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The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.
Subject(s)
Humans , Mice , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Acrylamides/pharmacology , ErbB Receptors/metabolism , Cell Line, Tumor , CD47 Antigen/therapeutic useABSTRACT
OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.
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Objective:To construct a risk prediction model for infection with Klebsiella pneumonia (KP) for patients with severe acute pancreatitis (SAP).Methods:Retrospective analysis was done on the clinical data of 109 SAP patients who were admitted to Shanghai General Hospital, between March 2016 and December 2021. Patients were classified into infection group ( n=25) and non-infection group ( n=84) based on the presence or absence of KP infection, and the clinical characteristics of the two groups were compared. The least absolute shrinkage and selection operator (LASSO) algorithm was used to reduce the dimension of the variables with statistical significance in univariate analysis. A nomogram prediction model was created by incorporating the optimized features from the LASSO regression model into the multivariate logistic regression analysis. Receiver operating characteristic curve (ROC) was drawn and the area under curve (AUC) was calculated; and consistency index (C-index) were used to assess the prediction model's diagnostic ability. Results:A total of 25 strains of KP were isolated from 109 patients with SAP, of which 21(84.0%) had multi-drug resistance. 20 risk factors (SOFA score, APACHEⅡ score, Ranson score, MCTSI score, mechanical ventilation time, fasting time, duration of indwelling of the peritoneal drainage tube, duration of deep vein indwelling, number of invasive procedures, without or with surgical intervention, without or with endoscopic retrograde cholangiopancreatography (ERCP), types of high-level antibiotics used, digestion disorders, abnormalities in blood coagulation, metabolic acidosis, pancreatic necrosis, intra-abdominal hemorrhage, intra-abdominal hypertension, length of ICU stay and total length of hospital stay) were found to be associated with KP infection in SAP patients by univariate analysis. The four variables (APACHEⅡ score, duration of indwelling of the peritoneal drainage tube, types of high-level antibiotics used, and total length of hospital stay) were extracted after reduced by LASSO regression. These four variables were found to be risk factors for KP infection in SAP patients by multiple logistic regression analysis (all P value <0.05). Nomogram prediction model for KP infection in SAP was established based on the four variables above. The verification results of the model showed that the C-index of the model was 0.939, and the AUC was 0.939 (95% CI 0.888-0.991), indicating that the nomogram model had relatively accurate prediction ability. Conclusions:This prediction model establishes integrated the basic clinical data of patients, which could facilitate the risk prediction for KP infection in patients with SAP and thus help to formulate better therapeutic plans for patients.
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【Objective】 To investigate the clinical characteristics and treatment strategy of giant multilocular prostatic cystadenoma(GMPC). 【Methods】 The clinical data of a GMPC patient treated in our hospital in July 2021 were retrospectively analyzed. The patient was 73 years old. The clinical manifestations were urgent urination and frequent urination. The prostate specific antigen (PSA) increased slightly. MRI showed giant cystic solid space occupying lesion of the prostate. Domestic and foreign cases of prostate cystadenoma from 2000 to 2021 were retrieved for literature review. 【Results】 Transabdominal laparoscopic radical prostatectomy was performed successfully. The postoperative pathological diagnosis was GMPC. Two weeks after operation, the urinary catheter was removed, and there was no discomfort such as urinary frequency or urinary incontinence. After follow-up for more than 8 months, there was no tumor recurrence or metastasis. 【Conclusion】 There are still some disputes about the oncological characteristics and diagnosis and treatment of GMPC, and there is a lack of long-term follow-up results. Laparoscopic prostatectomy is safe and feasible. Most patients have a good prognosis after surgical treatment. It is necessary to formulate an individualized standard treatment plan based on surgery combined with different patients’ conditions to actively improve the prognosis.
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Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRα-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.
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Described as a "don't eat me" signal, CD47 becomes a vital immune checkpoint in cancer. Its interaction with signal regulatory protein alpha (SIRPα) prevents macrophage phagocytosis. In recent years, a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer effect. Latest clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies, indicating the combination strategy as a general trend of the future. In this review, clinical and preclinical cases about the current combination strategies targeting CD47 are collected, their underlying mechanisms of action are discussed, and ideas from future perspectives are shared.
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OBJECTIVE@#To investigate whether dynamic monitoring of citrulline (Cit) has guiding value for early enteral nutrition (EN) in patients with severe gastrointestinal injury.@*METHODS@#A observational study was conducted. A total of 76 patients with severe gastrointestinal injury admitted to different intensive care units of Suzhou Hospital Affiliated to Nanjing Medical University from February 2021 to June 2022 were enrolled. Early EN was performed in 24-48 hours after admission as recommended by the guidelines. Those who did not terminate EN after 7 days were enrolled in the early EN success group, and those who terminated EN within 7 days due to persistent feeding intolerance or deterioration of general condition were enrolled in the early EN failure group. There was no intervention during the treatment. Serum Cit levels were measured by mass spectrometry at admission, before EN starting and EN 24 hours, respectively, and the changes in Cit within EN 24 hours (ΔCit) were calculated (ΔCit = EN 24-hour Cit-Cit before EN starting). Receiver operator characteristic curve (ROC curve) was plotted to investigate the predictive value of ΔCit for early EN failure, and the optimal predictive value was calculated. Multivariate unconditional Logistic regression was used to analyze the independent risk factors for early EN failure and death at 28 days.@*RESULTS@#Seventy-six patients were enrolled in the final analysis, of which 40 succeeded in early EN and 36 failed. There were significant differences in age, main diagnosis, acute physiology and chronic health evaluation II (APACHE II) score at admission, blood lactic acid (Lac) before EN initiation and ΔCit between the two groups. Multivariate Logistic regression analysis showed that age [odds ratio (OR) = 0.929, 95% confidence interval (95%CI) was 0.874-0.988, P = 0.018], ΔCit (OR = 2.026, 95%CI was 1.322-3.114, P = 0.001) and increased feeding rate within 48 hours (OR = 13.719, 95%CI was 1.795-104.851, P = 0.012) were independent risk factors for early EN failure in patients with severe gastrointestinal injury. ROC curve analysis showed that ΔCit had a good predictive value for early EN failure in patients with severe gastrointestinal injury [area under the ROC curve (AUC) = 0.787, 95%CI was 0.686-0.887, P < 0.001], and the optimal predictive value of ΔCit was 0.74 μmol/L (sensitivity was 65.0%, specificity was 75.0%). Combined with the optimal predictive value of ΔCit, "overfeeding" was defined as ΔCit < 0.74 μmol/L and increased feeding within 48 hours. Multivariate Logistic regression analysis showed that age (OR = 0.825, 95%CI was 0.732-0.930, P = 0.002), APACHE II score (OR = 0.696, 95%CI was 0.518-0.936, P = 0.017) and early EN failure (OR = 181.803, 95%CI was 3.916-8 439.606, P = 0.008) were independent risk factors for 28-day death in patients with severe gastrointestinal injury. The new variable "overfeeding" was also associated with an increased risk of death at 28 days (OR = 27.816, 95%CI was 1.023-755.996, P = 0.048).@*CONCLUSIONS@#Dynamic monitoring of Cit has guiding value for early EN in patients with severe gastrointestinal injury.
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Humans , Infant, Newborn , Enteral Nutrition , Citrulline , APACHE , Abdominal Injuries , Cognition , Thoracic InjuriesABSTRACT
OBJECTIVES@#To calculate the likelihood ratios of incest cases using identity by descent (IBD) patterns.@*METHODS@#The unique IBD pattern was formed by denoting the alleles from the members in a pedigree with a same digital. The probability of each IBD pattern was obtained by multiplying the prior probability by the frequency of non-IBD alleles. The pedigree likelihoods of incest cases under different hypotheses were obtained by summing all IBD pattern probabilities, and the likelihood ratio(LR) was calculated by comparing the likelihoods of different pedigrees.@*RESULTS@#The IBD patterns and the formulae of calculating LR for father-daughter incest and brother-sister incest were obtained.@*CONCLUSIONS@#The calculations of LR for incest cases were illustrated based on IBD patterns.
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Male , Humans , Incest , Siblings , ProbabilityABSTRACT
Objective:To analyze the indications for prenatal diagnosis and summarize the pregnancy outcomes and its influencing factors of pregnant women with fetal sex chromosome aneuploidy (SCA).Methods:This study retrospectively enrolled 1 372 fetuses prenatally diagnosed with SCA in Medical Genetics Center of Guangdong Women and Children Hospital from January 2013 to December 2021. The relationship between prenatal diagnosis indications and SCA as well as between ultrasound abnormalities, pregnancy outcomes and SCA types were analyzed by Chi-square test and trend Chi-square test. Results:The most common prenatal diagnosis indication was abnormal non-invasive prenatal testing (NIPT) (61.6%, 845/1 372). The most common SCA type was 47,XXY in cases with indications of abnormal NIPT and advanced maternal age, mosaic in cases with high or borderline risk of Down syndrome, and 45,X in cases with increased nuchal translucency or cystic hygroma. Of 1 372 pregnant women with fetal SCA, 17 were lost to follow-up, seven had intrauterine fetal death, and 1 348 (98.3%) were followed up for pregnancy outcomes including 36.3% (489/1 348) continued pregnancies and 63.7% (859/1 348) terminations. Pregnancy termination rates decreased sequentially in pregnant women carrying fetuses with 45,X, 47,XXY, mosaic, 47,XXX and 47,XYY [99.2% (247/249), 74.5% (307/412), 67.8% (156/230), 36.6% (86/235) and 28.4% (63/222), χ2trend=352.76, P<0.001]. There was no significant difference in pregnancy termination rates among the cases with different mosaic mutations (all P>0.05). The pregnancy termination rate was higher in fetuses with SCA complicated by ultrasound structural abnormalities than in those without ultrasound abnormalities and those with ultrasound soft markers [91.5% (182/199) vs 57.1% (535/937) and 67.0% (142/212), χ2 were 83.68 and 36.85, both P<0.001]. Moreover, the pregnancy termination rate in fetuses with SCA complicated by ultrasound soft markers was higher than those without ultrasound abnormalities ( χ2=7.13, P<0.05). Conclusions:NIPT abnormality is the most common indication for prenatal diagnosis of SCA. The types of SCA and ultrasound findings are important factors determining whether the pregnancy would be continued or not.
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At present, fatigue state monitoring of upper limb movement generally relies solely on surface electromyographic signal (sEMG) to identify and classify fatigue, resulting in unstable results and certain limitations. This paper introduces the sEMG signal recognition and motion capture technology into the fatigue state monitoring process and proposes a fatigue analysis method combining an improved EMG fatigue threshold algorithm and biomechanical analysis. In this study, the right upper limb load elbow flexion test was used to simultaneously collect the biceps brachii sEMG signal and upper limb motion capture data, and at the same time the Borg Fatigue Subjective and Self-awareness Scale were used to record the fatigue feelings of the subjects. Then, the fatigue analysis method combining the EMG fatigue threshold algorithm and the biomechanical analysis was combined with four single types: mean power frequency (MPF), spectral moments ratio (SMR), fuzzy approximate entropy (fApEn) and Lempel-Ziv complexity (LZC). The test results of the evaluation index fatigue evaluation method were compared. The test results show that the method in this paper has a recognition rate of 98.6% for the overall fatigue state and 97%, 100%, and 99% for the three states of ease, transition and fatigue, which are more advantageous than other methods. The research results of this paper prove that the method in this paper can effectively prevent secondary injury caused by overtraining during upper limb exercises, and is of great significance for fatigue monitoring.
Subject(s)
Humans , Electromyography/methods , Fatigue , Muscle Fatigue , Muscle, Skeletal , Upper ExtremityABSTRACT
Objective:To investigate the efficacy and safety of laparoscopic partial nephrectomy in the treatment of renal tumors with renal score of 10.Methods:From February 2016 to March 2021, 23 patients who underwent laparoscopic partial nephrectomy in Peking University Third Hospital with renal tumors of R. E.N.A.L. score of 10 was studied retrospectively, including 16 cases of male and 7 cases of female, with 11 cases on the right side and 12 cases on the left side. The patients’ age was (55.0±16.4) years, and BMI was (25.4±3.6) kg/m 2. The maximum diameter of the tumor was (3.5±1.4)cm. Laparoscopic partial nephrectomy was performed after complete examination. The observation indexes included operation time, blocking time, complications, postoperative hospital stay and the trifecta (negative surgical margin, blocking time ≤25 minutes, and no perioperative complications). Results:All operations were successfully completed, only 4 cases were converted to open surgery. The median operation time was 153 min(99-346 min). The median blocking time was 27 min(14-60min). The median postoperative hospital stay was 6 d(4-11 d). Postoperative complications occurred in 7 cases(fever in 5 cases, intestinal obstruction in 1 case, postoperative blood transfusion and leg intermuscular venous thrombosis in 1 case). 9 cases (39.1%) achieved the trifecta. 19 cases who completed by laparoscopy, their operation time was 151 min(99-303 min), blocking time was 28 min(18-60 min), postoperative hospital stay was 6 d(4-11 d), fever occurred in 4 cases, and 6 cases achieved the trifecta (31.6%). The follow-up time was 3-62 months, with a median of 32 months, and there was no recurrence or metastasis.Conclusions:Laparoscopic partial nephrectomy is safe and effective in the treatment of renal tumors with renal score of 10.Although the tumor is highly complex, it also achieves the purpose of preserving nephron to the greatest extent. If technical conditions permit, laparoscopic partial nephrectomy could be considered for the treatment of highly complex renal tumors.
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Objective:To compare the diagnostic performance in the hepatocellular carcinoma(HCC) with cirrhosis between the 2017 version of liver imaging reporting and data system (LI-RADS v2017) and 2018 version of LI-RADS (LI-RADS v2018) based on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced MRI.Methods:Clinical data of 213 patients with 246 hepatic lesions with cirrhosis who underwent Gd-EOB-DTPA enhanced MRI in the Third Affiliated Nantong Hospital of Nantong University from October 2015 to July 2020 were retrospectively collected. The MRI major features and LR categories of lesions were respectively reviewed by two radiologists according to LI-RADS v2017 and LI-RADS v2018, respectively. Taking postoperative histopathological results or follow-up imaging as references, with the LR-5 and LR-4+LR-5 as the diagnosis of HCC, the sensitivity, specificity and accuracy of the LI-RADS v2017 and LI-RADS v2018 were evaluated, respectively. The McNemar test or Fisher exact test was used to compare the diagnostic performance between the two LI-RADS versions.Results:In 246 hepatic lesions, 165 were HCCs, 31 were non-HCC malignancies and 50 were benign lesions. Due to the threshold growth and more simplified definition and changes in the LR-5 classification criteria in LI-RADS v2018, the categories of 38 (15.4%, 38/246) lesions were changed. The threshold growths of 84.6% (33/39) lesions in v2017 were reclassified to subthreshold growth in v2018. Using LI-RADS v2018, 10 lesions were down-categorized compared with LI-RADS v2017, including LR-5 to LR-4 in 7 lesions and LR-4 to LR-3 in 3 lesions, and 28 lesions were up-categorized LR-4 to LR-5, in which 25 were small HCC. With LR-5 as the diagnosis criteria of HCC, the sensitivity and accuracy of LI-RADS v2018 were 66.7% (110/165) and 73.6% (181/246); and the sensitivity and accuracy of LI-RADS v2017 were 55.8% (92/165) and 67.5% (166/246), both with statistical differences (χ2=4.13, P=0.001, χ2=6.20, P<0.001). No significant difference was found in the specificity values of LI-RADS v2018 and v2017 [87.7% (71/81) vs. 91.4% (74/81)], χ2=0.59, P=0.442). Compared with v2017, LI-RADS v2018 increased the sensitivity in the diagnosis of small HCC lesions (10-19 mm) [62.9% (56/89) vs. 40.4% (36/89), χ2=9.00, P<0.001]. With LR-4+LR-5 as the diagnostic criteria of HCC, there was no significant difference in the sensitivity, specificity and accuracy of LI-RADS v2017 and v2018 in the diagnosis of HCC (all P>0.05). Conclusions:Based on Gd-EOB-DTPA enhanced MRI, LI-RADS v2018 has higher sensitivity and similar specificity in the diagnosis of HCC compared to v2017, especially in the diagnosis of small HCC (10-19 mm).
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Objective:To establish a prediction model of acute upper gastrointestinal rebleeding (AUGIRB) for elderly patients by combining and applying multiple indicators.Methods:A retrospective observational study was conducted. The clinical data of 161 elderly patients (age ≥ 65 years old) who suffered from acute upper gastrointestinal bleeding (AUGIB) and who were hospitalized in Shanghai General Hospital from July 2018 to December 2020 were recorded. The patients were divided into the rebleeding group (31 cases) and the non-rebleeding group (130 cases) according to whether gastrointestinal rebleeding occurred. Univariate analysis was adopted to screen AUGIRB-related risk factors and Logistic regression analysis was used to screen independent predictors of AUGIRB so that a predictive model was constructed. Based on the area under the curve (AUC) of the receiver operator characteristic curve (ROC curve), the predictive ability of the prediction model for AUGIRB was evaluated, the optimal cut-off value was determined, and the odds ratio ( OR) and its 95% confidence interval (95% CI) were calculated. Bootstrap resampling technology was used to validate the predictive ability of the model. Results:Univariate Logistic analysis showed that oral anticoagulant drugs, oral antiplatelet drugs, albumin (ALB), platelet count (PLT), Glasgow-Blatchford bleeding score (GBS), D-dimer, fibrinogen (FIB), and international normalized ratio (INR) all had a significant effect on the occurrence of AUGIRB among elderly patients. Multivariate Logistic regression analysis showed that the oral antiplatelet drugs ( OR = 11.150, 95% CI was 1.888-65.852, P < 0.05) and GBS score ( OR = 2.503, 95% CI was 1.523-4.114, P < 0.05) were the independent risk factors of AUGIRB among elderly patients, while the ALB ( OR = 0.764, 95% CI was 0.626-0.932, P < 0.05) and FIB ( OR = 0.065, 95% CI was 0.011-0.370, P < 0.05) were the protective factors of AUGIRB among elderly patients. The AUC of the above four indexes joint prediction model was 0.979. The verification results of the model showed that the consistency index (C-index) of the model was 0.986. Conclusion:The prediction model fitted in this research has a high prediction accuracy and it also has a certain reference value for the judgment of elderly patients who suffer from AUGIRB.
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Objective:To investigate the clinical efficacy of gradual decompression in the treatment of severe traumatic brain injury and its effects on the improvement of intracranial pressure.Methods:The clinical data of 120 patients with severe traumatic brain injury who received treatment in the General Hospital of Taiyuan Iron and Steel (Group) Co., Ltd. from January 2015 to January 2020 were retrospectively analyzed. The included patients were divided into decompressive craniectomy group (control group, n = 64) and gradual decompression group ( n = 56). Intracranial pressure was compared between the two groups at different time points (before surgery, during the surgery, immediately after surgery, 3 and 6 months after surgery). The patient's self-care ability, coma degree, and neurological deficits pre-surgery and 6 months after surgery were evaluated in each group. The incidence of complications throughout the surgery and within 6 months after surgery was calculated to evaluate the quality of life. Results:There was no significant difference in intracranial pressure pre-surgery between the two groups ( P > 0.05). Intracranial pressure in the gradual decompression group was (30.74 ± 2.51) mmHg, (25.11 ± 2.06) mmHg, (21.34 ± 2.01) mmHg, and (16.74 ± 1.54) mmHg respectively during the surgery, immediately after surgery, and 3 and 6 months after surgery, which was significantly lower than that in the control group [(34.31 ± 3.06) mmHg, (30.64 ± 2.57) mmHg, (26.33 ± 2.35) mmHg, (22.64 ± 1.95) mmHg, t = 12.88, 19.03, 12.40, 18.20, all P < 0.001]. There were no significant differences in scores of the Modified Barthel Index (MBI), the Glasgow Coma Scale (GCS), the National Institutes of Health Stroke Scale (NIHSS) pre-surgery between the two groups (all P > 0.05). At 6 months after surgery, the MBI and GCS scores increased and the NIHSS score decreased in each group. There were significant differences in the NIHSS, MBI, and GCS scores between the two groups ( t = 7.61, 6.26, 13.07, all P < 0.001). During the surgery and 6 months after surgery, the incidences of cerebral infarction, delayed cerebral hematoma, and acute encephalocele were significantly lower in the gradual decompression group than in the control group ( χ2 = 4.23, 4.35, 4.83, all P < 0.05). The Generic Quality of Life Inventory-74 Questionnaire scores in environment, psychological health, social relationship, and psychological health domains were significantly higher in the gradual decompression group than in the control group ( t = 8.16, 9.80, 8.68, 7.76, all P < 0.001) Conclusion:This study is the first to analyze the feasibility of gradual decompression for the treatment of severe traumatic brain injury in terms of intracranial pressure, quality of life, and short- and medium-term complications. Findings from this study confirm that gradual decompression can effectively lower intracranial pressure of patients with severe traumatic brain injury, improve neurological function, reduce complications, and improve patients' self-care ability and quality of life.
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Objective:To investigate the effect of SKF96365, store-operated calcium entry (SOCE) inhibitor, on liver and kidney injury induced by paraquat (PQ).Methods:A549 cells were cultured in vitro and divided into the control group (DMSO group, SKF 2 μmol/L group, and SKF 10 μmol/L group) and PQ group (PQ+DMSO group, PQ+SKF 2 μmol/L group, and PQ+SKF 10 μmol/L group). The nuclear factor of activated T cells (NFAT) in A549 cells was detected by luciferase reporter gene technique. The mouse model of PQ poisoning was constructed and divided into the control group, SKF group, PQ group and PQ+SKF group. In the PQ group, mice were injected with 50 mg/kg PQ intraperitoneally; in the SKF group, mice were injected intraperitoneally with 10 mg/kg SKF96365 for 3 days. Mice in the PQ+SKF group received 50 mg/kg intraperitoneal injection of PQ once and 10 mg/kg intraperitoneal injection of SKF96365 daily for 3 days. On the fourth day, the mice were sacrificed, and the liver and kidney tissues were taken. The histopathological changes of liver and kidney tissues were observed by hematoxylin-eosin (H&E) staining, and the apoptosis of liver and kidney tissues was observed by TUNEL staining. One-way analysis of variance was used to compare the mean values of normally distributed measurement data between groups. Comparisons between groups were performed using the least significant difference t-test. Results:The luciferase reporter gene technology showed that NFAT was significantly activated in the PQ group. After pretreatment with SKF96365, NFAT activation decreased sharply in a dose-dependent manner. HE staining showed that the outline structure of liver and kidney tissues in the PQ groups were unclear, cells swelled and a large number of inflammatory cells infiltrated; in the PQ+SKF group, liver cell swelling and inflammatory cell infiltration decreased significantly. TUNEL staining showed that the apoptotic cells in liver and kidney tissues increased in the PQ groups, and the apoptosis decreased remarkably in the PQ+SKF group.Conclusions:SOCE inhibitor SKF96365 can significantly reduce the liver and kidney injury caused by PQ.
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The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.
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The global coronavirus disease 2019 epidemic is still in a pandemic state. Aging population with underlying diseases is prone to become severe, and have a higher mortality. The treatment capacity of the critical care department directly determines the treatment success rate of critical illness. At present, there is still a certain gap between domestic and foreign countries in intensive care unit (ICU), which is not only in the allocation of medical staff, but also in the beds and settings. The current medical model cannot fully meet the needs of development. The experience and lessons of many major public health emergencies suggested that " dual track of peace and war" approach in discipline construction of critical care is the best medical model. Following the concept of "combination of peace and war", strengthening the discipline construction of critical care department in municipal and district designated hospitals, allocating reasonable standard ICU, step-down ICU and combat readiness ICU, establishing rapid response team, and strengthening regular training and scientific management may be the key measures to deal with the epidemic.
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OBJECTIVE@#To explore the application value of next generation sequencing (NGS) in preimplantation genetic diagnosis of α/β complex thalassemia couple.@*METHODS@#The coding regions of α-globin genes (HBA1, HBA2) and β-globin gene (HBB) were selected as the target regions. The high-density and closely linked single nucleotide polymorphism (SNP) sites were selected as the genetic linkage markers in the upstream and downstream 2M regions of the gene. After NGS, the effective SNP sites were selected to construct the haplotype of the couple, and the risk chromosome of the mutation carried by the couple was determined. The NGS technology was used to sequence the variations of HBA1, HBA2 and HBB directly and construct haplotype linkage analysis for preimplantation genetic diagnosis.@*RESULTS@#Direct sequencing and haplotype linkage analysis of HBA1, HBA2 and HBB showed that two of the six blastocysts were α/β complex thalassemia, one was β-thalassemia heterozygote, two were α-thalassemias heterozygotes, and one was intermediate α-thalassemia. A well-developed embryo underwent preimplantation genetic diagnosis was implanted into the mother's uterus, and a healthy infant was born at term.@*CONCLUSION@#Preimplantation genetic diagnosis can be carried out by NGS technology in α/β complex thalassemia couples, and abortion caused by aneuploid embryo selection can be avoided.
Subject(s)
Female , Humans , Pregnancy , High-Throughput Nucleotide Sequencing , Mutation , Preimplantation Diagnosis , alpha-Thalassemia , beta-Globins/genetics , beta-Thalassemia/geneticsABSTRACT
Objective:To evaluate the detection of copy number variation (CNV) by chromosome microarray analysis (CMA) in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT).Methods:A total of 1 929 fetuses who were ultrasonically found with CAKUT and underwent CMA from Guangdong Women and Children's Hospital and Health Institute were enrolled in this retrospective study from January 2016 to July 2020. These fetuses were divided into isolated CAKUT group ( n=1 567), CAKUT with soft markers group ( n=269), and CAKUT with other structural anomalies group ( n=93) for comparing the detection rate of pathogenic CNV using Chi-square test or Fisher exact test. Results:(1)The detection rate of all and pathogenic CNVs were 6.5%(125/1 929) and 4.8%(93/1 929), respectively. The total detection rate of CNV, clinically significant CNV and large chromosome structural variations in the CAKUT with other structural anomalies group were higher than those of the CAKUT with soft markers group and isolated CAKUT groups[31.2%(29/93), 11.5%(31/269) vs 4.2%(65/1 567), χ2=119.002; 18.3%(17/93), 9.0%(24/269) vs 3.6%(56/1 567), χ2=49.677; 9.7%(9/93), 2.2%(6/269) vs 0.3%(4/1 567), χ2=42.727; all P<0.001]. CAKUT with other structural anomalies group had a higher detection rate of pathogenic CNV (18.3%, 17/93) than the CAKUT with soft markers group (8.6%, 23/269) and the isolated CAKUT group [3.4%(53/1 567)] ( χ2=51.932, P<0.001). (2) The detection rate of pathogenic CNV was the highest in fetuses with enhanced renal echo (14.7%, 23/156), followed by renal enlargement (8.2%, 5/61), renal dysplasia (5.0%,13/261), polycystic renal dysplasia (5.0%, 13/261), and hydronephrosis (4.8%, 20/413). Fetuses with polycystic renal dysplasia, renal agenesis, fused kidney and hydronephrosis in the CAKUT with other structural anomalies group had a higher detection rate of pathogenic CNV than those in the isolated CAKUT group [3/9 vs 3.5%(8/230), 2/17 vs 1.3%(3/237), 1/8 vs 0.0%(0/59) and 3/18 vs 3.4%(12/344), all P<0.017]. The CAKUT with other structural anomalies group had a higher detection rate of pathogenic CNV than CAKUT with soft markers group in fetuses with enhanced renal echo [4/8 vs 12.8%(5/39), P<0.017]. (3) The top three microdeletion/microduplication syndrome were 17q12 microdeletion syndrome (36.6%, 34/93), 22q11.2 microdeletion syndrome (23.7%, 22/93), and 16p11.2 microdeletion syndrome (7.5%, 7/93) among those with pathogenic CNV. Conclusions:The risk of CNV in fetuses with isolated CAKUT, CAKUT with soft markers, and CAKUT with additional structural anomalies increased progressively. CMA might be a better choice in fetuses with hydronephrosis, enhanced renal echo, renal enlargement, renal hypoplasia, and multicystic renal dysplasia to improve the detection rate of CNV.
ABSTRACT
Objective:To disiuss the application of liver free technique in renal cell carcinoma patients with Mayo Ⅱ-Ⅳ tumor thrombus.Methods:The clinical data of renal cell carcinoma patients with MayoⅡ-Ⅳ IVC tumor thrombus in our hospital from January 2014 to December 2019 were retrospectively analyzed. 25 patients underwent right part of liver or hepatic portal part dissection via open abdominal approach. There were 20 males and 5 females, aged 45-74 years (mean 61±6 years). All patients underwent urinary tract CTU or MRU examination, vena cava enhanced magnetic resonance angiography.There were left 8 cases, right 17 cases; the median length of tumor was 7 cm (3.6-12.1 cm). There were 1 case of Mayo grade Ⅱ tumor thrombus, 7 cases of Mayo grade Ⅲ tumor thrombus, and 17 cases of Mayo grade Ⅳ tumor thrombus. There were 7 cases of distant metastasis, including 6 cases of lung metastasis and 1 case of bone metastasis. After multi-disciplinary consultation (MDT), 19 patients underwent radical nephrectomy and 6 patients underwent tumor reducing nephrectomy. During the operation, the ligaments around the liver were completely dissociated and the space between the liver and kidney was opened. The bare area of the liver was fully dissociated, to expose the inferior vena cava. For Mayo grade Ⅳ tumor thrombus, 11 cases were treated with free diaphragmatic thrombus removal without thoracotomy, and 6 cases were treated with open chest cardiopulmonary bypass.Results:The median operation time was 444(258-694)min, the median intraoperative blood loss was 2 000(250-10 000)ml, and the median value of suspended red blood cell transfusion was 1 300(400-10 400)ml. The median postoperative hospital stay was 10(4-25)days.15 patients (60%) had postoperative complications, including 8 cases of liver injury, 5 cases of respiratory complications, 4 cases of kidney injury, 3 cases of anemia, 3 cases of infection and 1 case of thrombosis. Three patients died during perioperative period.Conclusions:The application of total liver free technique might obtain good exposure of surgical field, effectively control the hemorrhage of inferior vena cava, which is helpful for safe resection of tumor.