Veliparib­Induced Toxicity in Cancer Patients: A Systematic Review and Meta­Analysis.

In this study, we investigate the veliparib­induced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could increase the risk of hematologic and gastrointestinal toxicities. Anemia, neutropenia, thrombocytopenia, and nausea were the most common toxicities. Patients diagnosed with gastrointestinal tumors tend to have a higher risk of high-grade neutropenia; patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the ≥ second line setting. Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia. Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue.

Abelmoschus manihot (L.) medik. seeds alleviate rheumatoid arthritis by modulating JAK2/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown. AIM OF THE STUDY: This research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA. MATERIALS AND METHODS: The ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1ß, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats' synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking. RESULT: In the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1ß, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4'-methoxy-bavachromanol, and quercetin. CONCLUSION: According to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.

SOCS2 inhibits hepatoblastoma metastasis via downregulation of the JAK2/STAT5 signal pathway.

Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.

miR-181b-5p/SOCS2/JAK2/STAT5 axis facilitates the metastasis of hepatoblastoma.

Introduction: Hepatoblastoma (HB) is a malignant liver tumor predominantly found in children and tumor metastasis is one of the main causes of poor prognosis in affected patients. The precise molecular mechanisms responsible for HB metastasis remain incompletely understood. However, there is evidence suggesting a connection between the dysregulation of microRNAs (miRNAs) and the progression of tumor metastasis in HB. Methods: The study utilized weighted gene co-expression network analysis (WGCNA) to analyze a miRNA microarray dataset of HB. The expression of miR-181b-5p in HB tissues and cells was detected using quantitative real-time PCR. The impact of miR-181b-5p on the metastatic capacity of HB was evaluated through scratch and Transwell assays. The effects of exogenously expressing miR-181b on the metastatic phenotypes of HB cells were evaluated in vivo. Furthermore, a luciferase reporter assay was performed to validate a potential target of miR-181b-5p in HB. Results: We found that miR-181b-5p was highly expressed in HB tissues and HB cell lines. Overexpression of miR-181b enhanced scratch healing, cell migration, and invasion abilities in vitro, as well as enhancing HB lung metastasis potential in vivo. Dual-luciferase reporter assays showed that Suppressor Of Cytokine Signaling 2 (SOCS2) was a direct target of miR-181b. The overexpression of miR-181b resulted in the suppression of SOCS2 expression, subsequently activating the epithelial-mesenchymal transition and JAK2/STAT5 signaling pathways. The rescue experiment showed that SOCS2 overexpression attenuated the effects of miR-181b on HB cells. Conclusion: Our study showed that miR-181b promotes HB metastasis by targeting SOCS2 and may be a potential therapeutic target for HB.

LncRNA-mRNA coexpression analysis reveals distinct pathogenic mechanisms for subtypes of congenital biliary dilatation.

BACKGROUND/PURPOSE: Congenital biliary dilatation (CBD) is a bile duct malformation often associated with pancreaticobiliary maljunction. Different subtypes of CBD have been noted for clinical differences, but their pathogenic mechanisms are unclear. METHODS: To elucidate the genetic basis of CBD, we performed lncRNA and mRNA sequencing and bioinformatic analysis on 18 cystic and 18 fusiform CBD samples. RESULTS: We identified differentially expressed mRNAs and lncRNAs between the two types of CBD, and constructed coexpression modules that correlated with clinical characteristics of CBD using weighted gene coexpression network analysis. We found that the brown module was the highest positive correlation with fusiform CBD (R = 0.67, p = 7.9e-6) and contained the most genes. We then built a lncRNA-mRNA coexpression network to identify potential target genes of lncRNAs in CBD, and a protein-protein interaction network to investigate the hub genes from the target genes and the brown module. Finally, we performed enrichment analyses and found differences between cystic and fusiform CBD in hepatobiliary system development, liver and pancreas development involving hub genes ONECUT1 and HNF1B that could be regulated by corresponding lncRNAs. CONCLUSION: Our study suggests that lncRNAs may modulate pancreaticobiliary duct development differently in cystic and fusiform CBD, providing new insights for etiology studies and clinical treatment.

Corrigendum: Molecular characteristics of choledochal cysts in children: transcriptome sequencing.

[This corrects the article DOI: 10.3389/fgene.2021.709340.].

Influencing factors of parental selections of minimally invasive procedure in children's abdominal surgery: a cross-sectional study in China.

The purpose of our study was to explore the influencing factors of parental selections of minimally invasive procedure including laparoscopic or robotic methods in children's abdominal surgery. The questionnaire survey was conducted among the parents of patients who received abdominal laparoscopic or robotic surgery in our hospital from December 2020 to June 2022. The contents included basic information of the patients and parents, parental educational background, monthly income, insurance details and the parental considerations. Univariate and multivariate logistic regression were applied for the influencing factors analysis. Six categories of diseases involving choledochal cyst (198 cases), spleen related diseases (31 cases), hirschsprung disease (40 cases), inguinal hernia (330 cases), adrenal tumor (15 cases) and ureteropelvic junction obstruction (73 cases) were included in this study. After univariable and multivariable logistic regression analysis accomplished, we discovered that college degree or above (OR = 0.545, P < 0.001), monthly income > 5000 RMB (OR = 0.761, P < 0.001) and involving reconstruction during operation (OR = 0.842, P < 0.001) were the influencing factors for parental selections of robotic surgery. In children's abdominal surgery, parents with college degree or above, monthly income > 5000 RMB and considering the need for reconstruction during operation are more inclined to choose the robotic surgery.

Roux-en-Y hepaticojejunostomy or hepaticoduodenostomy for biliary reconstruction after resection of congenital biliary dilatation: a systematic review and meta-analysis.

The ideal surgical management for reconstruction after excision of congenital biliary dilatation remains controversial. This updated meta-analysis compared the clinical outcomes of hepaticoduodenostomy (HD) and hepaticojejunostomy (HJ) after resection of congenital biliary dilatation. PubMed, Web of Science, Embase, Ovid, and the Cochrane Library were searched for studies published from November 1981 through July 2020. The primary outcomes were the operative time, enteral feeding time, hospital stay, and postoperative complications. The quality and risk of bias were assessed with the Newcastle-Ottawa Quality Assessment Scale. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were pooled using random-effects models. Thirteen total studies included 518 (55.76%) HD cases and 411 (44.24%) HJ cases. Five studies were published post-2013; one was a randomized clinical trial. Patients undergoing HD had a shorter hospital stay (MD, 0.40; p = 0.02) and operative time (MD, 59.54; p < 0.00001) and a lower incidence of adhesive intestinal obstruction (OR, 0.20; p = 0.02) than HJ. HD was comparable to conventional HJ with regard to most postoperative outcomes; however, it was associated with a higher incidence of postoperative bilious gastritis (OR, 6.24; p = 0.002). HD is as safe and feasible as HJ with better outcomes in the short run, although reports with long-term follow-up are relatively few. Long-term follow-up will be necessary to monitor possible associated malignancies in the future.

Total versus conventional robotic-assisted cyst excisions and hepaticojejunostomies in children with choledochal cysts: a case-control study.

The current study's primary aim is to compare the safety and effectiveness between total and conventional robot-assisted cyst excisions and hepaticojejunostomies in children with choledochal cysts (CCs). Patients suffering from CCs treated with either total or conventional robot-assisted procedures (TRAS or CRAS) between December 2019 and February 2021 were analyzed retrospectively. Data collected included the characteristics, operative and postoperative details. The risk factors for conversion of TRAS to CRAS were analyzed by logistic regression analysis. There were 50 patients who underwent TRAS and CRAS, respectively, and 19 patients were transferred to CRAS. The operation time in the TRAS group was significantly higher than that of the CRAS group, while the time to taking water and hospital stay were significantly shorter (p < 0.05). No significant difference was observed in complications between the groups (p = 0.325). The risk factors for conversion of TRAS to CRAS were age ≥ 48 months, thickness of abdominal wall (TAW) ≥ 1.3 cm and upper abdominal length (UAL) ≥ 9.5 cm. Both TRAS and CRAS are safe and feasible. Performing TRAS is recommended for patients whose age ≥ 48 months, TAW ≥ 1.3 cm and UAL ≥ 9.5 cm, while for others, it is recommended to perform CRAS.

Surgical outcomes of robotic-assisted cyst excisions and hepaticojejunostomies in patients with perforated choledochal cysts: a single-center retrospective study.

Perforated choledochal cysts is usually treated by open approach through a one- or two-stage procedure. Laparoscopic procedures are gradually being used more commonly with advancements in minimally invasive technology, while the level of difficulty and conversion rate are still high due to adhesions and deranged anatomy. Robot-assisted choledochal cyst excisions have been proposed as another minimally invasive procedure that is thought to improve operability and precision compared with laparoscopic surgery. However, there is still a lack about the use of robotic assistance for bilio-enteric reconstruction in pediatric patients with perforated choledochal cyst excisions. The aim of this current study was to investigate the safety and effectiveness of robotic-assisted procedures in pediatric perforated choledochal cyst excisions. Patients suffering from perforated choledochal cysts and treated with surgical procedures including open, laparoscopic, and robotic procedures between January 2009 and December 2021 were retrospectively analyzed. Robotic cyst excisions and hepaticojejunostomies were mainly used to a one-stage procedure (the pseudocyst formation or intra-mural perforation) or in stage 2 of two-stage procedures (complete perforation). Data collection included patient characteristics, intraoperative outcomes, and postoperative complications. There were a total of 64 patients suffering from perforated choledochal cysts were treated at our institution. Thirty-one cases of cyst excisions and hepaticojejunostomies were completed by open procedures. Twenty-two cases of cyst excisions and hepaticojejunostomies were completed by laparoscopic procedures and 11 cases were completed by robotic procedures. The operating times were significantly longer in the laparoscopic procedures group (214.32 ± 51.33 min) than found with either the open procedures group (130.55 ± 10.51 min) or the robot-assisted procedures group (188.82 ± 16.55 min) (p < 0.001). The time to oral intake, total complication, and hospital stay were similar among all three groups (3.53 ± 0.28 days vs 3.47 ± 0.30 days vs 3.46 ± 0.29 days, 19.35% vs 27.27% vs 18.18%, 11.48 ± 1.29 days vs 11.95 ± 2.75 days vs 11.55 ± 2.38 days, respectively) (p > 0.05). The number of biliary complications was higher in the laparoscopic procedures group (18.18%) than in both the open procedures and robot-assisted procedures groups (0.00%) (p = 0.016). Robotic-assisted cyst excision and hepaticojejunostomy procedures in patients with perforated choledochal cysts are both safe and feasible. What is more, they can achieve the same results as open procedures and also reduce the level of difficulty of operations and bring fewer biliary complications compared with laparoscopic procedures.

Robotic versus laparoscopic surgery for choledochal cyst in children with aberrant hepatic ducts: A retrospective study.

BACKGROUND: The aim of this current study was to compare the safety and effectiveness between robotic and laparoscopic surgery in pediatric patients suffered from choledochal cysts associated with aberrant hepatic duct. METHODS: Patients suffered from choledochal cysts associated with aberrant hepatic duct who were treated with laparoscopic or robotic procedures between January 2009 and June 2022 were retrospectively analyzed. The patients were divided into laparoscopic and robotic group according to different surgical methods. The data collected included the demographic information, imaging information, operative details and postoperative complications. RESULTS: Twenty-two patients were included in the analysis consisting of 14 cases in laparoscopic group and 8 cases in robotic group. The male to female ratio was 1:6.33. The median age of the patients was 40.00 months with a mean weight of 16.99 kg. There were no significant differences in patient characteristics between the two groups. The operation and anesthesia time were significantly longer in the laparoscopic procedures group (238.14 ± 17.24 min, 265.93 ± 19.51 min, respectively) than robotic procedures group (208.00 ± 9.24 min, 230.13 ± 12.87 min, respectively) (p < 0.001). The time to take water and hospital stay were longer in laparoscopic group (3.33 ± 0.44 days, 8.92 ± 0.52 days, respectively) than robotic group (3.01 ± 0.22 days, 7.88 ± 1.13 days, respectively) (p < 0.05). There was no statistical difference in total complications between the two groups (p = 0.912). CONCLUSIONS: Robotic surgery can achieve the same results as laparoscopic surgery in the management of patients suffered from choledochal cysts associated with aberrant hepatic duct, at the same time reducing the difficulty of operation and recovering faster.

A comprehensive review of Shengdeng in Tibetan medicine: textual research, herbal and botanical distribution, traditional uses, phytochemistry, and pharmacology.

"Shengdeng", a group of Tibetan medicines with diverse biological origins, has long been utilized in Tibet for the treatment of rheumatoid arthritis. It showcases remarkable efficacy in alleviating rheumatism, reducing swelling, and relieving pain. This study aimed to clarify the plant species used as "Shengdeng" and summarize their botanical distribution, traditional uses, phytochemistry, and pharmacology to promote its utilization and development. "Shengdeng" is derived from a remarkable collection of 14 plant species belonging to six distinct families. Extensive phytochemical investigations have led to the identification of 355 chemical constituents within "Shengdeng". Pharmacological studies conducted on "Shengdeng" have revealed a wide range of beneficial properties, including antioxidant, anticancer, antimicrobial, antiviral, antiparasitic, anti-inflammatory, and anti-arthritic activities. Notably, flavonoids and triterpenoids emerge as the predominant groups among these constituents, contributing to the therapeutic potential and diverse applications of "Shengdeng". The present review provides a concise summary of the recent advancements in textual research concerning the herbal and botanical distribution, traditional uses, phytochemistry, and pharmacological activities of "Shengdeng". It is crucial to note that future research on "Shengdeng" should prioritize the analysis of its active ingredients and the establishment of rigorous quality standards. These aspects are essential for ensuring consistency, efficacy, and safety in its clinical application.

Laparoscopic surgery versus robot-assisted surgery for choledochal cyst excision: A systematic review and meta-analysis.

The aim of this following study is to systematically review and analyze the published data comparing laparoscopic surgery and robotic assisted surgery for choledochal cyst excisions through the metrics of operative time, length of hospital stay and postoperative outcome. PubMed, Web of Science, Embase, Ovid, and the Cochrane Library databases were combed through and data was retrieved from the timespan between January 1995 and October 2021. The primary measures included operative time, intraoperative bleeding, hospital stay, and postoperative complications. Quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scale. Making use of random-effects models, we pooled the odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs). Six studies comprising a total 484 patients who had undergone either laparoscopic surgery [307 (63.43%) patients] or robot-assisted surgery [177 (36.57%) patients] were included in this analysis. Three of the articles involved adults while the other three involved children. All of the studies were published after 2018 and were retrospective case-control studies. Patients undergoing robotic surgery had a shorter hospital stay (MD, 0.95; 95% CI, 0.56 to 1.35; p < 0.00001) and a longer operative time (MD, -57.52; 95% CI, -67.17 to -47.87; p < 0.00001). And there was no significant discrepancy in complications between the two groups. Compared to laparoscopic surgery, robot-assisted surgery is associated with a shorter hospital stay, scores highly in terms of both safety and feasibility, however it also results in a longer operative time. And the two procedures have the same short- and long-term results.

Discovery of (Z)-1-(3-((1H-Pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea Derivatives as Novel and Orally Highly Effective CSF-1R Inhibitors for Potential Colorectal Cancer Immunotherapy.

Inhibiting the polarization or survival of tumor-associated macrophages through blocking CSF-1/CSF-1R signal transduction has become a promising strategy for cancer immunotherapy. Herein, a series of (Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea derivatives were designed, synthesized, and evaluated as novel and orally highly effective CSF-1R inhibitors for colorectal cancer immunotherapy. Among these derivatives, compound 21 was found to possess excellent CSF-1R inhibitory activity (IC50 = 2.1 nM) and potent antiproliferative activity against colorectal cancer cells. Compound 21 inhibited the progression of colorectal cancer by suppressing the migration of macrophages, reprograming M2-like macrophages to the M1 phenotype, and enhancing the antitumor immunity. More importantly, compound 21, as a single agent, showed significantly superior in vivo anticolorectal cancer efficacy over PLX3397, highlighting a promising candidate for the immunotherapy of colorectal cancer.

Preliminary Experiences With Robot-Assisted Choledochal Cyst Excision Using the Da Vinci Surgical System in Children Below the Age of One.

The purpose of this study is to introduce our preliminary experiences with using the da Vinci surgical system to treat choledochal cysts in children under 1 year old and discuss the application of this robot-assisted surgery. We retrospectively analyzed all available clinical data of children below the age of 1 who underwent surgery for choledochal cysts using the da Vinci robotic surgical system between January 2015 and December 2020. Data collection mainly included demographic information, imaging data, perioperative details, and postoperative outcomes. Ten patients were included in this study. The average patient age was 8.5 months, and the average weight was 9.11 kg. Half of these patients suffered from abdominal pain, while 30% exhibited vomiting and 10% jaundice. Eight of them were type Ia, and two were Ic. The average operation time among the patients was 219.5 min. None of the 10 patients had to receive a blood transfusion or conversion. The average time of the patients' subsequent fluid diet was 3.28 days, and the solid diet was 3.76 days. Meanwhile, the average length of hospital stay was 7.6 days. All 10 patients recovered and were eventually discharged. We believe that the da Vinci surgical system is a safe and feasible form of treatment for choledochal cysts in children <1 year old.

Molecular Characteristics of Choledochal Cysts in Children: Transcriptome Sequencing.

A choledochal cyst (CC) is a common congenital biliary disease in children, yet the underlying molecular bases for the cystic and fusiform clinical subtypes are unknown. RNA sequencing (RNA-seq) has been performed on 22 high-quality CC samples, including 12 cystic CC and 10 fusiform CC samples, to search for molecular features. Weighted gene co-expression network analysis (WGCNA) was performed to identify key modules associated with clinical subtypes. Bioinformatic analyses were conducted to elucidate potential mechanisms. Then, we constructed protein-protein interaction (PPI) networks to identify candidate hub genes related to CC. Finally, we used the support vector machine (SVM) to eliminate redundant features and screen out the hub genes. The selected gene expression was determined in CC patients through quantitative real-time polymerase chain reaction (PCR). A total of 6,463 genes were found to be aberrantly expressed between cystic CC and fusiform CC. Twelve co-expression modules that correlated with clinical subtypes of CC were identified and assigned representative colors. Among the 12 modules, the blue module was considered the key module. Two functionally distinct sets of dysregulated genes have been identified in two major subtypes, metabolism-related genes in cystic CC and immune-related genes in fusiform CC. A total of 20 candidate hub genes that were correlated with clinical subtypes were found in the blue module. In addition, we found ERBB2 and WNT11 that have not been studied in CC and verified their differential expression in CC through quantitative real-time PCR experiments. For the first time, we have described the transcriptome characteristics of CC. These results suggest that cystic CC and fusiform CC have different molecular mechanisms. The bi-omics-identified novel candidate genes and pathways might be helpful for personalized treatment and are of great clinical significance for CC.