ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis.

Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar-ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of ß-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.

Local optimized Stokes polarimetry for specific polarization states.

In this Letter, we propose a locally optimized Stokes polarimetry. Focusing on the effect on polarization measurements by Poisson noise, the studies establish a new, to the best of our knowledge, optimization function combining the equally weighted variance with the condition number. This method considers both the stability and the precision of polarization measurements; by trading an increase in the condition number by 2.48%, we realize a decrease in equal-weighted variance by 19.1% near the north pole. The advantages of this local optimization method are demonstrated based on Monte Carlo (MC) simulations and experiments of continuous polarization state modulation. Finally, an imaging demonstration using a 4 µm pathological section implies the potential of this new local optimization method in improving polarization measurements and applying it to more biomedical research.

Effect of national holidays on health outcomes of patients receiving peritoneal dialysis in a single center over a ten-year period.

BACKGROUND: National holidays are associated with high mortality in some diseases, but little is known about patients undergoing peritoneal dialysis (PD). The research aimed to investigate the impact of national holidays on the health outcomes of PD patients. METHODS: Over ten years, all episodes of unplanned hospitalization, death, and peritonitis in PD patients were collected in our center. Seven national holidays in China were chosen, and non-holiday days were selected as the control period. The effect of national holidays was observed by comparing the hospitalization, death, and peritonitis rates between holiday and non-holiday groups. RESULTS: There were 297 events in all holiday periods and 1247 in non-holiday periods. There is no significant difference in hospitalization rate between holiday and non-holiday groups (32.4% ± 6.4% vs. 29.2% ± 3.4%, p = 0.175). So is the death rate [6.3% (4.8-12.3%) vs.5.0% (4.2-8.9%), p = 0.324] and peritonitis rate [0.19 (0.13-0.53) vs. 0.22 (0.18-0.27), p = 0.445] between the two groups. Significant differences were observed in the distribution of peritonitis causes between the two groups (p = 0.017). The rate of secondary to other infections in the holiday group was significantly higher than in the non-holiday group (25.0 vs. 10.3%, p = 0.015). CONCLUSION: Our study suggested no national holiday effect on health outcomes of PD patients based on ten-year data in our center.

Calculated inflammatory markers derived from complete blood count results, along with routine laboratory and clinical data, predict treatment failure of acute peritonitis in chronic peritoneal dialysis patients.

BACKGROUND & AIMS: Complete blood count (CBC)-derived inflammatory markers are predictive biomarkers for the prognosis of many diseases. However, there was no study on patients with peritoneal dialysis-associated peritonitis (PDAP). We aimed to investigate the value of these markers in predicting treatment failure of acute peritonitis in chronic PD patients. METHODS: The records of 138 peritonitis episodes were reviewed and divided into treatment success or failure groups in a single center for 10 years. CBC-derived markers and other routine data were recorded before peritonitis treatment was initiated. Univariate and multivariate regression analyses and the receiver operating characteristic (ROC) curve about the predictors of treatment outcomes were performed. RESULTS: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and derived NLR were significantly higher in the failure group. Univariate logistic regression results showed that NLR and PLR were risk factors of treatment outcomes. The backward stepwise multivariate logistic regression results demonstrated that NLR [adjusted odds ratio (aOR), 1.376; 95% confidence intervals (CI), 1.105-1.713; p = .004], PLR (aOR, 1.010; 95%CI, 1.004-1.017; p = .002) were risk factors, but hemoglobin-to-lymphocyte ratio (HLR) (aOR, 0.977; 95%CI, 0.963-0.991; p = .001), and SII (aOR, 0.999; 95%CI, 0.998-1.000; p = .040) were protective factors. A combination of age, PD vintage, Gram-positive peritonitis, staphylococcus aureus, culture-negative, NLR, PLR, HLR, and SII would improve prognostic performance. The area under this ROC curve was 0.85, higher than other factors. CONCLUSIONS: NLR, PLR, HLR, and SII were associated with PDAP outcomes. Age, PD vintage, NLR, and PLR were significant risk factors in PDAP patients.

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis.

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of ß-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

Identification and validation of a five-gene prognostic signature for hepatocellular carcinoma.

BACKGROUND: ARID1A is a commonly mutated tumor suppressor gene found in all human cancer types, but its clinical significance, oncogenic functions, and relevant mechanisms in hepatocellular carcinoma (HCC) are not well understood. OBJECTIVE: We aimed to improving the prognosis risk classification of HCC from the perspective of ARID1A mutations. MATERIALS AND METHODS: We examined the interaction between ARID1A mutations and the overall survival via Kaplan-Meier survival analysis. We used gene set enrichment analysis (GSEA) to elucidate the influence of ARID1A mutations on signaling pathways. A prognostic model was constructed using LASSO and multivariate Cox regression analyses. A receiver operating characteristic (ROC) curve was used to estimate the performance and accuracy of the model. RESULTS: HCC patients with ARID1A mutations presented poor prognosis. By GSEA, we showed that genes upregulated by reactive oxygen species (ROS) and regulated by MYC were positively correlated with ARID1A mutations. A prognostic signature consisting of 5 genes (SRXN1, LDHA, TFDP1, PPM1G, and EIF2S1) was constructed in our research. The signature showed good performance in predicting overall survival (OS) for HCC patients by internal and external validation. CONCLUSION: Our research proposed a novel and robust approach for the prognostic risk classification of HCC patients, and this approach may provide new insights to improve the treatment strategy of HCC.

Design and synthesis of thiazolylhydrazone derivatives as inhibitors of chitinolytic N-acetyl-ß-d-hexosaminidase.

N-acetyl-ß-d-hexosaminidase (Hex) is potential target for pesticide design. Here, a series of thiazolylhydrazone derivatives were designed, synthesized and evaluated as competitive inhibitors of OfHex1, a Hex from the agricultural pest Ostrinia furnacalis. The derivative 3k, with a (benzyloxy)methyl group at the N3 atom, demonstrated greater potency with a Ki of 10.2 µM. Molecular docking analysis indicated that the (benzyloxy)methyl group of 3k was bound to a previously unexplored pocket formed by Loop478-496. Then further optimization around naphthalene ring led to find the more potency substituent phenyl. The derivative 7, with phenoxyethyl group at R1 and a phenyl group at R2, demonstrated an augmented potency with a Ki of 2.1 µM. Molecular docking analysis indicated that 7 was bound to the active pocket of OfHex1 more favorably than 3k. This work suggests a novel scaffold for developing specific Hex inhibitors.

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase.

Induction of DNA damage by ionizing radiation (IR) and/or cytotoxic chemotherapy is an essential component of cancer therapy. The ataxia telangiectasia group D complementing gene (ATDC, also called TRIM29) is highly expressed in many malignancies. It participates in the DNA damage response downstream of ataxia telangiectasia-mutated (ATM) and p38/MK2 and promotes cell survival after IR. To elucidate the downstream mechanisms of ATDC-induced IR protection, we performed a mass spectrometry screen to identify ATDC binding partners. We identified a direct physical interaction between ATDC and the E3 ubiquitin ligase and DNA damage response protein, RNF8, which is required for ATDC-induced radioresistance. This interaction was refined to the C-terminal portion (amino acids 348-588) of ATDC and the RING domain of RNF8 and was disrupted by mutation of ATDC Ser-550 to alanine. Mutations disrupting this interaction abrogated ATDC-induced radioresistance. The interaction between RNF8 and ATDC, which was increased by IR, also promoted downstream DNA damage responses such as IR-induced γ-H2AX ubiquitination, 53BP1 phosphorylation, and subsequent resolution of the DNA damage foci. These studies define a novel function for ATDC in the RNF8-mediated DNA damage response and implicate RNF8 binding as a key determinant of the radioprotective function of ATDC.

Protein kinase A modulates transforming growth factor-ß signaling through a direct interaction with Smad4 protein.

Transforming growth factor ß (TGFß) signaling normally functions to regulate embryonic development and cellular homeostasis. It is increasingly recognized that TGFß signaling is regulated by cross-talk with other signaling pathways. We previously reported that TGFß activates protein kinase A (PKA) independent of cAMP through an interaction of an activated Smad3-Smad4 complex and the regulatory subunit of the PKA holoenzyme (PKA-R). Here we define the interaction domains of Smad4 and PKA-R and the functional consequences of this interaction. Using a series of Smad4 and PKA-R truncation mutants, we identified amino acids 290-300 of the Smad4 linker region as critical for the specific interaction of Smad4 and PKA-R. Co-immunoprecipitation assays showed that the B cAMP binding domain of PKA-R was sufficient for interaction with Smad4. Targeting of B domain regions conserved among all PKA-R isoforms and exposed on the molecular surface demonstrated that amino acids 281-285 and 320-329 were required for complex formation with Smad4. Interactions of these specific regions of Smad4 and PKA-R were necessary for TGFß-mediated increases in PKA activity, CREB (cAMP-response element-binding protein) phosphorylation, induction of p21, and growth inhibition. Moreover, this Smad4-PKA interaction was required for TGFß-induced epithelial mesenchymal transition, invasion of pancreatic tumor cells, and regulation of tumor growth in vivo.

Mechanism of the plant cytochrome P450 for herbicide resistance: a modelling study.

Plant cytochrome P450 is a key enzyme responsible for the herbicide resistance but the molecular basis of the mechanism is unclear. To understand this, four typical plant P450s and a widely resistant herbicide chlortoluron were analysed by carrying out homology modelling, molecular docking, molecular dynamics simulations and binding free energy analysis. Our results demonstrate that: (i) the putative hydrophobic residues located in the F-helix and polar residues in I-helix are critical in the herbicide resistance; (ii) the binding mode analysis and binding free energy calculation indicate that the distance between catalytic site of chlortoluron and heme of P450, as well as the binding affinity are key elements affecting the resistance for plants. In conclusion, this work provides a new insight into the interactions of plant P450s with herbicide from a molecular level, offering valuable information for the future design of novel effective herbicides which also escape from the P450 metabolism.

KLIPP - a precision CRISPR approach to target structural variant junctions in cancer.

Current cancer therapies typically give rise to dose-limiting normal tissue toxicity. We have developed KLIPP, a precision cancer approach that specifically kills cancer cells using CRISPR/Cas9 technology. The approach consists of guide RNAs that target cancer-specific structural variant junctions to nucleate two parts of a dCas9-conjugated endonuclease, Fok1, leading to its activation. We show that KLIPP causes induction of DNA double strand breaks (DSBs) at the targeted junctions and cell death. When cancer cells were grown orthotopically in mice, activation of Fok1 at only two junctions led to the disappearance of tumor cells in 7/11 mice. This therapeutic approach has high specificity for tumor cells and is independent of tumor-specific drivers. Individualized translation of KLIPP to patients would be transformative and lead to consistent and simplified cancer treatment decisions.

Ophiopogonin D Inhibiting Epithelial NF-κB Signaling Pathway Protects Against Experimental Colitis in Mice.

The sustained activation of the nuclear factor κB (NF-κB) signaling pathway has been observed in human inflammatory bowel disease (IBD). Ophiopogonin D (OP-D) is a small molecular compound isolated from Ophiopogon japonicus, a widely used herbal remedy. In this study, dextran sodium sulfate was used to make a mouse model of experimental colitis and verify the effect of OP-D on the mouse model of experimental colitis. Small molecule-protein molecular docking approaches were also used to discover the mechanisms underlying the OP-D-induced regulation of colitis. In colitis, the OP-D can inhibit the apoptosis of intestinal mucosa cells, restore the intestinal barrier, and alleviate inflammation. The molecular docking simulations showed that OP-D had a high affinity with the REL-homology domain of NF-κB-p65 that affected its translocation to the nucleus. In a cell study, the effects of OP-D on inflammation and barrier dysfunction were significantly decreased by a small interfering RNA targeting NF-κB-p65. Further, the LPS-induced increase in NF-κB-p65 in the nucleus was also significantly inhibited by OP-D. OP-D alleviated experimental colitis by inhibiting NF-κB. New insights into the pathogenesis and treatment options of colitis are provided through this study.

3-Chloro-pyridin-2-amine.

In the title compound, C(5)H(5)ClN(2), a by-product in the synthesis of ethyl 2-(3-chloro-pyridin-2-yl)-5-oxopyrazolidine-3-carboxyl-ate, the amine groups form inter-molecular hydrogen-bonding associations with pyridine N-atom acceptors, giving centrosymmetric cyclic dimers. Short inter-molecular Cl⋯Cl inter-actions [3.278 (3) Å] also occur.

5-Chloro-methyl-1,3-dimethyl-1H-pyrazole.

The pyazole ring in the title compound, C(6)H(9)ClN(2), is almost planar (r.m.s. deviation = 0.003 Å). In the crystal, mol-ecules are linked by C-H⋯N inter-actions, forming [100] chains.

Brain metastases from esophageal cancer: A case report.

INTRODUCTION: At present, there is no uniform consensus on the treatment of brain metastases from esophageal cancer. The studies on the treatment of brain metastases from esophageal cancer by radiotherapy combined with temozolomide (TMZ) are even rarer. PATIENT CONCERNS: A 69-year-old woman was admitted to our hospital for brain metastases from esophageal cancer after thoracic irradiation. DIAGNOSES: Magnetic resonance imaging of the head showed a round, heterogeneous metastatic tumor in the left parietal lobe. Brain magnetic resonance imaging showed edema around brain metastasesInterventions: After radiotherapy plus TMZ in this patient's head, the brain metastatic tumor was significantly decreased. OUTCOMES: At the end of radiotherapy, and 1 and 2 months after the end of radiotherapy, the metastatic tumor continued to shrink, and no obvious side effects were observed. LESSONS: This study suggests that radiotherapy plus TMZ might be a feasible option for brain metastases from esophageal cancer.

The Ras-GRF1 exchange factor coordinates activation of H-Ras and Rac1 to control neuronal morphology.

The Ras-GRF1 exchange factor has regulated guanine nucleotide exchange factor (GEF) activity for H-Ras and Rac1 through separate domains. Both H-Ras and Rac1 activation have been linked to synaptic plasticity and thus could contribute to the function of Ras-GRF1 in neuronal signal transduction pathways that underlie learning and memory. We defined the effects of Ras-GRF1 and truncation mutants that include only one of its GEF activities on the morphology of PC12 phaeochromocytoma cells. Ras-GRF1 required coexpression of H-Ras to induce morphological effects. Ras-GRF1 plus H-Ras induced a novel, expanded morphology in PC12 cells, which was characterized by a 10-fold increase in soma size and by neurite extension. A truncation mutant of Ras-GRF1 that included the Ras GEF domain, GRFdeltaN, plus H-Ras produced neurite extensions, but did not expand the soma. This neurite extension was blocked by inhibition of MAP kinase activation, but was independent of dominant-negative Rac1 or RhoA. A truncation mutant of Ras-GRF1 that included the Rac GEF domains, GRFdeltaC, produced the expanded phenotype in cotransfections with H-Ras. Cell expansion was inhibited by wortmannin or dominant-negative forms of Rac1 or Akt. GRFdeltaC binds H-Ras.GTP in both pulldown assays from bacterial lysates and by coimmunoprecipitation from HEK293 cells. These results suggest that coordinated activation of H-Ras and Rac1 by Ras-GRF1 may be a significant controller of neuronal cell size.

(E)-2-[(4-Chloro-1,3-dimethyl-1H-pyrazol-5-yl)methyl-eneamino]benzamide.

In the title compound, C(13)H(13)ClN(4)O, the dihedral angle between the aromatic rings is 33.47 (9)° and an intra-molecular N-H⋯N hydrogen bond generates an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds occur, resulting in R(2) (2)(8) loops.

Ethyl 3-bromo-1-(3-chloro-2-pyrid-yl)-4,5-dihydro-1H-pyrazole-5-carboxyl-ate.

The title compound, C(11)H(11)BrClN(3)O(2), contains two mol-ecules in the asymmetric unit in which the dihedral angles between the pyrazole and pyridine rings are 30.0 (2) and 22.3 (2)°.

ATDC mediates a TP63-regulated basal cancer invasive program.

Basal subtype cancers are deadly malignancies but the molecular events driving tumor lethality are not completely understood. Ataxia-telangiectasia group D complementing gene (ATDC, also known as TRIM29), is highly expressed and drives tumor formation and invasion in human bladder cancers but the factor(s) regulating its expression in bladder cancer are unknown. Molecular subtyping of bladder cancer has identified an aggressive basal subtype, which shares molecular features of basal/squamous tumors arising in other organs and is defined by activation of a TP63-driven gene program. Here, we demonstrate that ATDC is linked with expression of TP63 and highly expressed in basal bladder cancers. We find that TP63 binds to transcriptional regulatory regions of ATDC and KRT14 directly, increasing their expression, and that ATDC and KRT14 execute a TP63-driven invasive program. In vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. These results link TP63 and the basal gene expression program to ATDC and to aggressive tumor behavior. Defining ATDC as a molecular determinant of aggressive, basal cancers may lead to improved biomarkers and therapeutic approaches.