Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes

Diagnosis and Treatment of Pediatric Acquired Aplastic Anemia (AAA): An Initial Survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC)

BackgroundRandomized clinical trials in pediatric aplastic anemia (AA) are rare and data to guide standards of care are scarce. ProcedureEighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. ResultsOur survey indicates considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of immunosuppressive therapy (IST); uniform referral for hematopoietic stem cell transplantation as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. ConclusionsThese initial survey results reflect heterogeneity in diagnosis and care amongst pediatric centers and emphasize the need to develop evidence-based diagnosis and treatment approaches in this rare disease. Pediatr Blood Cancer 2014;61:869-874. (c) 2013 Wiley Periodicals, Inc

Development of a Molecular Signature to Monitor Pharmacodynamic Responses Mediated by In Vivo Administration of Glucocorticoids

© 2018 American College of Rheumatology. Objective: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. Methods: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a \u3e2-fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up-regulated and 18 down-regulated genes were identified. A composite score of the up-regulated genes was generated using a single-sample gene set enrichment analysis algorithm. Results: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose-dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. Conclusion: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure

Standardized video interviews do not correlate to United States medical licensing examination step 1 and step 2 scores

© 2019 Egan et al. Introduction: In 2017, the Standardized Video Interview (SVI) was required for applicants to emergency medicine (EM). The SVI contains six questions highlighting professionalism and interpersonal communication skills. The responses were scored (6-30). As it is a new metric, no information is available on correlation between SVI scores and other application data. This study was to determine if a correlation exists between applicants\u27 United States Medical Licensing Examination (USMLE) and SVI scores. We hypothesized that numeric USMLE Step 1 and Step 2 Clinical Knowledge (CK) scores would not correlate with the SVI score, but that performance on the Step 2 Clinical Skills (CS) portion may correlate with the SVI since both test communication skills. Methods: Nine EM residency sites participated in the study with data exported from an Electronic Residency Application Service (ERAS ® ) report. All applicants with both SVI and USMLE scores were included. We studied the correlation between SVI scores and USMLE scores. Predetermined subgroup analysis was performed based on applicants\u27 USMLE Step 1 and Step 2 CK scores as follows: (= 200, 201-220, 221-240, 241-260, \u3e260). We used linear regression, the Kruskal-Wallis test and Mann-Whitney U test for statistical analyses. Results: 1,325 applicants had both Step 1 and SVI scores available, with no correlation between the overall scores (p=0.58) and no correlation between the scores across all Step 1 score ranges, (p=0.29). Both Step 2 CK and SVI scores were available for 1,275 applicants, with no correlation between the overall scores (p=0.56) and no correlation across all ranges, (p=0.10). The USMLE Step 2 CS and SVI scores were available for 1,000 applicants. Four applicants failed the CS test without any correlation to the SVI score (p=0.08). Conclusion: We found no correlation between the scores on any portion of the USMLE and the SVI; therefore, the SVI provides new information to application screeners

Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801

© 2020 by The American Society of Hematology. Acutemyeloid leukemia (AML)witheither t(8;21)(q22;q22)or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11-positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged \u3c60 \u3eyears], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: Disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions

Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury

Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to \u3e/=99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation

The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel

OBJECTIVE: To establish a consensus on the utility of multiparametric magnetic resonance imaging (mpMRI) to identify patients for focal therapy. METHODS: Urological surgeons, radiologists, and basic researchers, from Europe and North America participated in a consensus meeting about the use of mpMRI in focal therapy of prostate cancer. The consensus process was face-to-face and specific clinical issues were raised and discussed with agreement sought when possible. All participants are listed among the authors. Topics specifically did not include staging of prostate cancer, but rather identifying the optimal requirements for performing MRI, and the current status of optimally performed mpMRI to (i) determine focality of prostate cancer (e.g. localising small target lesions of \u3e/=0.5 mL), (ii) to monitor and assess the outcome of focal ablation therapies, and (iii) to identify the diagnostic advantages of new MRI methods. In addition, the need for transperineal template saturation biopsies in selecting patients for focal therapy was discussed, if a high quality mpMRI is available. In other words, can mpMRI replace the role of transperineal saturation biopsies in patient selection for focal therapy? RESULTS: Consensus was reached on most key aspects of the meeting; however, on definition of the optimal requirements for mpMRI, there was one dissenting voice. mpMRI is the optimum approach to achieve the objectives needed for focal therapy, if made on a high quality machine (3T with/without endorectal coil or 1.5T with endorectal coil) and judged by an experienced radiologist. Structured and standardised reporting of prostate MRI is paramount. State of the art mpMRI is capable of localising small tumours for focal therapy. State of the art mpMRI is the technique of choice for follow-up of focal ablation. CONCLUSIONS: The present evidence for MRI in focal therapy is limited. mpMRI is not accurate enough to consistently grade tumour aggressiveness. Template-guided saturation biopsies are no longer necessary when a high quality state of the art mpMRI is available; however, suspicious lesions should always be confirmed by (targeted) biopsy

Propensity-matched analysis of patient-reported outcomes for neoadjuvant chemotherapy prior to radical cystectomy

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: To evaluate patient-reported outcomes (PROs) for bladder cancer patients undergoing neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) using longitudinal data and propensity-matched scoring analyses. Methods: 155 patients with muscle-invasive bladder cancer scheduled for RC completed the European Organization for Research and Treatment of Cancer questionnaires, EORTC QLQ-C30, EORTC QLQ-BLM30, Fear of Recurrence Scale, Mental Health Inventory and Satisfaction with Life Scale within 4 weeks of surgery. A propensity-matched analysis was performed comparing pre-surgery PROs among 101 patients who completed NAC versus 54 patients who did not receive NAC. We also compared PROs pre- and post-chemotherapy for 16 patients who had data available for both time points. Results: In propensity-matched analysis, NAC-treated patients reported better emotional and sexual function, mental health, urinary function and fewer financial concerns compared to those that did not receive NAC. Longitudinal analysis showed increases in fatigue, nausea and appetite loss following chemotherapy. Conclusion: Propensity-matched analysis did not demonstrate a negative effect of NAC on PRO. Several positive associations of NAC were found in the propensity-matched analysis, possibly due to other confounding differences between the two groups or actual clinical benefit. Longitudinal analysis of a small number of patients found small to modest detrimental effects from NAC similar to toxicities previously reported. Our preliminary findings, along with known survival and toxicity data, should be considered in decision-making for NAC