Molecular mechanisms of ROS-modulated cancer chemoresistance and therapeutic strategies.

Drug resistance is the main obstacle to achieving a cure in many cancer patients. Reactive oxygen species (ROS) are master regulators of cancer development that act through complex mechanisms. Remarkably, ROS levels and antioxidant content are typically higher in drug-resistant cancer cells than in non-resistant and normal cells, and have been shown to play a central role in modulating drug resistance. Therefore, determining the underlying functions of ROS in the modulation of drug resistance will contribute to develop therapies that sensitize cancer resistant cells by leveraging ROS modulation. In this review, we summarize the notable literature on the sources and regulation of ROS production and highlight the complex roles of ROS in cancer chemoresistance, encompassing transcription factor-mediated chemoresistance, maintenance of cancer stem cells, and their impact on the tumor microenvironment. We also discuss the potential of ROS-targeted therapies in overcoming tumor therapeutic resistance.

The Clinical Characteristics of 88 Patients with Total Anomalous Pulmonary Venous Connection and Risk Factors Associated with Early Postoperative Death.

Objective: This study aimed to analyze the outcomes and risk factors of early postoperative death (within 30 days after surgery) in a single-center after repair of total anomalous pulmonary venous connection (TAPVC). Methods: The clinical data of 88 children who had been diagnosed with TAPVC and underwent radical operation in the Shandong Provincial Hospital Affiliated with Shandong First Medical University (China) from January 2015 to July 2021 were retrospectively analyzed. All the patients were divided into the survival group (n = 81) and the death group (n = 7) for the analysis of preoperative and postoperative clinical data. The variables associated with early postoperative death were statistically analyzed to obtain the risk factors for early postoperative death of TAPVC. Results: Of the 88 patients included in this study, 7 (7.95%) patients died early, including 4 supracardiac and 3 infracardiac cases. Recurrent pulmonary vein obstruction occurred in 2 patients after discharged from hospital, and both were intracardiac TAPVC. Delayed death occurred in 2 children, both of which were intracardiac TAPVC cases. According to univariate analysis, the risk factors statistically significantly associated with the early postoperative death included infracardiac type (P = 0.08), preoperative maximum pulmonary vein flow velocity (P = 0.031), preoperative mechanical ventilation (P = 0.043), preoperative maximum pulmonary artery pressure (P = 0.000), intraoperative cardiopulmonary bypass time (P = 0.003) and intraoperative aortic cross-clamp time (P = 0.000). Conclusion: Infracardiac type of TAPVC, preoperative maximum pulmonary vein flow velocity, preoperative mechanical ventilation, preoperative maximum pulmonary artery pressure, intraoperative cardiopulmonary bypass time and aortic cross-clamp time are the risk factors for early postoperative death.

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance.

Immune checkpoint blockade (ICB) has rapidly transformed the treatment paradigm for various cancer types. Multiple single or combinations of ICB treatments have been approved by the US Food and Drug Administration, providing more options for patients with advanced cancer. However, most patients could not benefit from these immunotherapies due to primary and acquired drug resistance. Thus, a better understanding of the mechanisms of ICB resistance is urgently needed to improve clinical outcomes. Here, we focused on the changes in the biological functions of CD8+ T cells to elucidate the underlying resistance mechanisms of ICB therapies and summarized the advanced coping strategies to increase ICB efficacy. Combinational ICB approaches and individualized immunotherapies require further in-depth investigation to facilitate longer-lasting efficacy and a more excellent safety of ICB in a broader range of patients.

Integrated Analysis of the lncRNA-Associated ceRNA Network in Wilms Tumor via TARGET and GEO Databases.

Wilms tumor (WT) is the most common genitourinary renal tumor that typically occurs in children under 15 and is thought to be linked to somatic and germline mutations. However, the specific functional role of competing endogenous RNAs (ceRNAs) and their potential implications in WT remain unclear. In this study, we developed an lncRNA-mediated (long noncoding RNA-mediated) ceRNA network via the R packages for WT with expression data obtained from the tumor alterations relevant for genomics-driven therapy (TARGET) database. Unsupervised hierarchical clustering analysis revealed that the WT specimens could be clearly distinguished from healthy specimens with respect to the expression of disordered RNAs. A total of 1,607 differentially expressed (DE) lncRNAs, 116 DE microRNAs (DEmiRNAs), and 3,262 DE messenger RNAs (DEmRNAs) were identified as WT-specific RNAs, and a lncRNA-miRNA-mRNA ceRNA network with 159 DElncRNAs, 18 DEmiRNAs, 131 DEmRNAs, and 792 interactions was constructed. According to the clinical survival data, 12 DElncRNAs, 5 DEmRNAs, and 2 DEmiRNAs were selected from the ceRNA network that could significantly impact the overall survival of WT patients (P < 0.05). Functional enrichment analysis showed that the biological processes and pathways of DEmRNAs, such as cell cycle and virus infection, may be associated with WT. The present study constructed a dysregulated lncRNA-mediated ceRNA network in WT and discovered that lncRNA-mediated ceRNAs may serve as important regulators in WT development and progression. Survival-associated RNAs may serve as new potential biomarkers, suggesting that the constructed ceRNA network in WT might be important for determining optimal therapeutic strategies.

A clinical prediction model to estimate the risk for coarctation of the aorta: From fetal to newborn life.

AIM: A prenatal diagnosis of coarctation of the aorta (CoA) is challenging. This study aimed to develop a coarctation probability model incorporating prenatal cardiac sonographic markers to estimate the probability of an antenatal diagnosis of CoA. METHODS: We reviewed 89 fetuses as an investigation cohort with prenatal suspicion for CoA and categorized them into three subgroups: severe CoA: symptomatic CoA and surgery within the first 3 months; mild CoA: surgery within 4 months to 1 year (29); and false-positive CoA: not requiring surgery (45). Logistic regression was used to create a multiparametric model, and a validation cohort of 86 fetuses with suspected CoA was used to validate the model. RESULTS: The prediction model had an optimal criterion >0.25 (sensitivity of 97.7%; specificity of 59.1%), and the area under the receiver operator curve was 0.85. The parameters and their cut-off values were as follows: left common carotid artery to left subclavian artery distance/distal transverse arch (LCCA-LSCA)/DT Index >1.77 (sensitivity 62%, specificity 88%, 95% confidence interval [CI]: 0.6-0.8), and z-score of AAo peak Doppler > -1.7 (sensitivity 77%, specificity 56%, 95% CI: 0.6-0.8). The risk assessment demonstrated that fetuses with a model probability >60% should have inpatient observation for a high risk of CoA, whereas fetuses with a model probability <15% should not undergo clinical follow-up. CONCLUSION: The probability model performs well in predicting CoA outcomes postnatally and can also improve the accuracy of risk assessment. The objectivity of its parameters may allow its implementation in multicenter studies of fetal cardiology.

Iterative sure independent ranking and screening for drug response prediction.

BACKGROUND: Prediction of drug response based on multi-omics data is a crucial task in the research of personalized cancer therapy. RESULTS: We proposed an iterative sure independent ranking and screening (ISIRS) scheme to select drug response-associated features and applied it to the Cancer Cell Line Encyclopedia (CCLE) dataset. For each drug in CCLE, we incorporated multi-omics data including copy number alterations, mutation and gene expression and selected up to 50 features using ISIRS. Then a linear regression model based on the selected features was exploited to predict the drug response. Cross validation test shows that our prediction accuracies are higher than existing methods for most drugs. CONCLUSIONS: Our study indicates that the features selected by the marginal utility measure, which measures the conditional probability of drug responses given the feature, are helpful for drug response prediction.

Risk factors for dislocation after revision total hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: No formal systematic review or meta-analysis was performed up to now to summarize the risk factors of dislocation after revision total hip arthroplasty(THA). AIMS: The present study aimed to quantitatively and comprehensively conclude the risk factors of dislocation after revision total hip arthroplasty. METHODS: A search was applied to CNKI, Embase, Medline, and Cochrane central database (all up to October 2016). All studies assessing the risk factors of dislocation after revision THA without language restriction were reviewed, and qualities of included studies were assessed using the Newcastle-Ottawa Scale. Data were pooled and a meta-analysis completed. RESULTS: A total of 8 studies were selected, which altogether included 4656 revision THAs. 421 of them were cases of dislocation occurred after surgery, suggesting the accumulated incidence of 9.04%. Results of meta-analyses showed that age at surgery (standardized mean difference -0.222; 95% CI -0.413-0.031), small-diameter femoral heads (≤28 mm) (OR 1.451; 95%CI 1.056-1.994), history of instability (OR 2.739; 95%CI 1.888-3.974), number of prior revisions ≥ 3 (OR, 2.226; 95% CI, 1.569-3.16) and number of prior revisions ≥ 2 (OR 1.949; 95% CI 1.349-2.817), acetabular components with elevated rim liner were less likely to develop dislocation after revision THA (OR 0.611; 95% CI 0.415-0.898). CONCLUSIONS: Related prophylaxis strategies should be implemented in patients involved with above-mentioned risk factors to prevent dislocation after revision THA.

[Medical treatment following successful separation of thoracopagus conjoined twins].

OBJECTIVE: To analyze and summarize the medical treatment experience following separation of thoracopagus conjoined twins. METHOD: The clinical manifestations and the medical therapy of a pair of thoracopagus conjoined twins were analyzed. The conjunction of the female twins was from 5 cm above the nipple to the umbilicus. They also suffered from complex congenital heart diseases. At the 17th day of their lives, they were surgically separated. One girl died after the operation, the other survived but experienced heart failure, sepsis and multiple organ dysfunction (including liver, blood and kidney et al). In order to protect or maintain the main organ function, the vital signs and the objective indexes were monitored continually, such as blood routine test, C reactive protein, hepatorenal function, bacterial culture, and galactomannan test, blood gas analysis and chest radiogram. CONCLUSION: It is important to protect the main organ function and prevent or control infection. The early surgical correction of congenital heart disease may contribute to recovery of the children.

Medical treatment following successful separation of thoracopagus conjoined twins / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze and summarize the medical treatment experience following separation of thoracopagus conjoined twins.</p><p><b>METHOD</b>The clinical manifestations and the medical therapy of a pair of thoracopagus conjoined twins were analyzed. The conjunction of the female twins was from 5 cm above the nipple to the umbilicus. They also suffered from complex congenital heart diseases. At the 17th day of their lives, they were surgically separated. One girl died after the operation, the other survived but experienced heart failure, sepsis and multiple organ dysfunction (including liver, blood and kidney et al). In order to protect or maintain the main organ function, the vital signs and the objective indexes were monitored continually, such as blood routine test, C reactive protein, hepatorenal function, bacterial culture, and galactomannan test, blood gas analysis and chest radiogram.</p><p><b>CONCLUSION</b>It is important to protect the main organ function and prevent or control infection. The early surgical correction of congenital heart disease may contribute to recovery of the children.</p>

Surgical repair of sinus of Valsalva aneurysm in Asian patients.

BACKGROUND: Sinus of Valsalva aneurysm is a rare cardiac anomaly, and the difference between Asian and Western countries in its occurrence is not well established. This study was designed to investigate the difference between Asian and Western patients. METHODS: Between September 1988 and February 2006, 83 patients with sinus of Valsalva aneurysm underwent surgical repair in our institute. The aneurysms originated from the right and noncoronary sinus in 74 and 9, respectively, and ruptured into the right ventricle in 52 patients, the right atrium in 30, and the left ventricle in 1. Ventricular septal defect (n = 38), aortic regurgitation (n = 21), and bicuspid aortic valve (n = 4) were the common coexisting anomalies. To compare the differences between Asian and Western patients in sinus of Valsalva aneurysm, 1049 cases (654 Asian patients versus 395 Western) were collected from the literature. RESULTS: Sixty-six patients were followed up for 9.6 +/- 3.8 years. The cardiac function of 15 patients with aortic regurgitation was worse than that of those with no aortic regurgitation (p < 0.05). There was no difference between the direct closure and the patch closure (p > 0.05). Analysis of all collected cases revealed that aneurysm of the sinus of Valsalva in Asian patients compared with Western series is characterized by a higher incidence, more aneurysms originating from the right coronary sinus (85.8% versus 67.9%), more aneurysm rupture into the right ventricle (72.5% versus 60%), a higher incidence of association with ventricular septal defect (52.4% versus 37.5%), and lower incidence of association with bicuspid aortic valve (0.6% versus 7.8%). However, both Asian and Western patient series have similar incidence of combination with aortic regurgitation (33.6% versus 32.7%). CONCLUSIONS: Long-term results of ruptured sinus of Valsalva aneurysm are associated with preoperative aortic regurgitation. The difference between Asian and Western patients with ruptured aneurysm of the sinus of Valsalva is significant.

[Construction of vector tandem expressing rat ventricular myocyte Kir2.1 shRNA and its effect in vitro].

OBJECTIVE: To construct a recombinant vector that expresses 5 shRNAs targeting on the rat ventricular myocyte Kir2.1 gene in tandem and its effect in vitro METHODS: Ventricular myocytes were collected from newborn Wistar rats and cultured. Five sites targeting on the rat Kir2.1 gene were selected. Accordingly 5 pairs of oligonucleotide fragments were designed, synthesized, and annealed to obtain double-stranded DNAs. The 5 pairs of oligonucleotide were then cloned into the vector pGenesil-1 by repeated excision and ligation successively. The tandem recombinant vector pEGFP6-1Kir2.1 was thus constructed and transfected into the cultured rat myocytes. RT-PCR and Western blotting were used to detect the mRNA and protein expression of Kir2.1 in the myocytes. Sequence not related to Kir2.1 sequence with mismatched bases was designed and used as control. RESULTS: A recombinant vector that expresses 5 shRNAs targeting on the rat ventricular myocyte Kir2.1 gene in tandem was constructed. 96 hours after the transfection RT-PCR showed that the Kir2.1 mRNA transcription was suppressed by 83, 6%, and Western blotting showed that the Kir2.1 protein transcription was suppressed by 68.1% in comparison with the control. CONCLUSION: The vector that expresses the 5 shRNAs targeting on the rat ventricular myocyte Kir2.1 gene in tandem is able to suppress the expression of Kir2.1 in rat ventricular myocytes. Application of such vector may be a new method to produce a new type of heart biological pacemaker.

[Clinical analysis of 24 supracardiac total anomalous pulmonary venous connection treated with surgery].

OBJECTIVE: To review the surgical treatment of supracardiac type of total anomalous pulmonary venous connection (TAPVC). METHODS: Twenty-four patients with supracardiac total anomalous pulmonary venous connection underwent surgical correction from July 1995 to June 2004. There were 11 males, 13 females. The patients aged from 40 days to 35 years (mean 4.5 years). Twenty-three patients were under 6 years old. The weight was from 3.8 to 54.0 kg (mean 17.5 kg). Ten patients were through right atrial incision, 8 through double-atrium incision to anastomose the left atria and the common pulmonary veins. Two used large patches separating the portal of the common pulmonary veins and the enlarged atrial septal defects to the left atria. The left atrium and the common pulmonary veins were anastomosed in one case using a large patch separating the portal of the common pulmonary vein and the enlarged atrial septal defect to the left atrium. Three anastomosed the top of the left atria and the common pulmonary veins. RESULTS: One patient died postoperatively of low cardiac output syndrome. One with cardiac tamponade after operation was cured by reoperation. Six with arrhythia were all cured. One with acute pulmonary edema was cured by reopen of the vertical vein and closed later. The postoperative follow-up period ranged from 3 months to 7 years (mean 2.5 years). One complicated severe supracardiac arrhythia 2 weeks later. One with late pulmonary occlusion was cured by reoperation. There was no long term complication of the others. CONCLUSIONS: The operative methods of TAPVC depend on the cardiac deformation. Proper surgery timely treatment of the postoperative complications may achieve a satisfactory result. The method of only use patch in the right atrium should select proper repair material. Anastomosing the top of the left atrium and the common pulmonary vein is a good method. It is easy for exposure and operating, meanwhile it has low occurrence of arrhythmias and should be recommended.

Clinical analysis of 24 supracardiac total anomalous pulmonary venous connection treated with surgery / 中华外科杂志

<p><b>OBJECTIVE</b>To review the surgical treatment of supracardiac type of total anomalous pulmonary venous connection (TAPVC).</p><p><b>METHODS</b>Twenty-four patients with supracardiac total anomalous pulmonary venous connection underwent surgical correction from July 1995 to June 2004. There were 11 males, 13 females. The patients aged from 40 days to 35 years (mean 4.5 years). Twenty-three patients were under 6 years old. The weight was from 3.8 to 54.0 kg (mean 17.5 kg). Ten patients were through right atrial incision, 8 through double-atrium incision to anastomose the left atria and the common pulmonary veins. Two used large patches separating the portal of the common pulmonary veins and the enlarged atrial septal defects to the left atria. The left atrium and the common pulmonary veins were anastomosed in one case using a large patch separating the portal of the common pulmonary vein and the enlarged atrial septal defect to the left atrium. Three anastomosed the top of the left atria and the common pulmonary veins.</p><p><b>RESULTS</b>One patient died postoperatively of low cardiac output syndrome. One with cardiac tamponade after operation was cured by reoperation. Six with arrhythia were all cured. One with acute pulmonary edema was cured by reopen of the vertical vein and closed later. The postoperative follow-up period ranged from 3 months to 7 years (mean 2.5 years). One complicated severe supracardiac arrhythia 2 weeks later. One with late pulmonary occlusion was cured by reoperation. There was no long term complication of the others.</p><p><b>CONCLUSIONS</b>The operative methods of TAPVC depend on the cardiac deformation. Proper surgery timely treatment of the postoperative complications may achieve a satisfactory result. The method of only use patch in the right atrium should select proper repair material. Anastomosing the top of the left atrium and the common pulmonary vein is a good method. It is easy for exposure and operating, meanwhile it has low occurrence of arrhythmias and should be recommended.</p>

[Clinical analysis for 70 sinus of valsalva aneurysm].

OBJECTIVE: To review retrospectively the experience of surgical repair of sinus of valsalva aneurysm (SVA) in 70 patients. METHODS: Between September, 1988 and October, 2003, Seventy patients with SVA underwent surgical repair by the aid of general anesthesia and cardiopulmonary bypass, comprised 1.4% (70/4960) of all open-heart operation. Forty-five were male and 25 female. Age ranged from 3 to 69 years old [mean (29 +/- 15) years]. The aneurysms ruptured into the right ventricle in 46 patients, right atrium in 23 and left ventricle in 1 respectively. The aneurysms originated from right and noncoronary sinus in 61 patients (87%) and 9 patients (13%) respectively. The most common associated cardiovascular lesions were ventricular septal defect (VSD, n = 34) and aortic valve incompetence (n = 21). Repairs were achieved through an incision in right atriotomy, right ventriculotomy or aortotomy only or both aortotomy and right atriotomy (or right ventriculotomy). The defects in the sinus of valsalva was repaired with either direct sutures (n = 43) or a patch (n = 27). The aortic valve was replaced in 6 patients. RESULTS: There were no deaths in early time after repair. Postoperative hospital stay was 8 approximately 33 days [mean +/- standard deviation, (14.3 +/- 6.4) days] before 1997 and 6 approximately 15 days [mean +/- standard deviation, (9.1 +/- 2.6) days] after 1997 respectively. Complications included infection (n = 4), hemorrhage (n = 4), pneumothorax (n = 1), arrhythmia (n = 4) and residual shunt (n = 1) of VSD. Fifty-three (76%) patients (2 months approximately 13 years) were followed-up [mean +/- standard deviation, (6.6 +/- 3.8) years]. All patients survived except that one died of rupture of dissecting aortic aneurysm 7 years after operation. CONCLUSIONS: The ruptured sinus of valsalva aneurysm and unruptured sinus of valsalva aneurysm with ventricle septal defect or(and) aortic valve regurgitation should be repaired surgically as soon as the diagnosis was confirmed. Long-term results are associated with preoperative aortic valve regurgitation.

Clinical analysis for 70 sinus of valsalva aneurysm / 中华外科杂志

<p><b>OBJECTIVE</b>To review retrospectively the experience of surgical repair of sinus of valsalva aneurysm (SVA) in 70 patients.</p><p><b>METHODS</b>Between September, 1988 and October, 2003, Seventy patients with SVA underwent surgical repair by the aid of general anesthesia and cardiopulmonary bypass, comprised 1.4% (70/4960) of all open-heart operation. Forty-five were male and 25 female. Age ranged from 3 to 69 years old [mean (29 +/- 15) years]. The aneurysms ruptured into the right ventricle in 46 patients, right atrium in 23 and left ventricle in 1 respectively. The aneurysms originated from right and noncoronary sinus in 61 patients (87%) and 9 patients (13%) respectively. The most common associated cardiovascular lesions were ventricular septal defect (VSD, n = 34) and aortic valve incompetence (n = 21). Repairs were achieved through an incision in right atriotomy, right ventriculotomy or aortotomy only or both aortotomy and right atriotomy (or right ventriculotomy). The defects in the sinus of valsalva was repaired with either direct sutures (n = 43) or a patch (n = 27). The aortic valve was replaced in 6 patients.</p><p><b>RESULTS</b>There were no deaths in early time after repair. Postoperative hospital stay was 8 approximately 33 days [mean +/- standard deviation, (14.3 +/- 6.4) days] before 1997 and 6 approximately 15 days [mean +/- standard deviation, (9.1 +/- 2.6) days] after 1997 respectively. Complications included infection (n = 4), hemorrhage (n = 4), pneumothorax (n = 1), arrhythmia (n = 4) and residual shunt (n = 1) of VSD. Fifty-three (76%) patients (2 months approximately 13 years) were followed-up [mean +/- standard deviation, (6.6 +/- 3.8) years]. All patients survived except that one died of rupture of dissecting aortic aneurysm 7 years after operation.</p><p><b>CONCLUSIONS</b>The ruptured sinus of valsalva aneurysm and unruptured sinus of valsalva aneurysm with ventricle septal defect or(and) aortic valve regurgitation should be repaired surgically as soon as the diagnosis was confirmed. Long-term results are associated with preoperative aortic valve regurgitation.</p>