.8 years. At the end of follow-up, 158 patients had different degrees of decline in renal function. After adjusting for multiple confounding factors by Cox regression analysis, the risks of eGFR<60 mL/(min·1.73 m2), eGFR reduction rate≥50%, serum creatinine (Scr) doubling and composite endpoint (eGFR reduction rate≥50%, Scr doubling or ESRD) in the high trajectory group were significantly higher than those in the low trajectory group, with HR of 3.84 (95% CI 1.83 to 8.05), 6.90 (95% CI 2.27 to 20.96), 6.29 (95% CI 2.03 to 19.52), and 8.04 (95% CI 2.68 to 24.18), respectively. There was no significant difference in the risk of ESRD among the above 4 groups (all P>0.05). Subgroup analysis showed that: compared with the low trajectory group, the risks of eGFR<60 mL/(min·1.73 m2) in patients with high trajectory in the subgroup of male, female, age<65 years, course of disease<10 years, BMI≥24 kg/m2 and HbA1c≥7% were increased (all P<0.05). The SUA trajectory had no interaction with sex, age, course of disease, BMI and HbA1c (all interactive P>0.05).@*CONCLUSIONS@#The high SUA trajectory increases the risk for progression of renal function in patients with T2DM. Long-term longitudinal changes of SUA should be paid attention to.
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Humanos , Masculino , Feminino , Idoso , Diabetes Mellitus Tipo 2/complicações , Estudos de Coortes , Ácido Úrico , Hemoglobinas Glicadas , Insuficiência Renal Crônica , Falência Renal Crônica/complicações , Taxa de Filtração Glomerular , Rim/fisiologia , Fatores de RiscoRESUMO
Objective: To investigate the relationship between the levels of selenium, iron and copper in cord blood of neonates and the risk of congenital heart disease (CHD), and analyze their interaction effects. Methods: The subjects were obtained from the birth cohort in Lanzhou area established from 2010 to 2012. A baseline survey was conducted in the first trimester, and the follow-up was conducted in the second trimester, third trimester and 42 days after delivery. The umbilical vein blood was collected from newborns at delivery, and information on their birth outcomes was extracted from medical records. A nested case-control study was used to select 97 neonates with CHD newly diagnosed by echocardiography as the case group, and 194 neonates were selected as the control group by 1∶2 matching according to their mother's age, block and CHD onset time. Inductively coupled ion mass spectrometry was used to detect the concentrations of selenium, iron and copper in neonatal cord blood. The element exposure was categorized into three groups, the low, medium and high concentrations, according to the quartiles Q1 and Q3 of selenium, iron and copper concentrations in the control group. The association between cord blood selenium, iron and copper concentrations and CHD was analyzed by conditional logistic regression model using medium concentration as the reference standard. The association of their interactions with CHD was analyzed by a phase multiplication model. Results: The M (Q1, Q3) concentration of neonatal cord blood copper was 746.12 (467.48, 759.74) μg/L in the case group and 535.69 (425.21, 587.79) μg/L in the control group, with a statistically significant difference between the two groups (P<0.05). After adjustment for confounders, logistic regression models showed that the risk of CHD development was increased in neonates with either high copper in cord blood (OR=4.062, 95%CI: 2.013-8.199) or high copper combined with high iron (OR=3.226, 95%CI: 1.343-7.750). No correlation was observed between selenium and iron concentrations and the development of CHD in neonates. There was a multiplicative interaction between copper and iron in cord blood on the risk of developing CHD (OR=1.303, 95%CI: 1.056-1.608). Conclusion: There is a multiplicative interaction between iron and copper elements. The high copper and the high copper combined with high iron in umbilical cord blood are risk factors for neonatal CHD.
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Humanos , Recém-Nascido , Cobre/análise , Selênio , Ferro/análise , Sangue Fetal/química , Estudos de Casos e Controles , Cardiopatias CongênitasRESUMO
Objective: To compare the dwelling time and complications of low lying umbilical venous catheterization (UVC) in preterm infants with that of central UVC. Methods: This was a prospective cohort study. A total of 3 020 preterm infants from 44 neonatal intensive care units (NICU) who had UVC inserted from October 2019 to August 2021 were enrolled. Demographic and general baseline data, dwelling time of UVC and reasons for removal, complications and their occurrence time were collected. According to the position of the catheter tip, the preterm infants were divided into low lying UVC group (insertion depth of 3-5 cm) and central UVC group (the catheter tip was close to the entrance of right atrium, or at the 8th-9th thoracic vertebra level). The Mann-Whitney U test was used to compare the dwelling time and incidence of complications (cases/1 000 catheter days), and the independent t test and Chi-square test were used to compare the characteristics between the 2 groups. The receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off value of UVC dwelling time. Results: Among the included 3 020 preterm infants, 1 624 (53.8%) were males, the gestational age was 29.9 (28.4, 31.6) weeks, the birth weight was (1 264±301) g, and 2 172 (71.9%) premature babies had central UVC. There were no significant differences in the proportion of males, the gestational age and the birth weight of neonates between the 2 groups (all P>0.05). There were also no significant differences in the rate of maternal history, PPROM>18 hours, chorioamnionitis, antenatal antibacterial angents exposure and antibacterial angents usage through UVC (all P>0.05). The dwelling time of central UVC was longer than that of low lying UVC (7 (6, 10) vs. 4 (3, 7) days, U=23.42, P<0.001). The complication incidence of central and low lying UVC were 20.0 and 70.8 cases/1 000 catheter days, respectively. The top 3 complications of central UVC were occlusion, catheter tip migration, and CLABSI (9.3, 3.5, 3.0 cases/1 000 catheter days). The top 3 complications of low lying UVC were catheter occlusion, CLABSI, and catheter tip migration (45.8, 6.3, 5.4 cases/1 000 catheter days). The ROC curve of UVC dwelling time and complications showed that the cut-off values of central UVC and low lying UVC were 6.5 and 4.5 days, respectively. The 2 groups both showed a trend of increases in the 3 complications with the prolonged dwelling time. Cox regression analysis showed that the overall difference in the proportion of occlusion between the central UVC and low lying UVC groups was statistically significant (χ2=30.18, P=0.024). There were both no significant differences in catheter tip migration and CLABSI (both P>0.05). Conclusions: The most common UVC complication in preterm infants is occlusion. It is not recommended to keep a low lying UVC for longer than 4.5 days. During the whole dwelling period, a close monitoring for UVC complications is required.
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Gravidez , Masculino , Recém-Nascido , Humanos , Feminino , Lactente , Recém-Nascido Prematuro , Peso ao Nascer , Estudos Prospectivos , Cateterismo Venoso Central/efeitos adversos , Antibacterianos , Cateterismo Periférico/efeitos adversos , Estudos RetrospectivosRESUMO
In the outbreak of COVID-19,triage procedures based on epidemiology were implemented in a local hospital in Changsha to control the transmission of SARS-CoV-2 and avoid healthcare-associated infection.This re-trospective study analyzed the data collected during the triage period and found that COVID-19 patients were en-riched 7 folds into the Section A designated for patients with obvious epidemiological history.On the other side,nearly triple amounts of visits were received at the Section B for patients without obvious epidemiological history.8 COVID-19 cases were spotted out of 247 suspected patients.More than 50%of the suspected patients were submi-tted to multiple rounds of nucleic acid analysis for SARS-CoV-2 infection.Of the 239 patients who were diagnosed as negative of the virus infection,188 were successfully revisited and none was reported as COVID-19 case.Of the 8 COVID-19 patients,3 were confirmed only after multiple rounds of nucleic acid analysis.Besides comorbidities,delayed sharing of epidemiological history added complexity to the diagnosis in practice.The triaging experience and strategy will be helpful for the control of infectious diseases in the future.
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OBJECTIVES@#Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation.@*METHODS@#Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL.@*RESULTS@#Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05).@*CONCLUSIONS@#Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.
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Animais , Feminino , Humanos , Masculino , Camundongos , Injúria Renal Aguda/patologia , Apoptose/fisiologia , Cisplatino/efeitos adversos , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Objective: To provide reference and evidence for clinical application of neoadjuvant immunotherapy in patients with colorectal cancer through multicenter large-scale analysis based on real-world data in China. Methods: This was a retrospective multicenter case series study. From January 2017 to October 2021, data of 94 patients with colorectal cancer who received neoadjuvant immunotherapy in Peking University Cancer Hospital (55 cases), Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (19 cases), Sun Yat-sen University Cancer Center (13 cases) and Changhai Hospital of Navy Medical University (7 cases) were retrospectively collected, including 48 males and 46 females. The median age was 58 years. Eighty-one cases were rectal cancer and 13 cases were colon cancer (2 cases of double primary colon cancer). Twelve cases were TNM staging II and 82 cases were stage III. Forty-six cases were well differentiated, 37 cases were moderately differentiated and 11 cases were poorly differentiated. Twenty-six patients (27.7%) with mismatch repair defects (dMMR) and microsatellite instability (MSI-H) were treated with immunotherapy alone, mainly programmed cell death protein-1 (PD-1); sixty-eight cases (72.3%) with mismatch repair proficient (pMMR) and microsatellite stability (MSS) were treated with immune combined with neoadjuvant therapy, mainly CapeOx (capecitabine+oxaliplatin) combined with PD-1 antibody plus long- or short-course radiotherapy, or PD-1 antibody combined with cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody. Analysis and evaluation of adverse events during neoadjuvant immunotherapy were performed according to the National Cancer Institute Common Toxicity Standard version 3.0; the surgical complications were evaluated according to the Clavien-Dindo grading standard; the efficacy evaluation of neoadjuvant immunotherapy included the following indicators: major pathological remission (MPR) was defined as tumor regression induced by neoadjuvant therapy in pathology residual tumor ≤10%; pathological complete response (pCR) was defined as tumor regression induced by neoadjuvant therapy without residual tumor in pathology; the tumor response rate was disease control rate (DCR), namely the proportion of complete response (CR), partial response (PR) and stable disease (SD) in the whole group; the objective response rate (ORR) was CR+PR. Results: The median cycle of neoadjuvant immunotherapy was 4 (1-10) in whole group, and the incidence of immune-related adverse reactions was 37.2% (35/94), including 35 cases (37.2%) of skin-related adverse reactions, 21 cases (22.3%) of thyroid dysfunction and 8 cases (8.5%) of immune enteritis, of which grade III or above accounted for 1.1%. The median interval between completion of neoadjuvant therapy and surgery was 30 (21-55) days. There were 81 cases of radical resection of rectal cancer, 11 cases of radical resection of colon cancer, and 2 cases of colon cancer combined with other organ resection. The primary tumor resection of all the patients reached R0. The incidence of surgical-related complications was 22.3% (21/94), mainly anastomotic leakage (4 cases), pelvic infection (4 cases), abdominal effusion (3 cases), anastomotic stenosis (3 cases ) and abdominal and pelvic hemorrhage (2 cases). Grade I-II complications developed in 13 cases (13.8%), grade III and above complications developed in 8 cases (8.5%), no grade IV or above complications were found. During a median follow-up of 32 (1-46 ) months, DCR was 98.9% (93/94), ORR was 88.3 % (83/94), pCR was 41.5% (39/94), MPR was 60.6% (57/94). The pCR rate of 26 patients with dMMR and MSI-H undergoing simple immunotherapy was 57.7% (15/26), and MPR rate was 65.4% (17/26). The pCR rate of 68 pMMR and MSS patients undergoing combined immunotherapy was 35.3%(24/68), and MPR rate was 58.8% (40/68). Conclusions: Neoadjuvant immunotherapy has favorable tumor control rate and pathological remission rate for patients with initial resectable colorectal cancer. The incidences of perioperative adverse reactions and surgical complications are acceptable.
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Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Colorretais/cirurgia , Imunoterapia , Terapia Neoadjuvante , Neoplasias Retais/cirurgia , Estudos RetrospectivosRESUMO
Introduction and objectives Omenn syndrome (OS) is a very rare type of severe combined immunodeficiencies manifested with erythroderma, eosinophilia, hepatosplenomegaly, lymph-adenopathy, and elevated level of serum IgE. OS is inherited with an autosomal recessive mode of inheritance. Germline mutations in the human RAG1 gene cause OS. Materials and methods In this study, we investigated a 2-month-old boy with cough, mild anaemia, pneumonia, immunodeficiency, repeated infection, feeding difficulties, hepatomegaly, growth retardation, and heart failure. Parents of the proband were phenotypically normal. Results Karyotype analysis and chromosomal microarray analysis found no chromosomal structural abnormalities (46, XY) and no pathogenic copy number variations (CNVs) in the proband. Whole-exome sequencing identified a novel homozygous single nucleotide deletion (c.2662delC) in exon 2 of the RAG1 gene in the proband. Sanger sequencing confirmed that both the proband parents were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters and one elder brother of the proband and in the 100 ethnically matched normal healthy individuals. This novel homozygous deletion (c.2662delC) leads to the frameshift, which finally results in the formation of the truncated protein (p.Leu888Phefs*3) V(D)J recombination-activating protein 1 with 890 amino acids compared with the wildtype V(D)J recombination-activating protein 1 of 1043 amino acids. Hence, it is a loss-of-function variant. Conclusion Our present study expands the mutational spectrum of the RAG1 gene associated with OS. We also strongly suggested the importance of whole-exome sequencing for the genetic screening of patients with OS (AU)
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Humanos , Masculino , Feminino , Criança , Imunodeficiência Combinada Severa/genética , Sequenciamento do Exoma , Mutação/genética , Variações do Número de Cópias de DNA , Proteínas de Homeodomínio/genética , Deleção de Sequência , Aminoácidos/genética , Homozigoto , Cariótipo , LinhagemRESUMO
Objective:To investigate the effect of levosimendan on myocardial injury in patients with sepsis.Methods:Eighty-two patients with sepsis complicated by myocardial injury who received treatment in Yinzhou Second Hospital from June 2015 to September 2017 were included in this study. They were randomly assigned to receive either dobutamine treatment (control group, n = 41) or levosimendan treatment (study group, n = 41) based on conventional basic treatment. Before and after treatment, serum levels of heart-type fatty acid-binding protein (H-FABP), cardiac troponin I (cTnI), N-terminal pro brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LEVF), Acute Physiology, Age, and Chronic Health Evaluation II (APACHE II) score, intensive care unit (ICU) stay, and 28-day mortality were compared between the control and study groups. Results:Before treatment, there were no significant differences in serum levels of H-FABP, cTnI, and NT-proBNP as well as LVEF and APACHE II score between the control and study groups (all P > 0.05). At 6 hours after treatment, serum levels of H-FABP, cTnI, and NT-proBNP in the control and study groups [(26.22 ± 7.22) μg/L vs. (39.93 ± 9.85) μg/L, (25.97 ± 6.93) μg/L vs. (34.86 ± 8.55) μg/L, (0.004 ± 0.002) μg/L vs. (1.580 ± 0.360) μg/L, (0.003 ± 0.003) μg/L vs. (0.760 ± 0.210) μg/L, (1 561.73 ± 633.70) ng/L vs. (2 570.06 ± 747.95) ng/L, (1 602.28 ± 681.45) ng/L vs. (2 225.53 ± 585.14) ng/L] were significantly increased compared with before treatment ( t = 7.188, 5.172, 28.031, 23.079, 6.586, 4.443, all P < 0.05). After treatment, serum levels of H-FABP, cTnI, and NT-proBNP in the study group were significantly lower than those in the control group ( t = 2.489, 12.598, 2.323, all P < 0.05). In each group, serum level of H-FABP at 72 hours after treatment was significantly lower than that at 6 hours after treatment [(39.93 ± 9.85) μg/L vs. (6.28 ± 1.07) μg/L, (34.86 ± 8.55) μg/L vs. (5.82 ± 1.88) μg/L], serum levels of cTnI and NT-proBNP at 72 hours after treatment were significantly increased compared with those at 6 hours after treatment [(1.58 ± 0.36) μg/L vs. (2.72 ± 0.55) μg/L, (0.76 ± 0.21) μg/L vs. (1.78 ± 0.49) μg/L, (2 570.06 ± 747.95 ) ng/L vs. (3 623.27 ± 1 105.28) ng/L, (2 225.53 ± 585.14) ng/L vs. (3 128.08 ± 1 098.07) ng/L, t = 11.105, 12.251, 5.053, 4.645, all P < 0.05). At 72 hours after treatment, serum levels of cTnI and NT-proBNP levels in the control group were significantly higher than those in the study group ( t = 8.171, 2.035, both P < 0.05). At 72 hours after treatment, there was no significant difference in serum H-FABP level between the control and study groups ( P > 0.05). At 72 hours after treatment, APACHE II score in each group was significantly decreased and LVEF in each group was significantly increased compared with before treatment ( t = 7.718, 11.380, 9.049, 9.501, all P < 0.05). The change in APACHE II score at 72 hours after treatment relative to before treatment in the study group was more obvious than that in the control group ( t = 2.583, P < 0.05). At 72 hours after treatment, there were no significant differences in LVEF, ICU stay and 28-day mortality between the control and study groups (all P > 0.05). Conclusion:Levosimendan can reduce the serum levels of H-FABP, cTnI and NT-proBNP as well as APACHE II score in patients with sepsis, increase serum level of LVEF, and alleviate myocardial injury.
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Objective:To investigate the relationship between lateral hypothalamus and melatonin-induced reduction of wakefulness in rats and the receptor mechanism.Methods:Forty clean-grade adult male Sprague-Dawley rats, weighing 250-300 g, were divided into 4 groups ( n=10 each) using a random number table method: control group (group C), melatonin group (group M), melatonin type-1/2 receptor (MT 1R) antagonist luzindole plus melatonin group (group L+ M), and melatonin type-2 receptor (MT 2R) antagonist 4P-PDOT plus melatonin group (P+ M group). In group C, 0.5 μl of 0.9% NaCl solution was microinjected into the lateral hypothalamus.In group M, 1 μmol/L melatonin 0.5 μl was microinjected into the lateral hypothalamus.In group L+ M, 1 μmol/L MT 1/2R and 1 μmol/L melatonin (0.5 μl in total) was microinjected into the lateral hypothalamus.The microinjection time was from 19: 30 to 20: 00.The changes in sleep-wake duration and the oscillating energy in different frequency bands of electroencephalogram were detected by using electroencephalogram and electromyogram recording technology. Results:Compared with group C, the percentage of wakefulness time was significantly decreased, the percentage of non-rapid eye movement sleep and rapid eye movement sleep time was increased, the energy for delta oscillation was increased, the energy for theta oscillation was decreased, and no significant change was found in the energy for alpha oscillation in M and P+ M groups ( P<0.01), and no significant change was found in the parameters mentioned above in group L+ M ( P>0.05). Compared with group M, the percentage of wakefulness time was significantly increased, the percentage of non-rapid eye movement sleep and rapid eye movement sleep time was decreased, the energy for delta oscillation was decreased, and the energy for theta oscillation was increased in group L+ M ( P<0.01), and no significant change was found in the parameters mentioned above in group P+ M ( P>0.05). Conclusion:The lateral hypothalamus may be involved in melatonin-induced reduction of wakefulness in rats, and the mechanism may be related to activating MT 1R in the lateral hypothalamus.
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Objective:To investigate the clinical manifestations and characteristics of tracheobronchial foreign bodies in children, and improve the diagnosis and treatment of foreign bodies.Methods:A retrospective analysis was performed on the clinical data of children with tracheobronchial foreign bodies confirmed by fiberoptic bronchoscopy between January 2010 to December 2019.The children with tracheobronchial foreign body who were treated in the Maternal and Child Health Hospital of Gansu Province.Results:A total of 967 cases were operated by soft electronic bronchoscope, and foreign bodies were removed by means of foreign body forceps or nets.Among them, 19 cases(3 cases with subglottic foreign bodies, one with row of pins, and the rest 15 cases with foreign bodies completely wrapped by granulation)were not removed, two cases were spontaneously coughed, and 946 cases (97.8%)were removed.Bronchial foreign bodies in children were more common in boys, with the ratio of male to female being 2.14∶1.The main age of onset was 1-3 years old(88.8%). The incidence was slightly higher in rural areas than that in urban areas(46.5% in urban areas, 53.5% in rural areas). Foreign bodies were inhaled most in March and least in June.From the perspective of season, winter and spring were more than summer and autumn.The foreign body types inhaled were mainly exogenous plant foreign body, accounting for 93.0%, among which peanut(31.7%)and melon seeds(19.2%)were the most common.The duration of foreign body inhalation was up to 347 cases(35.9%)in 1-3 days.There were 501 cases(51.8%)with endoscopic endobronchial inflammation, and 196 cases of children with varying degrees of granulomatous hyperplasia, accounting for 39.1% and 20.3% of the total.The foreign body in the right bronchus accounted for 50.0% and the left bronchus for 43.7%.There were 793 cases confirmed by imaging, with a positive rate of 81.9%, and 90.9% confirmed by CT.Conclusion:About 88.8% of tracheobronchial foreign bodies occurred in 1 to 3 years of age.The occurrence of foreign bodies had obvious gender, urban-rural and seasonal distribution characteristics, and more cases were male, in rural and winter as well as spring.
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Objective:To evaluate the relationship between degrees of biliary obstruction and levels of lipid peroxidation in patients.Methods:A total of 140 patients of both sexes, with biliary obstruction, without biliary puncture and drainage, aged 40-64 yr, with body mass index of 18.5-23.9 kg/m 2, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, were selected.The patients with different degrees of biliary obstruction were divided into 4 groups ( n=35 each) according to Child-Pugh grade total bilirubin (TBIL) concentrations: group A (TBIL<17 μmol/L), group B (17 μmol/L≤TBIL<34 μmol/L), group C (34 μmol/L≤TBIL<51 μmol/L) and group D (TBIL≥51 μmol/L). The serum TBIL, direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and malondialdehyde (MDA) concentrations were measured.The correlation between serum MDA concentration and degree of biliary obstruction was tested by Spearman correlation analysis. Results:Compared with group A and group B, the serum DBIL, IBIL, ALT, AST, TBA and MDA concentrations were significantly increased in group C and group D ( P<0.05), and there was no significant difference in the parameters mentioned above between group A and group B ( P>0.05). Compared with group C, the serum DBIL, IBIL, ALT, AST, TBA and MDA concentrations were significantly increased in group D ( P<0.05). Serum MDA concentration was positively correlated with degree of biliary obstruction ( r=0.54, P<0.05). Conclusion:The degree of biliary obstruction can reflect the level of lipid peroxidation in patients.
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Objective: To investigate the clinical effects of single-stage auricular reconstruction and hearing rehabilitation in children with microtia and external auditory canal atresia. Methods: Sixty eight cases of microtia with external auditory canal atresia (53 males and 15 females, age from 7 to 12 years, with a median age of 8.8 years), who received operations in Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine from July 2017 to December 2019 were collected.A total of 28 cases received auricle reconstruction with high-density polyethylene (Medpor) framework and hearing reconstructions, among which 20 patients received the traditional external auditory canal and middle ear repair (EACR), and eight patients were implanted bone conduction device bone bridge(BB) simultaneously.In the control group, 40 patients only received Medpor frame implantation for auricle plasty. Postoperative changes in auricle morphology and auditory function and postoperative complications were evaluated. Results: After three to thirty months follow-ups, the auricles shape recovered well in all three groups. The average scores of 14 fine structures in the auricles were 9.43(EACR) and 10.67(BB) points. The average score of auricle symmetry were 6.83(EACR) and 6.00(BB) points. There was no significant difference compared to the auricle reconstruction group (8.23/6.20 points). P>0.05. After surgery, the average hearing improvement in the BB group was 43.33 dB HL and the average speech recognition threshold declined 42.28 dB HL. In the EACR group, the average hearing improvement was 4.13 dB HL and the average speech recognition threshold declined 11.36 dB HL. No vertigo, tinnitus, cerebrospinal fluid leakage and other complications occurred in all the patients. In the EACR group, sensorial hearing loss, auricle stent fracture, ear canal restenosis and ear canal atresia occurred in one patient respectively. In the auricle group, one auricle stent exposure and one facial branch nerve injury occurred. Nearly ten patients had difficulty in hair growth at scalp incisions. Conclusions: The operation of single-stage auricular reconstruction and hearing rehabilitation for microtia is feasible. The methods of hearing reconstruction should be determined by evaluating the development of the inner and middle ear of the patients. For those with poor mastoid development, bone bridge implantation is recommended to achieve a stable and significant hearing effect.
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Criança , Feminino , Humanos , Masculino , China , Microtia Congênita/cirurgia , Audição , Perda Auditiva/reabilitação , Polietilenos , Procedimentos de Cirurgia PlásticaRESUMO
Objective To explore the relationship between urinary iodine level and breast cancer,we compare urinary iodine excretion levels in patients with breast cancer,benign breast disease,other female malignant tumors and control subjects in Xiangya Hospital of Central South University.Methods From December 2018 to January 2019,64 patients with newly diagnosed breast cancer in Xiangya Hospital of Central South University were selected as case group,benign breast disease group (n =49),other female malignant tumor group (n =39) and health examination group (n =50) as control group.Urinary iodine was determined by colorimetry.According to the urinary iodine level the patients divided into three groups:iodine excess (>300 μg/L),medium iodine (100-300 μg/L) and iodine deficiency (< 100 μg/L).The relationship between urinary iodine and clinicopathology of breast cancer was analyzed.Results The level of urinary iodine in benign breast nodule group 319.13 (163.98) μg/L > breast cancer group 273.96 (151.30) μg/L > female other malignant tumor group 212.95 (161.71) μg/L > normal control group 199.15 (194.45) μg/L,with significantly differance (H =9.936,P =0.019).Urinary iodine level in the normal control group was significantly lower than that in the benign breast disease group (P =0.013).The patients were further divided into three groups according to the urinary iodine level:iodine excess,iodine medium and iodine deficiency,the number of urine iodine < 100 μg/L in the normal control group was significantly higher than that in the breast cancer group (P =0.021).The level of urinary iodine was negatively correlated with the size of the primary focus of breast cancer (Z =-2.307,P =0.021).The effect of urinary iodine was analyzed by multiple linear regression method.The size of primary focus was included in the regression equation (R2 =0.136,P=0.007),but had nothing to do with lymph node metastasis and the expression status of estrogen receptor (ER),androgen receptor (AR),progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2).Conclusions There is a negative linear correlation between urinary iodine level and the size of primary focus of breast cancer,but it has nothing to do with lymph node metastasis and the expression of ER,AR,PR and HER-2.