Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance.

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo.

METTL1 promotes neuroblastoma development through mG tRNA modification and selective oncogenic gene translation.

Background: Neuroblastoma (NBL) is the most common extra-cranial solid tumour in childhood, with prognosis ranging from spontaneous remission to high risk for rapid and fatal progression. Despite existing therapy approaches, the 5-year event-free survival (EFS) for patients with advanced NBL remains below 30%, emphasizing urgent necessary for novel therapeutic strategies. Studies have shown that epigenetic disorders play an essential role in the pathogenesis of NBL.

Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion.

PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode.

METTL3-mediated N6-methyladenosine modification of DUSP5 mRNA promotes gallbladder-cancer progression.

N-methyladenosine (mA) RNA methylation and its associated methyltransferase METTL3 play an important role in tumorigenesis of a series of tumors. However, dysregulation of METTL3 in gallbladder cancer (GBC) remains obscure. Here, we showed that upregulated METTL3 level predicted poor prognosis and correlated with increased lymphatic metastasis and high TNM stage.

p-STAT3 expression in breast cancer correlates negatively with tumor size and HER2 status.

Although some studies have reported the expression and clinical significance of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in breast cancer tissues, it is still controversial whether p-STAT3 play a role in promoting or suppressing cancer. Here, we used immunohistochemistry analysis to explore expression of p-STAT3 in 407 cases of breast cancer, and analyzed the relationship between p-STAT3 expression and the clinicopathological characteristics and prognosis of breast cancer patients. Positive p-STAT3 expression was seen in 112 cases (27.

Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.

Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds.

The Prognosis of Type III Biliary Atresia with Hilar Cyst.

Objective: To compare the outcome of biliary atresia (BA) patients with and without hilar cyst on preoperative ultrasound.

Methods: A single center retrospective review of patients of BA with (n = 27) and without hilar cyst (n = 27) over a 5 y period was done. The patients were analyzed using propensity score matching to reduce selection bias.

Novel mutations in intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors.

Several poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) have been approved for cancer therapy; however, intrinsic and acquired resistance has limited their efficacy in the clinic. In fact, cancer cells have developed multiple mechanisms to overcome PARPi cytotoxicity in even a single cancer cell. In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and simmiparib (Capan-1/SP).

IL13RA2 is overexpressed in malignant gliomas and related to clinical outcome of patients.

Objective: To study the expression of IL13RA2 in gliomas and to analyze its correlation with clinicopathological/molecular features, immune cell infiltration and prognostic significance.

Methods: mRNA expression data for IL13RA2 were downloaded and analyzed from two open access datasets (TCGA & CGGA). IL13RA2 protein expression was examined by immunohistochemistry.

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy with high mortality and lack of effective therapeutic targets. Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens. Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells.

Postsurgical Management of Dilated Biliary Tract in Children: Ultrasound-Guided Percutaneous Transhepatic Cholangial Drainage and Subsequent Percutaneous Ultrasound Cholangiography.

The purpose of this study was to evaluate the feasibility of ultrasound (US)-guided percutaneous transhepatic cholangial drainage (PTCD) and consequent percutaneous US cholangiography in managing the dilated biliary tracts of children who have undergone hepatobiliary surgery. Sixteen children (11 boys, five girls; age range, 3-144 months) who underwent hepatobiliary surgery from December 2016 to October 2018 and had US evidence of biliary dilatation were included. All patients had undergone US-guided PTCD because of elevated postoperative serum bilirubin levels or bile duct infection.

Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter.

Poly(ADP-ribose) polymerase 1 (PARP1) regulates gene transcription in addition to functioning as a DNA repair factor. Forkhead box O1 (FoxO1) is a transcription factor involved in extensive biological processes. Here, we report that PARP1 binds to two separate motifs on the FoxO1 promoter and represses its transcription in a polymerase-independent manner.

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of L-kynurenine.

The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to L-kynurenine. Here, we report that IDO1 is a new target gene of the BET family.

Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity.

PARP1 inhibitors (PARPis) are used clinically during cancer therapy and are thought to exert their cytotoxicity through PARP1 polymerase inhibition and PARP1-DNA trapping. Here, we showed no significant correlation between PARP1-DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1-knockout sublines with wild-type PARP1 and 11 mutants with different point mutations that affect the polymerase activity.

Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression.

With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP).

Percutaneous US-guided Cholecystocholangiography with Microbubbles for Assessment of Infants with US Findings Equivocal for Biliary Atresia and Gallbladder Longer than 1.5 cm: A Pilot Study.

Purpose To evaluate the feasibility of ultrasonographically (US) guided percutaneous cholecystocholangiography (PCC) for early exclusion of biliary atresia (BA) in infants suspected of having BA with equivocal US findings or indeterminate type of BA and a gallbladder longer than 1.5 cm at US. Materials and Methods This study was approved by the ethics committee; written informed parental consent was obtained.

Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage.

Patients with congenital adrenal hyperplasia have a predisposition for developing adrenal rest tumors. In contrast to testicular adrenal rest tumors, ovarian adrenal rest tumors are less common, and only a few cases have been reported in the literature. This report presents three Chinese female congenital adrenal hyperplasia patients (9 to 15 years of age) with small ectopic adrenal cortical nodules that were not detected by imaging but were diagnosed at surgery.

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials.

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members.

Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas.

Programmed cell death-ligand 1(PD-L1) was expressed in various malignancies, and interaction with its receptor programmed cell death 1 (PD-1) often contributed to immune evasion of tumor cells. In this study, we explored the expression of PD-L1 and its correlation with clinical outcomes in gliomas. Clinicopathological data of 229 patients with gliomas was collected.

Cytoplasmic expression of BAP1 as an independent prognostic biomarker for patients with gliomas.

Background: BRCA1-associated protein-1 (BAP1) has been investigated the prognostic value for some carcinomas, including mammary carcinoma, pulmonary carcinoma and mesothelioma and so on. However, the status of BAP1 expression and the relationship of that with overall survival were not still estimated in patients with gliomas. Therefore, it was necessary to investigate the effect of BAP1 expression for the survival of patients with gliomas in this study.

Intestinal obstruction due to dual gastrointestinal atresia in infants: diagnosis and management of 3 cases.

Background: Several types of congenital lesions can cause complete or incomplete obstruction of the intestine. Our purpose is to present 3 neonates with dual intestinal type I atresia, i.e.

Structural elucidation of a new flavone from Sarcopyramis nepalensis.

A novel flavone, named 4'-methoxy-3',5,7-trihydroxy-8-(1''-(3''',4''',5'''-trihydroxyphenyl)ethyl)flavone (1), was isolated from Sarcopyramis nepalensis, along with two known compounds syringaresinol (2) and aralidioside (3). Their structures were established by the spectroscopic analysis, especially by 2D NMR. All of the three compounds were isolated from the plant for the first time.

Aphanamolide A, a new limonoid from Aphanamixis polystachya.

Two new limonoids, namely aphanamolides A (1) and B (2), were isolated from the seeds of Aphanamixis polystachya . Their structures were established by spectroscopic methods. Aphanamolide A (1) featured an unprecedented carbon skeleton via the formation of a C-3-C-6 bond.

Mulavanins A-E: limonoids from Munronia delavayi.

Limonoids, mulavanins A-E (1-5), along with four known compounds, were isolated from whole plants of Munronia delavayi. Their structures were elucidated by spectroscopic methods. Two of the compounds showed modest antifungal activity.