Improving Antimicrobial Stewardship in Cancer Patients Through Implementation of Clinical Guidelines

Abstract

Purpose of review Antimicrobial stewardship programs have consistently demonstrated the ability to reduce excessive antibiotic utilization, improve the management of targeted diseases, improve outcomes, and reduce costs. Implementation of institutional guidelines are effective options to promote appropriate cost-effective antimicrobial utilization and are recommended by the Infectious Diseases Society of America and the U.S. Centers for Disease Control and Prevention. Cancer patients are frequent users of antimicrobials and present unique challenges for antimicrobial stewardship programs, due to high risk for infection and risk for opportunistic infection and infection with multi-drug-resistant pathogens. Thus, this review evaluates the impact of guidelines on antibiotic management and associated clinical outcomes in cancer patients.

Recent findings This review demonstrates that antibiotic stewardship guidelines targeting cancer patients can improve suboptimal or delayed antimicrobial prescribing and lead to subsequent reductions in mortality and decreased length of hospitalization. Additionally, guideline implementation can reduce excessive durations of unnecessary antimicrobial therapy without adversely impacting clinical outcomes.

Summary Implementation of antibiotic stewardship guidelines could be an effective tool to promote appropriate antibiotic prescribing and reduce unnecessary antibiotic utilization in cancer patients.

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Quorum sensing activity of the plant growth-promoting rhizobacterium Serratia glossinae GS2 isolated from the sesame ( Sesamum indicum L.) rhizosphere

Abstract

Plant growth-promoting rhizobacteria (PGPR) affect plant growth through various mechanisms, such as indole-3-acetic acid (IAA) production, 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activity, and biofilm formation. The aim of the study reported here was to isolate and characterize rhizobacteria that produce quorum-sensing signal molecules and other PGPR-related molecules. A biofilm-forming bacterium, GS2, was isolated from the rhizosphere of a sesame plant and subsequently found to produce two quorum-sensing signal molecules that were identified as N-hexanoyl-L-homoserine lactone (m/z 200) and N-octanoyl-L-homoserine lactone (m/z 228) by liquid chromatography–tandem mass spectrometry analysis. The strain was also found to produce IAA (17.2 μg mL⁻¹), gibberellins (113.7 μg mL⁻¹), and ACC deaminase (9.7 μM α-ketobutyrate mg⁻¹ protein h⁻¹). The strain was identified as Serratia glossinae based on a comparison of 16S rRNA gene sequences. Inoculation of the strain promoted growth of a gibberellin-deficient rice dwarf mutant (Waito-C). Different growth attributes, including shoot and root elongation, chlorophyll content, and plant weight could be attributed to the PGPR characteristics of strain GS2. These results suggest that S. glossinae strain GS2 can serve as a microbial agent that improves plant growth.

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Issue Information

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PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison

Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.

Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.

Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R² = 0.81–0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R² > 0.78, all clones).

Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938–44. ©2017 AACR.

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Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

Purpose: To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors.

Experimental Design: Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.

Results: Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild-type tumors and represented TETs enriched in expression of genes associated with T-cell signaling (TS group; 33%). The remaining two groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.

Conclusions: Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging and in the discovery and development of rational treatment options for patients with TETs. Clin Cancer Res; 23(16); 4855–64. ©2017 AACR.

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Molecular Pathways: Targeting the Protein Kinase Wee1 in Cancer

Wee1 is a protein kinase that regulates the G₂ checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G₂ into mitosis. There are two mechanisms by which the G₂ checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G₂ checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G₂ checkpoint. AZD1775 (formerly MK-1775) is a small-molecule, pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging antitumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents. Promising combination schedules are being investigated at the moment, for example, combining PARP inhibition and Wee1 inhibition. Also, a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the antitumor effect. Clin Cancer Res; 23(16); 4540–4. ©2017 AACR.

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Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.

Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.

Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.

Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." Clin Cancer Res; 23(16); 4805–16. ©2017 AACR.

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In Vivo Detection of EGFRvIII in Glioblastoma via Perfusion Magnetic Resonance Imaging Signature Consistent with Deep Peritumoral Infiltration: The {varphi}-Index

Purpose: The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma noninvasively, using routine clinically acquired imaging.

Experimental Design: We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of -index in preoperative perfusion scans of independent discovery (n = 64) and validation (n = 78) cohorts, revealed the generalizability of this EGFRvIII imaging signature.

Results: Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%), and sensitive (83.77%), with significantly distinctive ability (P = 4.0033 x 10^–10, AUC = 0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII⁺ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII^– tumors displayed perfusion dynamics consistent with peritumorally confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation.

Conclusions: This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders -index potentially resistant to inter-scanner variations. Overall, our findings enable noninvasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation. Clin Cancer Res; 23(16); 4724–34. ©2017 AACR.

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Clinical Pathways: Recommendations for Putting Patients at the Center of Value-Based Care

Two major trends that have been affecting the provision of oncology care in the United States are a shift from volume-based to value-based care and a push toward patient-centered healthcare. However, these two trends are not always completely aligned with each other. Value-based payment models, including clinical pathways, are one strategy being implemented by oncology stakeholders to help encourage the uptake of value-based oncology care. If structured with the patient in mind, they can improve quality of care for patients with cancer, decrease inappropriate care while enabling appropriate personalization of care, and constrain rising prices by demanding a stronger link between cost and value. If not structured appropriately, they can limit patient choice, impede access to innovative treatments, and encourage one-size-fits-all oncology care. Clin Cancer Res; 23(16); 4545–9. ©2017 AACR.

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Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T-cell Infiltration

Purpose: A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non–small cell lung carcinoma (NSCLC) following intratumoral administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen–specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222).

Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10⁶, 5 x 10⁶, 1 x 10⁷, or 3 x 10⁷ DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen–specific peripheral blood lymphocyte induction of IFN in ELISPOT assays. Tumor biopsies were evaluated for CD8⁺ T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).

Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor-associated antigens (TAA). Tumor CD8⁺ T-cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8⁺ T cells per mm²). Patients with increased CD8⁺ T cells following vaccination showed significantly increased PD-L1 mRNA expression.

Conclusions: Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen–specific immune responses; (ii) enhanced tumor CD8⁺ T-cell infiltration; and (iii) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination. Clin Cancer Res; 23(16); 4556–68. ©2017 AACR.

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Histone Deacetylase Inhibitor Enhances the Efficacy of MEK Inhibitor through NOXA-Mediated MCL1 Degradation in Triple-Negative and Inflammatory Breast Cancer

Purpose: Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative breast cancer (TNBC), diagnosed by molecular receptor status, are the two most aggressive forms of breast cancer, and both lack effective targeted therapies. We previously demonstrated involvement of histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis in IBC and TNBC cells; here, we aimed to identify novel combination therapy candidates.

Experimental Design: Potential therapeutic targets were identified by mRNA expression profiling of TNBC and IBC cells treated with entinostat. Drug action and synergism were assessed by in vitro proliferation assays, tumor growth in vivo, and proteomic analyses. Gain/loss-of-expression studies were utilized to functionally validate the role of identified targets in sensitivity of TNBC and IBC cells to combination therapy.

Results: Entinostat induced activity of the oncogenic ERK pathway and expression of proapoptotic NOXA. These are known to stabilize and degrade, respectively, MCL1, an antiapoptotic Bcl-2 protein. In breast cancer patients, high-MCL1/low-NOXA tumor expression correlated significantly with poor survival outcomes. Combination treatment of entinostat with MEK inhibitor pimasertib reduced the growth of TNBC and IBC cells in vitro and inhibited tumor growth in vivo. The synergistic action of combination therapy was observed in TNBC and IBC cell lines in which NOXA expression was induced following entinostat treatment. The therapeutic activity depended on induction of mitochondrial cell death pathways initiated by NOXA-mediated MCL1 degradation.

Conclusions: Our preclinical findings provide a rationale for the clinical testing of combination HDAC and MEK pathway inhibition for TNBC and IBC that exhibit elevated baseline tumor MCL1 expression. Clin Cancer Res; 23(16); 4780–92. ©2017 AACR.

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Intra- and Interobserver Reproducibility Assessment of PD-L1 Biomarker in Non-Small Cell Lung Cancer

Purpose: Reliable and reproducible methods for identifying PD-L1 expression on tumor cells are necessary to identify responders to anti–PD-1 therapy. We tested the reproducibility of the assessment of PD-L1 expression in non–small cell lung cancer (NSCLC) tissue samples by pathologists.

Experimental Design: NSCLC samples were stained with PD-L1 22C3 pharmDx kit using the Dako Autostainer Link 48 Platform. Two sample sets of 60 samples each were designed to assess inter- and intraobserver reproducibility considering two cut points for positivity: 1% or 50% of PD-L1 stained tumor cells. A randomization process was used to obtain equal distribution of PD-L1 positive and negative samples within each sample set. Ten pathologists were randomly assigned to two subgroups. Subgroup 1 analyzed all samples on two consecutive days. Subgroup 2 performed the same assessments, except they received a 1-hour training session prior to the second assessment.

Results: For intraobserver reproducibility, the overall percent agreement (OPA) was 89.7% [95% confidence interval (CI), 85.7–92.6] for the 1% cut point and 91.3% (95% CI, 87.6–94.0) for the 50% cut point. For interobserver reproducibility, OPA was 84.2% (95% CI, 82.8–85.5) for the 1% cut point and 81.9% (95% CI, 80.4–83.3) for the 50% cut point, and Cohen's coefficients were 0.68 (95% CI, 0.65–0.71) and 0.58 (95% CI, 0.55–0.62), respectively. The training was found to have no or very little impact on intra- or interobserver reproducibility.

Conclusions: Pathologists reported good reproducibility at both 1% and 50% cut points. More adapted training could potentially increase reliability, in particular for samples with PD-L1 proportion, scores around 50%. Clin Cancer Res; 23(16); 4569–77. ©2017 AACR.

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Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-{kappa}B Pathway in Melanoma

Purpose: Abnormal activation of the NF-B pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-B activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-B pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.

Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-B, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.

Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-B1 p105 into p50, thereby modulating NF-B target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r –0.455; P < 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).

Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-B pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831–42. ©2017 AACR.

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Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer

Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment.

Experimental Design: We evaluated under blinded conditions the ability of cell-free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab.

Results: Prior to treatment, sequencing of archival tissue detected mutations in 25 of 42 patients (60%), while the cfDNA assay detected mutations in 37 of 42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41 of 42 patients (98%) had a cfDNA-detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild-type tumors at baseline, 4 of 5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.

Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had preexisting mutations in the pathway, demonstrating a convergent evolutionary pattern. Clin Cancer Res; 23(16); 4578–91. ©2017 AACR.

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Whole-Exome Sequencing of Metaplastic Breast Carcinoma Indicates Monoclonality with Associated Ductal Carcinoma Component

Purpose: Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor, and HER-2 amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions.

Experimental Design: We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in 8 patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments.

Results: In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence.

Conclusions: A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers. Clin Cancer Res; 23(16); 4875–84. ©2017 AACR.

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Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer

Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.

Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes.

Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05).

Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592–601. ©2017 AACR.

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Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K–AKT–mTOR pathway is associated with specific sites of breast cancer metastasis.

Experimental Design: Next-generation sequencing–based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K–AKT–mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K–AKT–mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.

Results: PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.

Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K–AKT–mTOR signaling network. Clin Cancer Res; 23(16); 4919–28. ©2017 AACR.

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Highlights from Recent Cancer Literature

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Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA

Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. Cancer Res; 77(16); 4207–16. ©2017 AACR.

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A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD–positive and –negative AML patients and as maintenance therapy. To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR-pooled library to screen new genes whose loss of function confers resistance to AC220. We identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated reactivation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to AC220. We confirmed these findings in primary AML patient samples. Expression of SPRY3 and GSK3A was dramatically reduced in AC220-resistant AML samples, and SPRY3-deleted primary AML cells were resistant to AC220. Intriguingly, expression of SPRY3 was greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function conferred resistance to a selective FLT3 inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in AML. Cancer Res; 77(16); 4402–13. ©2017 AACR.

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MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma

Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.

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Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. Cancer Res; 77(16); 4228–37. ©2017 AACR.

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Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells

GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a phase I clinical study. Expression of human GITR was comparable with that of mouse GITR in tumor-infiltrating Tregs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of Tregs in vitro. In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating Tregs, suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the Treg-mediated suppressive tumor microenvironment. Cancer Res; 77(16); 4378–88. ©2017 AACR.

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Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNF{alpha} Treatment

Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNFα, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. Cancer Res; 77(16); 4426–33. ©2017 AACR.

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RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression

African American (AA) men exhibit a relatively high incidence and mortality due to prostate cancer even after adjustment for socioeconomic factors, but the biological basis for this disparity is unclear. Here, we identify a novel region on chromosome 4p16.3 that is lost selectively in AA prostate cancer. The negative regulator of G-protein signaling RGS12 was defined as the target of 4p16.3 deletions, although it has not been implicated previously as a tumor-suppressor gene. RGS12 transcript levels were relatively reduced in AA prostate cancer, and prostate cancer cell lines showed decreased RGS12 expression relative to benign prostate epithelial cells. Notably, RGS12 exhibited potent tumor-suppressor activity in prostate cancer and prostate epithelial cell lines in vitro and in vivo. We found that RGS12 expression correlated negatively with the oncogene MNX1 and regulated its expression in vitro and in vivo. Further, MNX1 was regulated by AKT activity, and RGS12 expression decreased total and activated AKT levels. Our findings identify RGS12 as a candidate tumor-suppressor gene in AA prostate cancer, which acts by decreasing expression of AKT and MNX1, establishing a novel oncogenic axis in this disparate disease setting. Cancer Res; 77(16); 4247–57. ©2017 AACR.

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Heme-oxygenase-1 Production by Intestinal CX3CR1+ Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis

CX3CR1+ macrophages in the intestinal lamina propria contribute to gut homeostasis through the immunomodulatory interleukin IL10, but there is little knowledge on how these cells or the CX3CR1 receptor may affect colorectal carcinogenesis. In this study, we show that CX3CR1-deficient mice fail to resolve gut inflammation despite high production of IL10 and have increased colitis and adenomatous polyps in chemical and genetic models of colon carcinogenesis. Mechanistically, CX3CL1-mediated engagement of the CX3CR1 receptor induced upregulation of heme-oxygenase-1 (HMOX-1), an antioxidant and anti-inflammatory enzyme. CX3CR1-deficient mice exhibited significantly lower expression of HMOX-1 in their adenomatous colon tissues. Combining LPS and CX3CL1 displayed a strong synergistic effect in vitro, but HMOX-1 levels were significantly lower in KO macrophages. Cohousing of wild-type and CX3CR1−/− mice during the AOM/DSS treatment attenuated disease severity in CX3CR1−/− mice, indicating the importance of the microbiome, but did not fully reinstate HMOX-1 levels and did not abolish polyp formation. In contrast, pharmacologic induction of HMOX-1 in vivo by cobalt protoporphyrin-IX treatment eradicated intestinal inflammation and fully protected KO mice from carcinogenesis. Taken together, our results establish an essential role for the receptor CX3CR1 in gut macrophages in resolving inflammation in the intestine, where it helps protects against colitis-associated cancer by regulating HMOX-1 expression. Cancer Res; 77(16); 4472–85. ©2017 AACR.

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Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case–control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D–XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D–XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517–29. ©2017 AACR.

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EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268–78. ©2017 AACR.

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Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365–77. ©2017 AACR.

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Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279–92. ©2017 AACR.

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Normal and Malignant Cells Exhibit Differential Responses to Calcium Electroporation

Calcium electroporation may offer a simple general tool for anticancer therapy. Transient permeabilization of cancer cell membranes created by applying short, high-voltage pulses in tumors enables high calcium influxes that trigger cell death. In this study, we compared the relative sensitivity of different human tumor models and normal tissues to calcium electroporation. Plasma membrane Ca2+-ATPase (PMCA) protein expression was confirmed in vitro in all cancer cell lines and normal primary dermal fibroblasts studied. In all tumor types tested in vivo, calcium electroporation effectively induced necrosis, with a range of sensitivities observed (36%–88%) 2 days after treatment. Necrosis was induced using calcium concentrations of 100–500 mmol/L and injection volumes 20%–80% of tumor volume. Notably, only limited effects were seen in normal tissue. Calcium content increased >7-fold in tumor and skin tissue after calcium electroporation but decreased in skin tissue 4 hours after treatment to levels comparable with untreated controls, whereas calcium content endured at high levels in tumor tissue. Mechanistic experiments in vitro indicated that calcium influx was similar in fibroblasts and cancer cells. However, we observed decreased PMCA expression in cancer cells compared with fibroblasts, offering a potential explanation for the different calcium content in tumor cells versus normal tissues. Overall, our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues. Cancer Res; 77(16); 4389–401. ©2017 AACR.

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Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells

Tumor-initiating cells (TIC) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation, and metastasis. Here we report that SRC-3 supports the TIC/CSC state and induces an epithelial-to-mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small-molecule inhibitor, targets the CSC/TIC population both in vitro and in vivo. Collectively, these results identify SRC coactivators as regulators of stem-like capacity in cancer cells and that these coactivators can serve as potential therapeutic targets to prevent the recurrence of cancer. Cancer Res; 77(16); 4293–304. ©2017 AACR.

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Cyclospora infection

Cyclospora infection: Infection with Cyclospora cayetanensis, a single-celled parasite. The first known human cases of illness caused by Cyclospora were reported in 1979. More recently, outbreaks of cyclosporiasis have been reported in the US and Canada. Cyclospora is spread by people ingesting water or food that was contaminated with infected stool. Outbreaks of cyclosporiasis have been linked to various types of fresh produce. People of all ages are at risk for the infection. The time between becoming infected and becoming sick is usually about 1 week. Cyclospora infects the small intestine (bowel) and usually causes watery diarrhea, with frequent, sometimes explosive, bowel movements. Other symptoms can include loss of appetite, substantial loss of weight, bloating, increased gas, stomach cramps, nausea, vomiting, muscle aches, low-grade fever, and fatigue. If not treated, the illness may last from a few days to a month or longer. Symptoms may seem to go away and then return one or more times (relapse).

Identification of this parasite in stool requires special laboratory tests that are not routinely done. The recommended treatment for infection with Cyclospora is a combination of two antibiotics, trimethoprim-sulfamethoxazole, also known as Bactrim, Septra, or Cotrim. People who have diarrhea should rest and drink plenty of fluids. Avoiding water or food that may be contaminated with stool may help prevent Cyclospora infection. People who have previously been infected with Cyclospora can become infected again.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Pernambuco index: predictability of the complexity of surgery for impacted lower third molars

This study aimed to develop and validate an index of surgical difficulty for the removal of impacted lower third molars. The study was performed in two steps. The first was a cross-sectional analysis of clinical, demographic, and radiographic variables collected from patients undergoing the removal of an impacted lower third molar between 2008 and 2012. The second step was a prospective cohort study involving the same surgical procedures to validate the index; this was performed between 2013 and 2016.

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The expression of endogenous hydrogen sulfide signal during distraction osteogenesis in a rabbit model

The hydrogen sulfide (H2S) signal system plays an important role in bone metabolism. However, the role of endogenous H2S during distraction osteogenesis (DO) remains unclear. Sixty-two male New Zealand White rabbits were subjected to right mandibular DO. Before distraction, the animals were divided randomly into two groups: group A, 0.5mm twice/day for 10 days; group B, 1.25mm twice/day for 4 days. Plasma and distraction gap tissue were harvested to determine the H2S signal. The osteogenesis effect was also evaluated.

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Dr. Weiss Discusses Prevention in Head and Neck Cancer - OncLive

OncLive

Dr. Weiss Discusses Prevention in Head and Neck Cancer OncLive This abstract showed that the HPV vaccine appears extremely effective in the strains of oropharyngeal infection that cause head and neck cancer. Additionally, Weiss said, it showed the low rate of vaccinations—a fact of which should be widely ... and more »

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Trapezoidal mandibular osteotomy for augmentation of the airway in sleep apnoea

Trapezoidal osteotomy is indicated for patients with severe obstructive sleep apnoea for whom it is necessary to advance the genial muscles without altering the facial profile. The use of prototyped surgical guides ensures precision by limiting the size of the osteotomy to avoid damage to anatomical structures. They provide a better prognosis, more predictable outcomes, lower morbidity, and shorter operating time.1–5

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Use of buccal cortex as interpositional graft in mandibular setbacks

The most commonly used options for mandibular fixation after sagittal split ramus osteotomy (SSRO) are monocortical plates and bicortical screws, which have comparable stability.1 We have recently changed our practice to the routine use of bicortical screws where possible, particularly for mandibular setbacks. They are faster to place and need to be removed less often than miniplates.2

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Moving Toward a Universal Digital Era in Mass Casualty Incidents and Disasters: Emergency Personnel's Perspective in Romania

Telemedicine and e-Health , Vol. 0, No. 0.


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Three-Dimensional Bioprinting of Polycaprolactone Reinforced Gene Activated Bioinks for Bone Tissue Engineering

Tissue Engineering Part A , Vol. 0, No. 0.


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Biomineralized Recombinant Collagen-Based Scaffold Mimicking Native Bone Enhances Mesenchymal Stem Cell Interaction and Differentiation

Tissue Engineering Part A , Vol. 0, No. 0.


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Cancer Took Most of His Tongue, but This Pastor Is Still Singing God's Praise - CBN News

CBN News

Cancer Took Most of His Tongue, but This Pastor Is Still Singing God's Praise CBN News ... he lost 60 percent of his tongue. "I was told I might never sing again, speak again, or even walk again," he wrote in a Facebook post. "These Walls" is an original song Pastor David wrote and it became his anthem as he fought cancer for more than a ...

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Development of a new Rasch-based scoring algorithm for the National Eye Institute Visual Functioning Questionnaire to improve its interpretability

The NEI VFQ-25 has undergone psychometric evaluation in patients with varying ocular conditions and the general population. However, important limitations which may affect the interpretation of clinical trial ...

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Health-related quality of life in the Brazilian Amazon: a population-based cross-sectional study

To analyze perceptions of health-related quality of life and associated factors in populations from the Manaus Metropolitan Region.

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One-step nucleic acid amplification assay is an accurate technique for sentinel lymph node biopsy of breast cancer patients: a meta-analysis

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Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

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Comprehensive geriatric assessment in 326 older women with early breast cancer

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Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

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Structural analyses of the bacterial primosomal protein DnaB reveal that it is a tetramer and forms a complex with a primosomal re-initiation protein [Protein Structure and Folding]

The DnaB primosomal protein from Gram-positive bacteria plays a key role in DNA replication and restart as a loader protein for the recruitment of replisome cascade proteins. Previous investigations have established that DnaB is composed of an N-terminal domain, a middle domain, and a C-terminal domain. However, structural evidence for how DnaB functions at the atomic level is lacking. Here, we report the crystal structure of DnaB, encompassing the N-terminal and middle domains (residues 1-300), from Geobacillus stearothermophilus (GstDnaB1-300) at 2.8 Å resolution. Our structure revealed that GstDnaB1-300 forms a tetramer with two basket-like architecture, a finding s consistent with those from solution studies using analytical ultracentrifugation. Furthermore, our results from both GST pull-down assays and analytical ultracentrifugation show that GstDnaB1-300 is sufficient to form a complex with PriA, the primosomal re-initiation protein. Moreover, with the aid of small angle X-ray scattering (SAXS) experiments, we also determined the structural envelope of full-length DnaB (GstDnaBFL) in solution. These SAXS studies indicated that GstDnaBFL has an elongated conformation and that the protruding density envelopes originating from GstDnaB1-300 could completely accommodate the GstDnaB C-terminal domain (residues 301-461) . Taken together with biochemical assays, our results suggest that GstDnaB uses different domains to distinguish the PriA-interaction and ssDNA-binding. This finding can further extend our understanding of primosomal assembly in replication restart.

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Ablating TBC1D1 impairs contraction-induced sarcolemmal glucose transporter type 4 redistribution, but not insulin-mediated responses in rats [Metabolism]

TBC1 domain family member 1 (TBC1D1), a Rab GTPase-activating protein and paralogue of Akt substrate of 160 kDa (AS160), has been implicated in both insulin- and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (AICAR)-mediated glucose transporter type (GLUT4) translocation. However, the role of TBC1D1 in contracting muscle remains ambiguous. We therefore explored the metabolic consequence of ablating TBC1D1 in both resting and contracting skeletal muscles, utilizing a rat TBC1D1-KO model. While insulin administration rapidly increased (p<0.05) plasma membrane GLUT4 content in both red (RG) and white gastrocnemius (WG) muscles, the TBC1D1 ablation did not alter this response, nor did it affect whole-body insulin tolerance, suggesting that TBC1D1 is not required for insulin-induced GLUT4 trafficking events. Consistent with findings in other models of altered TBC1D1 protein levels, whole-animal and ex vivo skeletal muscle fat oxidation was increased in the TBC1D1-KO rats. While there was no change in mitochondrial content in the KO rats, maximal ADP-stimulated respiration was higher in permeabilized muscle fibers, which may contribute to the increased reliance on fatty acids in resting KO animals. Despite this increase in mitochondrial oxidative capacity, run time to exhaustion at various intensities was impaired in the KO rats. Moreover, contraction-induced increases in sarcolemmal GLUT4 content and glucose uptake were lower in the WG of the KO animals. Altogether, our results highlight a critical role for TBC1D1 in exercise tolerance and contraction-mediated translocation of GLUT4 to the plasma membrane in skeletal muscle.

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Linchpin DNA-binding residues serve as go/no-go controls in the replication factor C-catalyzed clamp loading mechanism [Enzymology]

DNA polymerases depend on circular sliding clamps for processive replication. Clamps must be loaded onto primer-template DNA (ptDNA) by clamp loaders that open and close clamps around ptDNA in an ATP-fueled reaction. All clamp loaders share a core structure in which five subunits form a spiral chamber that binds the clamp at its base in a twisted open form and encloses ptDNA within, while binding and hydrolyzing ATP to topologically link the clamp and ptDNA. To understand how clamp loaders perform this complex task, here we focused on conserved arginines that might play a central coordinating role in the mechanism, since they can alternately contact ptDNA or Walker B glutamate in the ATPase site, and lie close to the clamp loader-clamp binding interface. We mutated Arg-84, Arg-88 and Arg-101 in the ATPase-active B, C, and D subunits of Saccharomyces cerevisiae replication factor C (RFC) clamp loader, respectively, and assessed the impact on multiple transient events in the reaction: proliferating cell nuclear antigen (PCNA) clamp binding/opening/ closure/release, ptDNA binding/release, and ATP hydrolysis/product release. The results show that these arginines relay critical information between the PCNA-binding, DNA-binding and ATPase sites at all steps of the reaction, particularly at a checkpoint before RFC commits to ATP hydrolysis. Moreover, their actions are subunit-specific, with RFC-C Arg-88 serving as an accelerator that enables rapid ATP hydrolysis upon contact with ptDNA, and RFC-D Arg-101 serving as a brake that confers specificity for ptDNA as the correct substrate for loading PCNA.

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AKidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation [Genomics and Proteomics]

The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D3 to its hormonal form, 1,25(OH)2D3, occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH)2D3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1. We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by local factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfill separate functional roles: first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease.

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The human RNA-binding protein and E3 ligase MEX-3C binds the MEX-3-recognition element (MRE) motif with high affinity [RNA]

MEX-3 is a KH domain−containing RNA-binding protein, first identified as a translational repressor in Caenorhabditis elegans, while its four orthologs (MEX-3A−D) in human and mouse were subsequently found to have E3 ubiquitin ligase activity mediated by a RING domain and critical for RNA degradation. Current evidence implicates human MEX-3C in many essential biological processes and suggests a strong connection with immune diseases and carcinogenesis. The highly conserved dual KH domains in MEX-3 proteins enable RNA binding and are essential for the recognition of the 3' UTR and posttranscriptional regulation of MEX-3 target transcripts. However, the molecular mechanisms of translational repression and the consensus RNA sequence recognized by the MEX-3C KH domain are unknown. Here, using X-ray crystallography and isothermal titration calorimetry, we investigated the RNA-binding activity and selectivity of human MEX-3C dual KH domains. Our high-resolution crystal structures of individual KH domains complexed with a noncanonical U-rich and a GA-rich RNA sequences revealed that the KH1/2 domains of hMEX-3C bound MRE10, a 10-mer RNA (5'-CAGAGUUUAG-3') consisting of an eight-nucleotide MEX-3−recognition element (MRE) motif, with high affinity. Of note, we also identified a consensus RNA motif recognized by human MEX-3C. The potential RNA-binding sites in the 3' UTR of the human leukocyte antigen serotype (HLA-A2) mRNA were mapped with this RNA-binding motif and were further confirmed by fluorescence polarization. The binding motif identified here will provide valuable information for future investigations of the functional pathways controlled by human MEX-3C and for predicting potential mRNAs regulated by this enzyme.

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Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes [Cell Biology]

ATP-binding cassette subfamily B member 10 (Abcb10) is a mitochondrial ABC transporter that complexes with mitoferrin1 and ferrochelatase to enhance heme biosynthesis in developing red blood cells. Reductions in Abcb10 levels have been shown to reduce mitoferrin1 protein levels and iron import into mitochondria resulting in reduced heme biosynthesis. As an ABC transporter, Abcb10 binds and hydrolyzes ATP, but its transported substrate is unknown. Here, we determined that decreases in Abcb10 did not result in protoporphyrin IX accumulation in morphant treated zebrafish embryos nor in differentiated Abcb10-specific shRNA murine Friend erythroleukemia (MEL) cells in which Abcb10 was specifically silenced with shRNA. We also found that the ATPase activity of Abcb10 is necessary for hemoglobinization in MEL cells, suggesting that the substrate transported by Abcb10 is important in mediating increased heme biosynthesis during erythroid development. Inhibition of 5-aminolevulinic acid dehydratase (ALA-D, EC 4.2.1.24) with succinylacetone resulted in both ALA accumulation in control and Abcb10-specific shRNA MEL cells, demonstrating that reductions in Abcb10 do not affect ALA export from mitochondria and indicating that Abcb10 does not transport ALA. Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1, which could be partially rescued by overexpression of Alas2 or Gata1, providing a mechanistic explanation for why Abcb10-shRNA MEL cells exhibit reduced hemoblobinization. In conclusion, our findings rule out that Abcb10 transports ALA and indicate that Abcb10 ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization.

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Dynamin-dependent amino acid endocytosis activates mechanistic target of rapamycin complex 1 (mTORC1) [Signal Transduction]

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis and potential target for modifying cellular metabolism in various conditions, including cancer and aging. mTORC1 activity is tightly regulated by the availability of extracellular amino acids, and previous studies have revealed that amino acids in the extracellular fluid are transported to the lysosomal lumen. There, amino acids induce recruitment of cytoplasmic mTORC1 to the lysosome by the Rag GTPases, followed by mTORC1 activation by the small GTPase Ras homolog enriched in brain (Rheb). However, how the extracellular amino acids reach the lysosomal lumen and activate mTORC1 remains unclear. Here, we show that amino acid uptake by dynamin-dependent endocytosis plays a critical role in mTORC1 activation. We found that mTORC1 is inactivated when endocytosis is inhibited by overexpression of a dominant-negative form of dynamin 2 or by pharmacological inhibition of dynamin or clathrin. Consistently, the recruitment of mTORC1 to the lysosome was suppressed by the dynamin inhibition. The activity and lysosomal recruitment of mTORC1 were rescued by increasing intracellular amino acids via cycloheximide exposure or by Rag overexpression, indicating that amino acid deprivation is the main cause of mTORC1 inactivation via the dynamin inhibition. We further show that endocytosis inhibition does not induce autophagy even though mTORC1 inactivation is known to strongly induce autophagy. These findings open new perspectives for the use of endocytosis inhibitors as potential agents that can effectively inhibit nutrient utilization and shut down the upstream signals that activate mTORC1.

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The crystal structure of full-length Sizzled from Xenopus laevis yields insights into Wnt-antagonistic function of secreted frizzled-related proteins [Signal Transduction]

The Wnt signaling pathway is crucial to cell proliferation, differentiation and migration. The secreted frizzled-related proteins (sFRPs) represent the largest family of secreted Wnt inhibitors. However, their function in antagonizing Wnt signaling has remained somewhat controversial. Here we report the crystal structure of Sizzled from Xenopus laevis, the first full-length structure of an sFRP. Tethered by an inter-domain disulfide bond and a linker, the N-terminal CRD domain and the C-terminal NTR domain of Sizzled are arranged in a tandem fashion, with the NTR domain occluding the groove of CRD for Wnt accessibility. A dual-luciferase assay demonstrated that removing the NTR domain and replacing the CRD groove residues H116 and H118 with aromatic residues may significantly enhance antagonistic function of Sizzled in inhibiting Wnt3A signaling. Sizzled is a monomer in solution and Sizzled CRD exhibited different packing in the crystal, suggesting that sFRPs do not have a conserved CRD dimerization mode. Distinct from the canonical NTR domain, the Sizzled NTR adopts a novel α/β folding with two perpendicular helices facing the central mixed β-sheet. The subgroup of human sFRP1/2/5 and Sizzled should have a similar NTR domain that features a highly positively charged region, opposite the NTR-CDR interface, suggesting that the NTR domain in human sFRPs, at least sFRP1/2/5, is unlikely to bind to Wnt, but likely involved in biphasic Wnt signaling modulation. In summary, the Sizzled structure provides the first insights into how the CRD and the NTR domains relate to each other for modulating Wnt antagonistic function of sFRPs.

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A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis [Research]

The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody-induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.—Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.

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Amyloid-{beta} and islet amyloid pathologies link Alzheimer disease and type 2 diabetes in a transgenic model [Research]

Alzheimer's disease (AD) and type 2 diabetes (T2D) present a significant risk to each other. AD and T2D are characterized by deposition of cerebral amyloid-β (Aβ) and pancreatic human islet amyloid polypeptide (hIAPP), respectively. We investigated the role of amyloidogenic proteins in the interplay between these diseases. A novel double transgenic mouse model combining T2D and AD was generated and characterized. AD-related amyloid transgenic mice coexpressing hIAPP displayed peripheral insulin resistance, hyperglycemia, and glucose intolerance. Aβ and IAPP amyloid co-deposition increased tau phosphorylation, and a reduction in pancreatic β-cell mass was detected in islets. Increased brain Aβ deposition and tau phosphorylation and reduced insulin levels and signaling were accompanied by extensive synaptic loss and decreased neuronal counts. Aβ immunization rescued the peripheral insulin resistance and hyperglycemia, suggesting a role for Aβ in T2D pathogenesis for individuals predisposed to AD. These findings demonstrate that Aβ and IAPP are key factors in the overlapping pathologies of AD and T2D.—Wijesekara, N., Ahrens, R., Sabale, M., Wu, L., Ha, K., Verdile, G., Fraser, P. E. Amyloid-β and islet amyloid pathologies link Alzheimer disease and type 2 diabetes in a transgenic model.

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Low versus high radioiodine activity for ablation of the thyroid remnant after thyroidectomy in Han Chinese with low ... - Dove Medical Press

Low versus high radioiodine activity for ablation of the thyroid remnant after thyroidectomy in Han Chinese with low ... Dove Medical Press Aim: The aim of this study was to compare the efficacy and adverse effects of radioiodine (131I) therapy between two groups of patients with low-risk differentiated thyroid cancer (DTC) who received 30 mCi or 100 mCi radioiodine for ablation of the ...

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Systemic LPS resulted in a transient hippocampus malfunction but a prolonged corpus callosum injury

To investigate the effect of systemic lipopolysaccharide (LPS) on function of hippocampus and corpus callosum (CC) in adult rats.

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Chromatin-associated protein SIN3B prevents prostate cancer progression by inducing senescence.

Distinguishing between indolent and aggressive prostate adenocarcinoma (PCa) remains a priority to accurately identify patients who need therapeutic intervention. SIN3B has been implicated in the initiation of senescence in vitro. Here we show that in a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression. SIN3B was required for PTEN-induced cellular senescence and prevented progression to invasive PCa. Furthermore, SIN3B was downregulated in human PCa correlating with upregulation of its target genes. Our results suggest a tumor suppressor function for SIN3B that limits PCa progression, with potential implications for the use of SIN3B and its target genes as candidate diagnostic markers to distinguish indolent from aggressive disease.

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Nuclear FAK and Runx1 cooperate to regulate IGFBP3, cell cycle progression and tumor growth

Nuclear focal adhesion kinase (FAK) is a potentially important regulator of gene expression in cancer, impacting both cellular function and the composition of the surrounding tumor microenvironment. Here we report in a murine model of skin squamous cell carcinoma (SCC) that nuclear FAK regulates Runx1-dependent transcription of insulin-like growth factor binding protein 3 (IGFBP3), and that this regulates SCC cell cycle progression and tumor growth in vivo. Furthermore, we identified a novel molecular complex between FAK and Runx1 in the nucleus of SCC cells and showed that FAK interacted with a number of Runx1 regulatory proteins, including Sin3a and other epigenetic modifiers known to alter Runx1 transcriptional function through post-translational modification. These findings provide important new insights into the role of FAK as a scaffolding protein in molecular complexes that regulate gene transcription.<br />

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Mitotic vulnerability in triple-negative breast cancer associated with LIN9 is targetable with BET inhibitors

Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. While BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks a SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi.

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The Rac GTPase in cancer: from old concepts to new paradigms

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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PRC2-mediated transcriptomic alterations at the embryonic stage govern tumorigenesis and clinical outcome in MYCN-driven neuroblastoma

Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed in vitro sphere formation, derepressed its target genes and suppressed in situ tumor growth. In clinical specimens, expression of MYC and PRC2 target genes correlated strongly and predicted survival outcomes. Together, our findings highlighted PRC2-mediated transcriptional control during embryogenesis as a critical step in the development and clinical outcome of neuroblastoma.

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S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma

Glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast to previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target.

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HNF1B loss exacerbates the development of chromophobe renal cell carcinomas

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell cycle checkpoint proteins RB1 and p27. Further, it altered the chromatin accessibility of Mad2l1, Bub1b and Rb1 genes and triggered aneuploidy development. Analysis of the TCGA database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC.

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Genomic alterations in circulating tumor DNA from diverse cancer patients identified by next-generation sequencing

Non-invasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort

of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers.

The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%) or lung (20.7%). ctDNA obtained from most patients (N = 423 (63%)) displayed at least 1 alteration. The most frequent alterations seen, as characterized mutations or variations of unknown significance, occurred in TP53 (32.5% of patients), EGFR (13%), KRAS (12.5%) and PIK3CA (9.1%); for characterized alterations, 30.7% (TP53), 7.6% (EGFR), 12.2% (KRAS), and 7.7% (PIK3CA). We found that 32% of brain tumors had at least 1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations in a multivariable analysis (P=0.019). Notably, 320/670 (48%) of patients displayed potentially actionable alterations with 241 patients possible candidates for on-label or off-label treatment with an FDA-approved drug. Several illustrations of the clinical utility of the information obtained for improving treatment of specific patients is provided. Our findings demonstrate the feasibility and impact of genomic profiling of tumors by ctDNA next-generation sequencing, greatly encouraging broader investigations of the application of this technology for precision medicine in cancer management.

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URMC receives $770K in grant funding - Monroe County Post

URMC receives $770K in grant funding Monroe County Post Severe loss of salivary gland function is an outcome of radiation therapy for more than 550,000 patients annually diagnosed with throat and neck cancers worldwide. The funding will to be used to research and develop a drug that would prevent radiation ...

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Even ‘healthy’ overweight people have a higher cardiac risk

Being overweight or obese is linked to coronary heart disease and heart attacks even when a person has healthy blood pressure, blood sugar, and cholesterol

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Bowel cancer deaths frop by a third in 20 years

The rate of people dying from bowel cancer in the UK has plummeted by more than 30 per cent in the last 20 years, according to new figures released today by Cancer Research UK. Bowel cancer was responsible for 38 deaths per 100,000 people in 1995,...

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Even ‘healthy’ overweight people have a higher cardiac risk

Being overweight or obese is linked to coronary heart disease and heart attacks even when a person has healthy blood pressure, blood sugar, and cholesterol

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A rare case of transvesical cesarean section

Sunil Kumar Juneja, Pooja Tandon, Bakul Kochhar, Harman Deep Singh, Bhanupriya Sharma

International Journal of Applied and Basic Medical Research 2017 7(3):205-206

Cesarean section, also commonly known as C-section, is a surgical procedure in which incision is made through a mother's abdomen and uterus to deliver one or more babies. According to urgency, they are classified either as elective or emergency. According to technique, they have been classified as classical, lower uterine segment and cesarean hysterectomy. Intentional transvesical cesarean though not a routinely practiced technique is used for delivery in women born with imperforate anus, ectopic intravaginal urethra, vaginal and urethral strictures, and bladder adherent completely over the uterus. Since such cases are very rare, we are reporting one such case of transvesical cesarean section.

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Hashimoto's encephalitis: Rare manifestation of hypothyroidism

Manish Gutch, Annesh Bhattacharjee, Sukriti Kumar, Durgesh Pushkar

International Journal of Applied and Basic Medical Research 2017 7(3):193-195

Hashimoto's encephalitis is a rare, heterogeneous and completely treatable form of neuroendocrine disorder manifesting with seizures, stroke-like episodes, encephalopathy, dementia and variable neuropsychiatric manifestations. It is generally associated with a background of Hashimoto's Thyroiditis, and the patient has high titers of antithyroid antibodies, especially antithyroid peroxidase antibodies. This entity responds dramatically to corticosteroids, hence should be always considered and excluded while treating a patient with encephalopathy in the background of a thyroid disease.

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Insulin resistance: Quest for surrogate markers

Rajiv Mahajan

International Journal of Applied and Basic Medical Research 2017 7(3):149-149



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Congenital cyst adenoid malformation masquerading as bronchial asthma

Jagdish Prasad Goyal, Shishir Jindal, Mayank Mishra, Bhanu Kiran Bhakhri

International Journal of Applied and Basic Medical Research 2017 7(3):199-201

Congenital cyst adenoid malformation (CCAM) is a rare congenital malformation occurring in approximately 1–4 in 100,000 births. It is classified into five subtypes with type 1 CCAM is most common subtype. The diagnosis of CCAM is usually made in infancy, and it is rare in adolescents and adults. We report a 15-year-old female, who presented in pediatric outpatient department with a history of recurrent cough since infancy. On the basis of clinical examination, provisional diagnosis of asthma was considered and patient was started on inhaled corticosteroid and long-term β2 agonist. Lung function of the patient revealed low forced expiratory volume-1 s but without bronchodilator reversibility. Therefore, alternative diagnosis was suspected, and the patient was further evaluated with X-ray chest and high resolution computed tomography thorax. Based on radiological findings, a final diagnosis of CCAM was established. The case was highly unusual due to its atypical and late age of presentation. Acquaintance about this condition benefit clinician in making differential diagnosis of recurrent cough.

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Novel cardiovascular risk markers in Nigerian cigarette smokers

Godwin O Adunmo, AbdulFatah Ayoade Adesokan, Olufemi Olumuyiwa Desalu, Sikiru Abayomi Biliaminu, Eyitayo O Adunmo

International Journal of Applied and Basic Medical Research 2017 7(3):160-164

Background: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. While the effect of cigarette smoking on conventional markers that account for <50% of CVD s has been well studied, there are only a few studies on the effect of cigarette smoking on novel cardiovascular (CV) risk markers. Objective: To evaluate the effect of cigarette smoking on the novel CV markers such as homocysteine (HCY), lipoprotein (a) (Lp(a)), and C-reactive protein (CRP). Materials and Methods: One hundred and forty smokers, 12 ex-smokers, and 84 controls were recruited for the study. A structured questionnaire was used to obtain information on their clinical history, daily cigarette consumption, and duration of smoking. The smokers were further grouped according to the amount of cigarette consumption: light (<5 sticks/day), moderate (6–10 sticks/day), and heavy (>10 sticks/day) and duration of smoking: short (5–10 years), medium (11–20 years), and long (>20 years). HCY was determined by enzyme-linked immunosorbent assay method, and Lp(a) and CRP were determined spectrophotometrically. Results: HCY, Lp(a), and CRP were significantly elevated in smokers when compared with control (P < 0.05) and they correlated with daily cigarette consumption and duration of smoking. Ex-smokers also exhibited a significant increase in HCY, Lp(a), and CRP level (P < 0.05) when compared with the control, but were significantly lower than the current smokers. Conclusion: There is a linear relationship between the intensity and duration of cigarette smoking and serum levels of all three novel risk CV markers. These findings suggest that these markers may be an important mechanism by which smoking promotes atherosclerosis.

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Cervical lymph nodes: Harbinger of benign inclusions as well as metastatic deposits of thyroid malignancy

Samarth Shukla, Sourya Acharya

International Journal of Applied and Basic Medical Research 2017 7(3):210-212

Lymph nodes can be harbinger to benign epithelial inclusions as well as metastatic deposits. Cervical lymph nodes are home to benign epithelial inclusions from thyroid better known as lateral aberrant thyroid as well as inclusions from salivary gland due to the unique embryologic origins of nodes with these organs. We present a case of a young female suspected of thyroid malignancy who was intraoperative diagnosed by frozen sections with papillary carcinoma of the thyroid along with bilateral cervical nodes (Level I–V) positive for reactive lymphadenopathy with Level II node being positive to benign salivary gland inclusions and Level VI node being positive to metastatic deposits of papillary carcinoma of the thyroid.

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