Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174: Αυγούστου 2017

Πέμπτη 31 Αυγούστου 2017

Eisai gets insurance coverage for thyroid cancer drug - Korea Biomedical Review

Eisai gets insurance coverage for thyroid cancer drug
Korea Biomedical Review
"We expect [the drug] will be recognized for its effectiveness in the market as the first line of treatment for radioactive iodine-refractory differentiated thyroid cancer," said Eisai Korea CEO Charlie Hongbyung Ko. The drug's efficacy was ...
Eisai to Present New Clinical Data in Variety of Advanced Cancers at the ESMO 2017 CongressMarkets Insider

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Oncology admissions to the intensive care unit: what factors should influence the decision?

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A hyperacute neurology team - transforming emergency neurological care

We present the results of an 18-month study of a new model of how to care for emergency neurological admissions. We have established a hyperacute neurology team at a single district general hospital. Key features are a senior acute neurology nurse coordinator, an exclusively consultant-delivered service, acute epilepsy nurses, an acute neurophysiology service supported by neuroradiology and acute physicians and based within the acute medical admissions unit. Key improvements are a major increase in the number of patients seen, the speed with which they are seen and the percentage seen on acute medical unit before going to the general wards. We have shown a reduced length of stay and readmission rates for patients with epilepsy. Epilepsy accounted for 30% of all referrals. The cost implications of running this service are modest. We feel that this model is worthy of widespread consideration.

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The ageing population in healthcare: a challenge to, and in, the workforce

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A contemporary review of peripartum cardiomyopathy

Peripartum cardiomyopathy reflects the presence of cardiac failure in the absence of determinable heart disease and occurs in late third trimester of pregnancy or up to 6 months postpartum. A full understanding of pathophysiological mechanisms is lacking, but excess prolactin levels, haemodynamic alterations, inflammation and nutritional deficiencies have all been implicated. Its clinical presentation has distinct overlap with physiological alterations in healthy pregnancy and this presents a diagnostic challenge. However, echocardiography can provide significant benefit in accurate assessment and narrowing of differentials. Pharmacotherapy is broadly aligned with established guidelines for cardiac failure, but specific therapies are indicated for treatment of clinical sequelae. Moreover, an individualistic approach is required based on clinical context to manage delivery. Further research appears imperative to optimise management strategies and reduce disease burden.

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When laboratory tests can mislead even when they appear plausible

A laboratory test has three phases, pre-analytical, analytical and post-analytical. The purpose of this review is to highlight an issue concerning the analytical phase of one of the most widely deployed groups of in vitro diagnostic tests using a common technology – namely immunoassay.

Immunoassay entails an inherently high error rate and, therefore, has the potential for inaccurate and misleading results susceptible to misinterpretation and/or diagnostic misapplication by clinicians. An approach based on Bayesian inference (without mathematics or equations) – illustrated by examples – is presented; this may help clinicians in discerning potentially erroneous results even when they appear plausible and not unreasonable.

Essentially, false positive results are most likely to occur when the disease prevalence/incidence is low. False negative results become more prominent when the prevalence/incidence of disease increases. When concern is raised, available follow-up laboratory tests should be initiated to establish with confidence the diagnostic reliability or unreliability of such results.

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Imaging in Parkinsons disease

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The emergence of sarcopenia as an important entity in older people

Sarcopenia refers to the loss of muscle mass and strength seen with advancing age. The pathophysiology is multifactorial, with loss of muscle satellite cells, changes in hormonal systems, chronic inflammation, oxidative stress and anabolic resistance to protein utilisation all implicated. Older age, female sex and immobility are important risk factors. Sarcopenia is clinically important as it is a major risk factor for physical frailty, falls, prolonged hospitalisation, dependency and earlier death. Diagnosis requires evidence of reduced muscle mass measured by handgrip strength or walk speed, together with evidence of low muscle mass, measured by one of a variety of techniques such as bioimpedance analysis or dual X-ray absorptiometry. Resistance training is the only intervention of proven efficacy to treat sarcopenia, but a range of nutritional and pharmacological interventions are under test, including myostatin inhibitors, leucine and protein supplementation, angiotensin-converting enzyme inhibitors and allopurinol.

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Hypertension - state of the art 2017

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HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Purpose: Resistance to anti-HER2 therapies in HER2⁺ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2⁺ breast cancer can reactivate the HER network under potent HER2-targeted therapies.

Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER⁺/HER2⁺ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition.

Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2–irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo.

Conclusions: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. Clin Cancer Res; 23(17); 5123–34. ©2017 AACR.

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The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis

Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTC) and other cells to evaluate their potential prognostic value of prostate cancer.

Experimental Design: Malignancy of CTCs undergoing epithelial-to-mesenchymal transition (EMT) was confirmed by repeated FISH. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters. AUC analysis was applied to compare the performance for metastasis prediction between serum PSA level alone and a combined risk score using both PSA and EMTing CTC count. Circulating megakaryocytes and cancer patient survival association was performed using Cox model.

Results: The majority of vimentin (VIM)⁺/CD45^– cells were malignant, with genomic alterations in several genomic regions. The number of cytokeratin (CK)^–/VIM⁺/CD45^– CTCs correlated with disease burden, tumor aggressiveness, and poorer survival. Meanwhile, CK⁺/VIM⁺/CD45^– CTCs were associated with metastases better than other subtypes of CTCs in these limited samples. Combination of PSA level and the number of CK⁺/VIM⁺/CD45^– CTCs enhanced the prediction of cancer metastases [AUC, 0.921; 95% confidence interval (CI), 0.858–0.985]. The number of circulating megakaryocytes was potentially associated with good patient survival in advanced prostate cancer (HR, 0.849; 95% CI, 0.628–1.146, per cell increase), and the difference between the number of mesenchymal CTCs and megakaryocytes strongly correlated to poor survival (HR, 10.17; 95% CI, 2.164–47.789, if score ≥2.0).

Conclusions: This CTC analysis approach and the potential association of megakaryocytes with cancer prognosis may greatly enhance our ability to investigate the cancer metastasis process and to predict/monitor cancer progression. Clin Cancer Res; 23(17); 5112–22. ©2017 AACR.

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Retraction: Polymorphisms of the CYP1B1 Gene as Risk Factors for Human Renal Cell Cancer

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mTOR Pathway Mutations and Response to Rapalogs in RCC--Letter

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Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non–small cell lung cancer (NSCLC).

Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.

Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.

Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311–9. ©2017 AACR.

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Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer

Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.

Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.

Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.

Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS–mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267–80. ©2017 AACR.

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Can Microsatellite Status of Colorectal Cancer Be Reliably Assessed after Neoadjuvant Therapy?

Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, IHC of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on postneoadjuvant therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC.

Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and posttreatment specimens were compared. In parallel, 2 isogenic cell lines conditioned for MMR functioning and 2 different patient-derived xenografts (PDXs) were exposed to chemotherapy, radiation, or both. We also examined whether establishment of PDXs induced MSI changes in 5 tumors. IHC and MSI were tested after treatment to assess for changes.

Results: We identified paired pre- and posttreatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All 3 patients with PCR had microsatellite stable pre- and posttreatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and posttreatment specimens, 1 had equivocal MLH1 staining in the pretreatment and loss in the posttreatment specimen, and 4 had intact pretreatment MSH6 but variable posttreatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals.

Conclusions: Our findings show that the expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy. Clin Cancer Res; 23(17); 5246–54. ©2017 AACR.

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A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma

Purpose: While stereotactic body radiotherapy (SBRT) can reduce tumor volumes in patients with metastatic renal cell carcinoma (mRCC), little is known regarding the immunomodulatory effects of high-dose radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of patients with mRCC and analyze the immunological impact of high-dose radiation.

Experimental Design: Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, patients with mRCC were treated with 15 Gray SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T-cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930).

Results: RCC cells treated in vitro with radiation had increased TAA expression compared with untreated tumor cells. Fourteen patients received SBRT followed by surgery, and treatment was well-tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67⁺ -proliferating CD8⁺ T cells and FOXP3⁺ cells were increased in SBRT-treated patient specimens in tumors and at the tumor–stromal interface compared with archived patient specimens.

Conclusions: It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared with archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC. Clin Cancer Res; 23(17); 5055–65. ©2017 AACR.

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Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study

Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy.

Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care.

Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3⁺, CD3⁺/CD4⁺, and CD8⁺/CD28⁺ T-cell subsets were elevated (P < 0.05), while the CD3⁺/CD8⁺, CD3⁺/CD16⁺/CD56⁺ and CD4⁺/CD25⁺ cell subsets were significantly decreased after DC-CIK cell therapy (P < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival.

Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066–73. ©2017 AACR.

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Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF^V600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.

Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.

Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0–2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7–1.8; P = 0.66).

Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238–45. ©2017 AACR.

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Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum–derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.

Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.

Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.

Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074–81. ©2017 AACR.

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Genome-Wide Testing of Exonic Variants and Breast Cancer Risk in the California Teachers Study

Background: Few studies have focused on the relationship of exonic variation with breast cancer and subtypes defined by tumor markers: estrogen receptor (ER), progesterone receptor (PR), and HER2.

Methods: We genotyped 1,764 breast cancer patients and 1,400 controls from the California Teachers Study cohort using the Infinium HumanExome Beadchip. Individual variant and gene-based analyses were conducted for overall breast cancer and by individual tumor marker subtype.

Results: No exonic variants or gene-based analyses were statistically significantly associated with breast cancer overall or by ER-, PR-, or HER2-defined subtype.

Conclusions: We did not detect any novel statistically significant exonic variants with overall breast cancer risk or by subtype.

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Highlights of This Issue

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Opportunities and Challenges for Environmental Exposure Assessment in Population-Based Studies

A growing number and increasing diversity of factors are available for epidemiological studies. These measures provide new avenues for discovery and prevention, yet they also raise many challenges for adoption in epidemiological investigations. Here, we evaluate 1) designs to investigate diseases that consider heterogeneous and multidimensional indicators of exposure and behavior, 2) the implementation of numerous methods to capture indicators of exposure, and 3) the analytical methods required for discovery and validation. We find that case-control studies have provided insights into genetic susceptibility but are insufficient for characterizing complex effects of environmental factors on disease development. Prospective and two-phase designs are required but must balance extended data collection with follow-up of study participants. We discuss innovations in assessments including the microbiome; mass spectrometry and metabolomics; behavioral assessment; dietary, physical activity, and occupational exposure assessment; air pollution monitoring; and global positioning and individual sensors. We claim the the availability of extensive correlated data raises new challenges in disentangling specific exposures that influence cancer risk from among extensive and often correlated exposures. In conclusion, new high-dimensional exposure assessments offer many new opportunities for environmental assessment in cancer development. Cancer Epidemiol Biomarkers Prev; 26(9); 1370–80. ©2017 AACR.

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Quantifying the Genetic Correlation between Multiple Cancer Types

Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.

Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.

Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 x 10^–6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.

Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.

Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427–35. ©2017 AACR.

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Colorectal Cancer Screening: How Health Gains and Cost-Effectiveness Vary by Ethnic Group, the Impact on Health Inequalities, and the Optimal Age Range to Screen

Background: Screening programs consistently underserve indigenous populations despite a higher overall burden of cancer. In this study, we explore the likely health gains and cost-effectiveness of a national colorectal cancer screening program for the indigenous Māori population of New Zealand (NZ).

Methods: A Markov model estimated: health benefits (quality-adjusted life-year; QALY), costs, and cost-effectiveness of biennial immunochemical fecal occult blood testing (FOBTi) of 50- to 74-year-olds from 2011. Input parameters came from literature reviews, the NZ Bowel Screening Programme Pilot, and NZ linked health datasets. Equity analyses substituted non-Māori values for Māori values of background (noncolorectal cancer) morbidity and mortality, colorectal cancer survival and incidence, screening coverage, and stage-specific survival. We measured the change in "quality-adjusted life expectancy" (QALE) as a result of the intervention.

Results: Based upon a threshold of GDP per capita (NZ$45,000), colorectal cancer screening in NZ using FOBTi is cost-effective: NZ$2,930 (US$1,970) per QALY gained [95% uncertainty interval: cost saving to $6,850 (US$4,610)]. Modeled health gains per capita for Māori were less than for non-Māori: half for 50- to 54-year-olds (0.031 QALYs per person for Māori vs. 0.058 for non-Māori), and a fifth (0.003 c.f. 0.016) for 70- to 74-year-olds and ethnic inequalities in QALE increased with colorectal cancer screening.

Conclusions: Colorectal cancer screening in NZ using FOBTi is likely to be cost-effective but risks increasing inequalities in health for Māori.

Impact: To avoid or mitigate the generation of further health inequalities, attention should be given to underserved population groups when planning and implementing screening programs. Cancer Epidemiol Biomarkers Prev; 26(9); 1391–400. ©2017 AACR.

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The Impact of a Population-Based Screening Program on Income- and Immigration-Related Disparities in Colorectal Cancer Screening

Background: A population-based program promoting the Fecal Occult Blood Test (FOBT) for colorectal cancer screening was introduced in 2008 in Ontario, Canada, where opportunistic screening with colonoscopy had been increasing in frequency. We evaluated the impact of the program on income and immigration-related disparities in screening.

Methods: We used linked administrative data to calculate colorectal cancer screening rates for eligible Ontarians in each year between 2001/02 (n = 2,852,619) and 2013/14 (n = 4,139,304). We quantified disparities using an "inequality ratio" of screening rates in the most disadvantaged group relative to the most advantaged group. We performed segmented logistic regression analyses stratified by screening modality and adjusted for age, sex, rurality, comorbidity, and morbidity.

Results: Between 2001/02 and 2013/14, the income and immigration inequality ratios narrowed from 0.74 to 0.80 and 0.55 to 0.69, respectively. Before the screening program, the income inequality ratio was widening by 1% per year (95% CI 1% to 1%); in the year it was introduced, it narrowed by 4% (95% CI 2% to 7%) and in the years following, it remained stable [0% decrease (95% CI 1% decrease to 0% decrease) per year]. Results were similar for immigration-related disparities. After program introduction, disparities in receiving FOBT were narrowing at a faster rate while disparities in receiving colonoscopy were widening at a slower rate.

Conclusions: Introduction of a population-based screening program promoting FOBT for colorectal cancer was associated with only modest improvements in immigration and income-related disparities.

Impact: Reducing immigration and income-related disparities should be a focus for future research and policy work. Disparities in Ontario seem to be driven by a higher uptake of colonoscopy among more advantaged groups. Cancer Epidemiol Biomarkers Prev; 26(9); 1401–10. ©2017 AACR.

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No Association of Vitamin D Pathway Genetic Variants with Cancer Risks in a Population-Based Cohort of German Older Adults

Background: Several investigations assessed the association of vitamin D receptor (VDR) SNPs with cancer risk. Less is known about the implications of other vitamin D pathway SNPs on cancer risk.

Methods: In a population-based cohort study of 9,949 German older adults, we used Cox regression to assess the association of 6 SNPs in the VDR, vitamin D–binding protein (GC), 7-dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), and vitamin D 24-hydroxylase (CYP24A1) genes with total and site-specific cancer incidence endpoints.

Results: Overall, no association of SNPs with cancer incidence endpoints was observed, except for a genotype score based on SNPs associated with lower 25(OH)D, which was associated with higher lung cancer risk [HR, 1.20; 95% confidence intervals (CI), 1.03–1.39], although this was no longer significant after correcting for multiple testing.

Conclusions: Our data provide little to no evidence of a major influence of vitamin D genetic predisposition on cancer risks.

Impact: Large-scale genetic epidemiology consortia and meta-analysis of smaller published studies are needed to verify a potential modest influence of genetic variation in the association of vitamin D with the risk of cancer. Cancer Epidemiol Biomarkers Prev; 26(9); 1459–61. ©2017 AACR.

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Stool DNA Test of Methylated Syndecan-2 for the Early Detection of Colorectal Neoplasia

Background: Although the incidence of colorectal cancer is steadily increasing, screening for colorectal cancer with conventional approaches is not routinely performed in China. Noninvasive screening methods are attractive options to resolve this issue. Syndecan-2 (SDC2) is frequently methylated in colorectal cancer. However, the value of a stool test of methylated SDC2 for the detection of colorectal cancer is unknown.

Methods: Methylation status of SDC2 was tested in cell lines and 398 colorectal tissue samples and further evaluated with 497 stool samples, including 196 from colorectal cancer patients, 122 from adenoma patients, and 179 from normal individuals, using real-time methylation-specific PCR. The impacts of one quantitative partial stool sampling device and 17 potentially interfering substances on the performance of fecal methylated SDC2 were also analyzed. SDC2 expression was also measured.

Results: SDC2 methylation level was higher in 96.8% (120/124) of colorectal cancer tissues compared with paired adjacent normal epithelia. Stool test of methylated SDC2 detected 81.1% (159/196) of colorectal cancer and 58.2% (71/122) of adenomas at a specificity of 93.3% (167/179). No significant difference was found between partial and whole stool collection on colorectal cancer detection (P > 0.05, R² = 0.80). Among 17 interfering substances, only berberine at high concentrations inhibited fecal detection of methylated SDC2. SDC2 was overexpressed in colorectal cancer tissues compared with normal epithelia.

Conclusions: Fecal methylated SDC2 is a valuable biomarker for the noninvasive detection of colorectal neoplasms.

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Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study

Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival.

Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer–specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years.

Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86–1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77–1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80–1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations.

Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality.

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How Many Deaths from Colorectal Cancer Can Be Prevented by 2030? A Scenario-Based Quantification of Risk Factor Modification, Screening, and Treatment in Norway

Background: Colorectal cancer mortality can be reduced through risk factor modification (adherence to lifestyle recommendations), screening, and improved treatment. This study estimated the potential of these three strategies to modify colorectal cancer mortality rates in Norway.

Methods: The potential reduction in colorectal cancer mortality due to risk factor modification was estimated using the software Prevent, assuming that 50% of the population in Norway—who do not adhere to the various recommendations concerning prevention of smoking, physical activity, body weight, and intake of alcohol, red/processed meat, and fiber—started to follow the recommendations. The impact of screening was quantified assuming implementation of national flexible sigmoidoscopy screening with 50% attendance. The reduction in colorectal cancer mortality due to improved treatment was calculated assuming that 50% of the linear (positive) trend in colorectal cancer survival would continue to persist in future years.

Results: Risk factor modification would decrease colorectal cancer mortality by 11% (corresponding to 227 prevented deaths: 142 men, 85 women) by 2030. Screening and improved treatment in Norway would reduce colorectal cancer mortality by 7% (149 prevented deaths) and 12% (268 prevented deaths), respectively, by 2030. Overall, the combined effect of all three strategies would reduce colorectal cancer mortality by 27% (604 prevented deaths) by 2030.

Conclusions: Risk factor modification, screening, and treatment all have considerable potential to reduce colorectal cancer mortality by 2030, with the largest potential reduction observed for improved treatment and risk factor modification.

Impact: The estimation of these health impact measures provides useful information that can be applied in public health decision-making. Cancer Epidemiol Biomarkers Prev; 26(9); 1420–6. ©2017 AACR.

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Gestational Diabetes Mellitus and Incident Invasive Breast Cancer--Letter

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Retraction: Abstract 408: ACP-196, An Orally Bioavailable Covalent Selective Inhibitor of Btk, Modulates the Innate Tumor Microenvironment, Exhibits Antitumor Efficacy and Enhances Gemcitabine Activity in Pancreatic Cancer

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Proton Pump Inhibitor-related Mortality: Let Us Not Be Dead Wrong

We need to be very wary when research might be misinterpreted easily in ways that might scare patients and physicians away from appropriate medication use.

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Calendar Listings

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IKK{beta}-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

IKKβ (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-B pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor–protective role of IKKβ is independent of p53, but dependent on the activity of the Ink4a/Arf locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell–like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKβ activity prevents skin tumor development, and shed light on the complex nature of IKKβ effects on cancer progression, as IKKβ can both promote and prevent carcinogenesis depending on the cell type or molecular context.

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Instructions for Contributors

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PPAR{delta} Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC

The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator–activated receptor- (PPAR), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPAR, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPAR contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPAR activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPAR constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.

Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPAR in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230–42. ©2017 AACR.

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Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution

High-throughput genomic technologies have revealed a remarkably complex portrait of intratumor heterogeneity in cancer and have shown that tumors evolve through a reiterative process of genetic diversification and clonal selection. This discovery has challenged the classical paradigm of clonal dominance and brought attention to subclonal tumor cell populations that contribute to the cancer phenotype. Dynamic evolutionary models may explain how these populations grow within the ecosystem of tissues, including linear, branching, neutral, and punctuated patterns. Recent evidence in breast cancer favors branching and punctuated evolution driven by genome instability as well as nongenetic sources of heterogeneity, such as epigenetic variation, hierarchal tumor cell organization, and subclonal cell–cell interactions. Resolution of the full mutational landscape of tumors could help reconstruct their phylogenetic trees and trace the subclonal origins of therapeutic resistance, relapsed disease, and distant metastases, the major causes of cancer-related mortality. Real-time assessment of the tumor subclonal architecture, however, remains limited by the high rate of errors produced by most genome-wide sequencing methods as well as the practical difficulties associated with serial tumor genotyping in patients. This review focuses on novel approaches to mitigate these challenges using bulk tumor, liquid biopsies, single-cell analysis, and deep sequencing techniques. The origins of intratumor heterogeneity and the clinical, diagnostic, and therapeutic consequences in breast cancer are also explored. Mol Cancer Res; 15(9); 1127–37. ©2017 AACR.

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The Landscape of Isoform Switches in Human Cancers

Alternative usage of transcript isoforms from the same gene has been hypothesized as an important feature in cancers. However, differential usage of gene transcripts between conditions (isoform switching) has not been comprehensively characterized in and across cancer types. To this end, we developed methods for identification and visualization of isoform switches with predicted functional consequences. Using these methods, we characterized isoform switching in RNA-seq data from >5,500 cancer patients covering 12 solid cancer types. Isoform switches with potential functional consequences were common, affecting approximately 19% of multiple transcript genes. Among these, isoform switches leading to loss of DNA sequence encoding protein domains were more frequent than expected, particularly in pancancer switches. We identified several isoform switches as powerful biomarkers: 31 switches were highly predictive of patient survival independent of cancer types. Our data constitute an important resource for cancer researchers, available through interactive web tools. Moreover, our methods, available as an R package, enable systematic analysis of isoform switches from other RNA-seq datasets.

Implications: This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level. Mol Cancer Res; 15(9); 1206–20. ©2017 AACR.

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Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (ELANE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells in vitro. IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33⁺ MDSCs.

Implications: This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138–52. ©2017 AACR.

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Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody

Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG₁ anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro. In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor–background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 μg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 μg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans.

Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153–62. ©2017 AACR.

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Highlights of This Issue

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Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether ⁶⁸Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with ⁶⁸Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether ⁶⁸Ga-citrate can detect MYC-positive prostate cancer. Importantly, ⁶⁸Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with ⁶⁸Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that ⁶⁸Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of ⁶⁸Ga-citrate for tumors with hyperactive MYC.

Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

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Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19^Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.

Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173–83. ©2017 AACR.

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KITD816V Induces SRC-Mediated Tyrosine Phosphorylation of MITF and Altered Transcription Program in Melanoma

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KIT^D816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KIT^D816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KIT^D816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KIT^D816V transformed cells.

Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KIT^D816V, can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265–74. ©2017 AACR.

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Huannao Yicong Decoction (还脑益聪方) extract reduces inflammation and cell apoptosis in Aβ 1-42 -induced Alzheimer's disease model of rats

Abstract

Objective

Huannao Yicong Decoction (还脑益聪方, HYD), an effective herbal formula against Alzheimer's disease (AD), has been proven to have neuroprotective action in amyloid β-protein_1-42 (Aβ_1-42)-induced rat model. This study was designed to characterize mechanisms by which HYD leads to suppression of inflflammation and apoptosis in the brains of Aβ_1-42-induced rat.

Methods

A total of 72 rats were divided into 6 groups, which were referred to as: sham operation group, model group, donepezil-treated group, HYD low-dose group (HYDL), HYD middle-dose group (HYDM) and HYD high-dose group (HYDH). Rats in HYDL, HYDM and HYDH were injected with Aβ_1-42 at the CA1 region of hippocampus to form AD model and were fed the HYD extract at different dose of 3.78, 7.56 and 18.90 g crude drug/kg. The behavioral changes of rats were evaluated by Morris water maze (MWM) before sacrififice. Pathological changes of the brain tissue were evaluated using hematoxylin eosin (HE) staining. The levels of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) were measured by radioimmunoassay. The levels of Aβ and proteins that are associated with apoptosis such as B-cell lymphoma-2 protein (Bcl-2), Bcl-2-associated X protein (Bax), cysteine-aspartic protease (caspase)-3, -8, -9 and -12 in serum were measured by immunohistochemistry.

Results

Compared with the sham operation group, the spatial learning and memory abilities of AD rats were signifificantly decreased (P<0.05 or P<0.01; Expressions of IL-1, TNF-α, Aβ and apoptosis-signaling proteins caspase-3, -8, -9, -12 were signifificantly up-regulated (P<0.05 or P<0.01). The ratio of Bcl-2 to Bax were signifificantly decreased in the model group (P<0.01). When treated with HYD extract, the spatial learning and memory abilities of AD-model rats were significantly increased (P<0.05 or P<0.01), IL-1, TNF-α, Aβ, caspase-3, -8, -9 and -12 were down-regulated (P<0.05 or P<0.01), and the ratio of Bcl-2 to Bax were reduced (P<0.05 or P<0.01).

Conclusions

HYD extract can improve the learning and memory ability defificits, alleviate the inflflammatory response and pathological manifestations induced by Aβ_1-42 injection in the rat model of AD. HYD down-regulates the levels of IL-1, TNF-α and Aβ, and decreases the rate of apoptosis by modulating apoptosis-signaling-related proteins such as caspase-3, -8, -9, and -12.

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Effect of Qingfei Mixture (清肺合剂) on pediatric mycoplasma pneumoniae pneumonia with phlegm heat obstructing Fei (Lung) syndrome

Abstract

Objective

To explore the effect and mechanism of Qingfei Mixture (清肺合剂), a Chinese medicine, in treating mycoplasma pneumonia (MP) in MP patients and rat model

Methods

A total of 46 MP children with phlegm heat obstructing Fei (Lung) syndrome were randomly assigned to two groups by the method of random number table, with 23 children in each group. The control group was treated with intravenous infusion of azithromycin; the treatment group received intravenous infusion of azithromycin and oral administration of Qingfei Mixture. The treatment course was 7 days. Major symptoms and minor symptoms were observed and scored before and after treatments. A rat model of MP was also established. A total of 120 wistar rats were randomly divided into 5 groups: a normal group, infection group, Qingfei Mixture treatment group, azithromycin treatment group, and Qingfei Mixture + azithromycin treatment group. Each group contained 24 rats, from which every 6 were euthanatized 1, 3, 7 and 14 days after infection. MP DNA in pulmonary tissue homogenates was detected using real-time fluorescence quantitative polymerase chain reaction. Pathology was assessed after hematoxylin (HE) staining and lung tissue pathology scores were determined in pulmonary tissue. Transmission electron microscopic detection and electronic image analysis were performed on lung tissue 3 days after infection. Interleukin (IL)-17 was detected in serum using enzymelinked immunosorbent assay (ELISA) 7 days after infection.

Results

In the clinical study, both control and the treatment group showed improved results on removing symptoms of phlegm heat syndrome compared to the control group (P<0.05). In animal experiments, On the 7th day after MP infection, as detected by electron microscopy, the pulmonary capillary basement membranes of the azithromycin + Qingfei Mixture treatment group were much thinner than those of the azithromycin or Qingfei mixture treatment groups (P<0.05). The level of serum IL-17 in the azithromycin + Qingfei Mixture treatment group was lower than that in the azithromycin or Qingfei Mixture groups (P<0.01).

Conclusion

Both Qingfei Mixture and azithromycin have therapeutic effects on mycoplasma pneumoniae pneumonia, but the combination of both agents had the greatest effect.

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Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-κB inhibition

Abstract

Objective

To examine the effects of the combination of quercetin (Q), cinnamaldehyde (C) and hirudin (H), a Chinese medicine formula on high glucose (HG)-induced apoptosis of cultured dorsal root ganglion (DRG) neurons.

Methods

DRG neurons exposed to HG (45 mmol/L) for 24 h were employed as an in vitro model of diabetic neuropathy. Cell viability, reactive oxygen species (ROS) level and apoptosis were determined. The expression of nuclear factor of Kappa B (NF-κB), inhibitory kappa Bα(IκBα), phosphorylated IκBα and Nf-E2 related factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. The expression of hemeoxygenase-1 (HO-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and caspase-3 were also examined by RT-PCR and Western blot assay.

Results

HG treatment markedly increased DRG neuron apoptosis via increasing intracellular ROS level and activating the NF-κB signaling pathway (P<0.05). Co-treatment with Q, C, H and their combination decreased HG-induced caspase-3 activation and apoptosis (P<0.05 or P<0.01). The expressions of NF-κB, IL-6 and TNF-α were down-regulated, and Nrf2/HO-1 expression was up-regulated (P<0.05 or P<0.01). QCH has better effect in scavenging ROS, activating Nrf-2/HO-1, and down-regulating the NF-κB pathway than other treatment group.

Conclusions

DRG neurons' apoptosis was increased in diabetic conditions, which was reduced by QCH formula treatment. The possible reason could be activating Nrf-2/HO-1 pathway, scavenging ROS, and inhibition of NF-κB activation. The effect of QCH combination was better than each monomer or the combination of the two monomers.

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Huannao Yicong Decoction (还脑益聪方) extract reduces inflammation and cell apoptosis in Aβ 1-42 -induced Alzheimer's disease model of rats

Abstract

Objective

Methods

Results

Conclusions

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Insights of Chinese medicine on ventricular remodeling: Multiple-targets, individualized-treatment

Abstract

Ventricular remodeling (VR) can be induced by myocardial injury, leading to progressive cardiac dysfunction and heart failure, and is associated with high morbidity and mortality. Despite being studied for more than 3 decades, current therapeutic strategies still remain unsatisfactory in effificacy, expensive, and with side effects and drug resistances. Chinese medicine (CM) has been used to treat heart diseases for thousands of years. This article reviews the published studies on the mechanisms and therapeutic applications of CM in VR. The major aspects include: mechanistic studies of VR, molecular biology and myocardial functional studies of CM therapies on VR, and mechanism of CM therapies on VR.

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Effect of Qingfei Mixture (清肺合剂) on pediatric mycoplasma pneumoniae pneumonia with phlegm heat obstructing Fei (Lung) syndrome

Abstract

Objective

To explore the effect and mechanism of Qingfei Mixture (清肺合剂), a Chinese medicine, in treating mycoplasma pneumonia (MP) in MP patients and rat model

Methods

Results

Conclusion

Both Qingfei Mixture and azithromycin have therapeutic effects on mycoplasma pneumoniae pneumonia, but the combination of both agents had the greatest effect.

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Red yeast rice prevents atherosclerosis through regulating inflammatory signaling pathways

Abstract

Objective

To observe the effects of red yeast rice (RYR) on blood lipid levels, aortic atherosclerosis (AS), and plaque stability in apolipoprotein E gene knockout (ApoE-/-) mice.

Methods

Twenty-four ApoE-/- mice were fed with a high-fat diet starting from 6 weeks of age. Mice were randomized into three groups (n = 8 in each group): model group (ApoE-/- group), RYR group (ApoE-/- + RYR group), and simvastatin group (ApoE-/- + simvastatin group). Eight 6-week-old C57BL/6 mice were assigned as the control group and fed with a basic diet. After 36 weeks, plasma lipids and inflflammatory factors were measured. Aortic atherosclerotic lesions by microscope, scanning electron microscope and transmission electron microscope were observed. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured with enzyme-linked immunosorbent assay. The level of high sensitivity C-reaction protein (Hs-CRP) was detected by the scattering immunoturbidimetric assay. Protein expression of matrix metalloproteinase-9 (MMP-9) and nuclear factor κB (NF-κB) in aorta were tested by immunohistochemistry.

Results

Compared with the model group, treatment with RYR significantly decreased the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, lipoprotein (a), and apolipoprotein B100 in ApoE-/- mice (P<0.01). Compared with the model group, treatment with RYR decreased the levels of Hs-CRP, IL-6, and TNF-α (P<0.01). RYR also reduced the protein levels of NF-κB and MMP-9 of the aorta.

Conclusions

RYR has the anti-atherosclerotic and stabilizing unstable plaque effects. The mechanism might be related to the inflflammatory signaling pathways.

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Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-κB inhibition

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Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis

Due to the presence of both classical estrogen receptor (ERα) and another ER subtype (ERβ) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is mod...

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NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity

N-acetyltransferase 10 (NAT10) is a histone acetyltransferase which is involved in a wide range of cellular processes. Recent evidences indicate that NAT10 is involved in the development of human cancers. Prev...

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Identification of predictive markers of the therapeutic effect of eribulin chemotherapy for locally advanced or metastatic breast cancer

The recently developed reagent, eribulin mesylate (eribulin), is a microtubule dynamics inhibitor with a mechanism of action that differs from those of taxanes and vinca alkaloids. This drug is considered to b...

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Development of quality indicators for non-small cell lung cancer care: a first step toward assessing and improving quality of cancer care in China

Large gap exists between clinical practice and recommended care and large room exists for the improvement of care quality for non-small cell lung cancer (NSCLC) in China. Results of some studies have shown tha...

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Frequency modulation: The likelihood of floods is changing with the climate

Print section Print Rubric: Centuries ain't what they used to be Print Headline: Frequency modulation Print Fly Title: The chances of disaster UK Only Article: standard article Issue: How government policy exacerbates hurricanes like Harvey Fly Title: Frequency modulation IN 1979 it was Claudette; in 2001 it was Allison; now it is Harvey: in 50 years, the city of Houston has been hit by three separate "500-year floods". A 500-year flood does not have to happen only twice a millennium. But a run of three in one place does make it feel as if the past climate were no longer a reliable guide to the present—as if the climate itself were changing. So, of course, it is. The world's average temperature is between 0.6 and 0.7°C (1.1- 1.3°F) higher than it was in 1979. Scientists have understood since the 1850s that hotter air holds more water vapour; a law known as the Clausius-Clapeyron equation states that for every degree Celsius of ...

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Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa

Abstract

Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide.

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Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease [Research]

Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (LE) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. In this study, we performed comparative proteomic profiling of the response of NPC1I1061T fibroblasts to Vorinostat. After stringent statistical criteria to filter identified proteins, we observed 202 proteins that are differentially expressed in Vorinostat-treated fibroblasts. These proteins are members of diverse cellular pathways including the endomembrane dependent protein folding-stability-degradation-trafficking axis, energy metabolism, and lipid metabolism. Our study shows that treatment of NPC1I1061T fibroblasts with Vorinostat not only enhances pathways promoting the folding, stabilization and trafficking of NPC1 (I1061T) mutant to the LE/Ly, but alters the expression of lysosomal proteins, specifically the lysosomal acid lipase (LIPA) involved in the LIPA->NPC2->NPC1 based flow of cholesterol from the LE/Ly lumen to the LE/Ly membrane. We posit that the Vorinostat may modulate numerous pathways that operate in an integrated fashion through epigenetic and post-translational modifications reflecting acetylation/deacetylation balance to help manage the defective NPC1 fold, the function of the LE/Ly system and/or additional cholesterol metabolism/distribution pathways, that could globally contribute to improved mitigation of NPC1 disease in the clinic based on as yet uncharacterized principles of cellular metabolism dictating cholesterol homeostasis.

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Impact of dysfunction of the facial nerve after superficial parotidectomy: a prospective study

Publication date: Available online 31 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): V.E. Prats-Golczer, E. Gonzalez-Cardero, J.A. Exposito-Tirado, E. Montes-Latorre, L.M. Gonzalez-Perez, P. Infante-Cossio
To evaluate the impact of dysfunction of the facial nerve after superficial parotidectomy for pleomorphic adenoma of the superficial lobe, we prospectively analysed the data of 79 patients using the Facial Disability Index (FDI) and the Short-Form 36-Item (SF-36) questionnaires up to 12 months postoperatively. The function of the facial nerve was grading on the House-Brackmann Scale. Results at 1 week and 1, 3, 6, and 12 months were compared with preoperative (baseline) measurement. The maximum reduction in FDI scores coincided with the highest facial paresis values at one week. Physical values on the FDI significantly decreased during the first three months (p=.039 at 3 months) and psychosocial values improved significantly from then onwards (p=.001 at 12 months). At 12 months, there were signs of full recovery compared with the preoperative baseline, and it was even exceeded in some psychosocial items. The SF-36 questionnaire showed no significant differences at any time during the study. The FDI was a useful instrument with which to understand the impact of facial disability and wellbeing associated with physical, social, and emotional aspects after superficial parotidectomy. Unlike the SF-36 questionnaire, the FDI offers clinicians a tool with which to counsel patients and better inform them about the anticipated results of operation before superficial parotidectomy.

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Analysis of DNA binding by human factor xeroderma pigmentosum complementation group A (XPA) provides insight into its interactions with nucleotide excision repair substrates [Molecular Bases of Disease]

Xeroderma pigmentosum (XP) complementation group A (XPA) is an essential scaffolding protein in the multi-protein nucleotide excision repair (NER) machinery. The interaction of XPA with DNA is a core function of this protein; a number of mutations in the DNA binding domain (DBD) are associated with XP disease. Although structures of the central globular domain of human XPA and data on binding of DNA substrates have been reported, the structural basis for XPAs DNA binding activity remains unknown. X-ray crystal structures of the central globular domain of yeast XPA (Rad14) with lesion-containing DNA duplexes have provided valuable insights, but the DNA substrates used for this study do not correspond to the substrates of XPA as it functions within the NER machinery. To better understand the DNA binding activity of human XPA in NER, we used NMR to investigate the interaction of its DBD with a range of DNA substrates. We found that XPA binds different single-stranded/double-stranded junction DNA substrates with a common surface. Comparisons of our NMR based mapping of binding residues with the previously reported Rad14-DNA crystal structures revealed similarities and differences in substrate binding between XPA and Rad14. This includes direct evidence for DNA contacts to the residues extending C-terminally from the globular core, which are lacking in the Rad14 construct. Moreover, mutation of the XPA residue corresponding to Phe-262 in Rad14, previously reported as being critical for DNA binding, had only a moderate effect on the DNA binding activity of XPA. The DNA binding properties of several disease-associated mutations in the DBD were investigated. These results suggest that for XPA mutants exhibiting altered DNA binding properties, a correlation exists between the extent of reduction in DNA binding affinity and the severity of symptoms in XP patients.

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Heat shock protein 47 and 65 KDa FK506 binding protein weakly but synergistically interact during collagen folding in the endoplasmic reticulum [Protein Structure and Folding]

Collagen is the most abundant protein in the extracellular matrix in humans and is critical to the integrity and function of many musculoskeletal tissues. A molecular ensemble comprising more than twenty molecules is involved in collagen biosynthesis in the rough endoplasmic reticulum (rER). Two proteins, Heat shock protein 47 (Hsp47/SERPINH1) and 65 KDa FK506 binding protein (FKBP65/FKBP10) have been shown to play important roles in this ensemble. In humans, autosomal recessive mutations in both genes cause similar Osteogenesis Imperfecta (OI) phenotypes. While it has been proposed that Hsp47 and FKBP65 interact in the rER, there is neither clear evidence for this interaction nor any data regarding their binding affinities for each other. In this study, using purified endogenous proteins, we examined the interaction between Hsp47, FKBP65 and collagen and also determined their binding affinities and functions in vitro. Hsp47 and FKBP65 show a direct but weak interaction and FKBP65 prefers to interact with Hsp47 rather than type I collagen. Our results suggest that a weak interaction between Hsp47 and FKBP65 confers mutual molecular stability and also allows for a synergistic effect during collagen folding. We also propose that Hsp47 likely acts as a hub molecule during collagen folding and secretion by directing other molecules to reach their target sites on collagens. Our findings may explain why OI-causing mutations in both genes result in similar phenotypes.

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Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation [Methods and Resources]

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders such as cancer, fibrosis, immune dysregulation and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9 or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis (EAE) model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

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Conformational dynamics as a key factor of signaling mediated by the receiver domain of sensor histidine kinase from Arabidopsis thaliana [Plant Biology]

Multistep phosphorelay (MSP) cascades mediate responses to a wide spectrum of stimuli, including plant hormonal signaling, but several aspects of MSP await elucidation. Here, we provide first insight into the key step of MSP-mediated phosphotransfer in a eukaryotic system, the phosphorylation of the receiver domain of the histidine kinase CYTOKININ INDEPENDENT 1 (CKI1RD) from Arabidopsis thaliana. We observed that the crystal structures of free, Mg2+-bound, and beryllofluoridated CKI1RD (a stable analog of the labile phosphorylated form) were identical and similar to the active state of receiver domains of bacterial response regulators. However, the three CKI1RD variants exhibited different conformational dynamics in solution. NMR studies revealed that Mg2+ binding and beryllofluoridation alter the conformational equilibrium of the β3-α3 loop close to the phosphorylation site. Mutations that perturbed the conformational behavior of the β3-α3 loop while keeping the active site aspartate intact resulted in suppression of CKI1 function. Mechanistically, homology modeling indicated that the β3-α3 loop directly interacts with the ATP-binding site of the CKI1 histidine kinase domain. The functional relevance of the conformational dynamics observed in the β3-α3 loop of CKI1RD was supported by a comparison with another A. thaliana histidine kinase, ETR1. In contrast to the highly dynamic β3-α3 loop of CKI1RD, the corresponding loop of the ETR1 receiver domain (ETR1RD) exhibited little conformational exchange and adopted a different orientation in crystals. Biochemical data indicated that ETR1RD is involved in phosphorylation-independent signaling, implying a direct link between conformational behavior and the ability of eukaryotic receiver domains to participate in MSP.

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Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production [Metabolism]

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in blood and brain, and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10, but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with those of Slc30a10 single knockouts. Compared with wildtype controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain, but not the liver. In contrast, Slc30a10 single knockouts had elevated manganese in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and had normal thyroid function. Moreover, intra-thyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

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Structure-functional insights into the interaction between the Cas family scaffolding protein p130Cas and the focal adhesion-associated protein paxillin [Protein Structure and Folding]

The CAs family scaffolding 130Cas is a Src substrate localized in focal adhesions (FAs) and functions in integrin signaling to promote cell motility, invasion, proliferation, and survival. P130Cas targeting to FAs is essential for its tyrosine phosphorylation and downstream signaling. Although the N-terminal SH3 domain is important for p130Cas localization, it has also been reported that the C-terminal region is involved in p130Cas FA targeting. The Cterminal region of p130Cas or Cas family homology domain (CCHD), has been reported to adopt a structure similar to that of the focal adhesion kinase (FAK) C-terminal focal adhesion targeting (FAT) domain. The mechanism by which the CCHD promotes FA targeting of p130Cas, however, remains unclear. In this study, using a calorimetry approach, we identified the first LD motif (LD1) of the FA-associated protein paxillin as the binding partner of the p130Cas CCHD (in a 1:1 stoichiometry with a Kd ~4.2 μM) and elucidated the structure of the p130Cas CCHD in complex with the paxillin LD1 motif by Xray crystallography. Of note, a comparison of the CCHD/LD1 complex with a previously solved structure of CCHD in complex with the SH2-containing protein NSP3 revealed that LD1 had almost identical positioning of key hydrophobic and acidic residues relative to NSP3. Because paxillin is one of the key scaffold molecules in FAs, we propose that the interaction between the p130Cas CCHD and the LD1 motif of paxillin plays an important role in p130Cas FA targeting.

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The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein (FADD). [Genomics and Proteomics]

The inhibition of host innate immunity pathways is essential for the persistence of attaching and effacing (A/E) pathogens such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium during mammalian infections. To subvert these pathways and suppress the antimicrobial response, A/E pathogens use type III secretion systems (T3SS) to introduce effectors targeting key signaling pathways in host cells. One such effector is the arginine glycosyltransferase NleB1 (NleBCR in C. rodentium) that modifies conserved arginine residues in death domain-containing host proteins with N-acetylglucosamine (GlcNAc), thereby blocking extrinsic apoptosis signaling. Ectopically expressed NleB1 modifies the host proteins Fas-associated via death domain (FADD), TNFRSF1A-associated via death domain (TRADD), and receptor-interacting serine/threonine kinase 1 (RIPK1). However, the full repertoire of arginine-GlcNAcylation induced by pathogen-delivered NleB1 is unknown. Using an affinity proteomic approach for measuring arginine-GlcNAcylated glycopeptides, we assessed the global profile of arginine-GlcNAcylation during ectopic expression of NleB1, EPEC infection in vitro, or C. rodentium infection in vivo. NleB overexpression resulted in arginine-GlcNAcylation of multiple host proteins. However, NleB delivery during EPEC and C. rodentium infection caused rapid and preferential modification of Arg-117 in FADD. This FADD modification was extremely stable and insensitive to physiological temperatures, glycosidase activies or host cell degradation. Despite its stability and effect on the inhibition of apoptosis, arginine-GlcNAcylation did not elicit any proteomic changes, even in response to prolonged NleB1 expression. We conclude that at normal levels of expression during bacterial infection, NleB1/NleBCR antagonizes death receptor-induced apoptosis of infected cells by modifying FADD in an irreversible manner.

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Αρχειοθήκη ιστολογίου

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Πέμπτη 31 Αυγούστου 2017

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