Utility of specific laboratory biomarkers to predict severe sepsis in pediatric patients with SIRS.

OBJECTIVE: To identify the association between readily available laboratory biomarkers and the development of severe sepsis in children presenting to the emergency department (ED) with systemic inflammatory response syndrome (SIRS). METHODS: In this retrospective cohort study, ED patient encounters from June 2018 to June 2019 that triggered an automated sepsis alert based on SIRS criteria were analyzed. Encounters were included if the patient had any of the following laboratory tests sent within 6 h of ED arrival: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactic acid, and procalcitonin. For each of the biomarkers, a receiver operating characteristic (ROC) curve was created for our primary outcome, severe sepsis within 24 h of ED disposition, and our secondary outcome, severe sepsis with a positive bacterial culture. For each ROC curve, we calculated the area under the curve (AUC) with 95% confidence intervals (95% CI) and created cutoff points to achieve 90% sensitivity and 90% sensitivity for the primary and secondary outcomes. RESULTS: During the study period, 4349/61,195 (7.1%) encounters triggered an automated sepsis alert. Of those, 1207/4349 (27.8%) had one of the candidate biomarkers sent within 6 h of ED arrival and were included in the study. A total of 100/1207 (8.3%) met criteria for severe sepsis within 24 h of arrival, and 41/100 severe sepsis cases (41%) were deemed culture-positive. Procalcitonin had the highest AUC for identifying severe sepsis [0.62 (95% CI 0.52-0.73)] while ESR and CRP had the highest AUC for culture-positive sepsis [0.68 (95% CI 0.47-0.89) and 0.67 (95% CI 0.53-0.81), respectively]. At 90% sensitivity for detecting severe sepsis, all of the biomarker threshold values fell within that laboratory test's normal range. At 90% specificity for severe sepsis, threshold values were as follows: procalcitonin 2.72 ng/mL, CRP 16.79 mg/dL, ESR 79.5 mm/h and lactic acid 3.6 mmol/L. CONCLUSION: Our data indicate that CRP, ESR, lactic acid, and procalcitonin elevations were all specific, but not sensitive, in identifying children in the ED with SIRS who go on to develop severe sepsis.

Cultivating Interest in Oncology Through a Medical Student Oncology Society.

The purpose of this descriptive analysis is to describe a formal method to foster interest in oncology among medical students through a Student Oncology Society (SOS). The SOS is a student-run multidisciplinary interest group that offers oncology-related events to interested medical students at the Boston University School of Medicine (BUSM). We employed a student survey to document the impact of the SOS on student interest in careers in oncology and students' perceived accessibility of mentors in oncology at our institution. All 35 students who attended the event reported that they found the discussion panels "valuable" or "somewhat valuable." A minority of students reported that student and faculty were "somewhat accessible" or "very accessible." At the end of the survey, 37 % of the students reported that a discussion of career paths of various physicians or a student/resident panel on oncology would be beneficial. By giving students an opportunity to learn about the different medical and surgical specialties within oncology, the SOS is able to cultivate early interest and understanding of the field of oncology among pre-clinical medical students. Further work must be done to connect medical students to faculty mentors in oncology. Although this short report provides a model for other medical schools to begin their own student oncology interest groups, further rigorous evaluation of pre-clinical oncology education initiatives are necessary in order to document their long-term impact on medical education.

The Effects of Histone Deacetylase Inhibitor and Calpain Inhibitor Combination Therapies on Ovarian Cancer Cells.

BACKGROUND: Ovarian cancer is difficult to treat due to absence of selective drugs and tendency of platinum drugs to promote resistance. Combination therapy using epigenetic drugs is predicted to be a beneficial alternative. MATERIALS AND METHODS: This study investigated the effects of combination therapies using two structurally different histone deacetylase (HDAC) inhibitors (HDACi), sodium butyrate and suberanilohydroxamic acid (SAHA), with the calpain inhibitor calpeptin on two characteristically different ovarian cancer cell lines, CAOV-3 and SKOV-3. RESULTS: Suboptimal doses of HDACi and calpeptin produced several effects. Growth inhibition was enhanced and the epigenetically silenced tumor suppressor genes ARHI, p21 and RARß2 were re-expressed. Methylation of specific CpG residues in ARHI were reduced. Cell-cycle progression was inhibited and apoptosis, as well as autophagy, were induced. The phosphorylation of ERK and Akt were differentially effected by these inhibitors. CONCLUSION: The re-expression of tumor suppressors may sensitize ovarian cancer cells, which then undergo apoptosis and autophagy for cell death.

EMT and tumor metastasis.

EMT and MET comprise the processes by which cells transit between epithelial and mesenchymal states, and they play integral roles in both normal development and cancer metastasis. This article reviews these processes and the molecular pathways that contribute to them. First, we compare embryogenesis and development with cancer metastasis. We then discuss the signaling pathways and the differential expression and down-regulation of receptors in both tumor cells and stromal cells, which play a role in EMT and metastasis. We further delve into the clinical implications of EMT and MET in several types of tumors, and lastly, we discuss the role of epigenetic events that regulate EMT/MET processes. We hypothesize that reversible epigenetic events regulate both EMT and MET, and thus, also regulate the development of different types of metastatic cancers.

Drug resistance in cancer: an overview.

Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

Genetic and epigenetic aspects of breast cancer progression and therapy.

Although breast cancer is a heterogeneous disease that is challenging to characterize and treat, the recent explosion of genetic and epigenetic research may help improve these endeavors. In the present review, we use genetic diversity to characterize and classify different types of breast cancer. We also discuss genetic and epigenetic changes that are involved in the development of different breast cancer types and examine how these changes affect prognosis. It appears that while a combination of mutations and copy number changes determine the type of breast cancer, epigenetic alterations may be the primary initiators of cancer development. Understanding these critical biomarkers and molecular changes will advance our ability to effectively treat breast cancer. Next, we examine potential drug therapies directed at epigenetic changes, as such epigenetic drug treatments may prove useful for treating patient-specific tumors, breast cancer progenitor cells, and drug-resistant cells. Lastly, we discuss on mechanisms of carcinogenesis, including a novel hypothesis outlining the role of epigenetics in the development of cancer progenitor cells and metastasis. Overall, breast cancer subtypes may have a similar epigenetic signal that promotes cancer development, and treatment may be most effective if both epigenetic and genetic differences are targeted.

Cancer development, progression, and therapy: an epigenetic overview.

Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell-cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.

Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy.

Epigenetic regulation in eukaryotic and mammalian systems is a complex and emerging field of study. While histone modifications create an open chromatin conformation allowing for gene transcription, CpG methylation adds a further dimension to the expression of specific genes in developmental pathways and carcinogenesis. In this review, we will highlight DNA methylation as one of the distinct mechanisms for gene silencing and try to provide insight into the role of epigenetics in cancer progenitor cell formation and carcinogenesis. We will also introduce the concept of a dynamic methylation-demethylation system and the potential for the existence of a demethylating enzyme in this process. Finally, we will explain how re-expression of epigenetically silenced tumor suppressor genes could be exploited to develop effective drug therapies. In particular, we will consider how a combination therapy that includes epigenetic drugs could possibly kill cancer progenitor cells and reduce the chance of relapse following chemotherapy.