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The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.

BackgroundThe high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.MethodsWe performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression.ResultsWe found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone.ConclusionsOur study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.

Background Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies.Methods Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers.Results High rates of grade 3–4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127−GARP− T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse.Conclusions Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3–4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation.Trial registration number NCT01176474 and NCT02970981.

Abstract Background Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT. Methods Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS. Results Interferon-γ response (IFNγRes) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p = 8.80E−14). We observed that patients with high TMB, high IFNγRes and high MacReg had significantly better OS compared to high TMB, low IFNγRes and low MacReg (HR = 2.8, p = 3.55E−08). This association was not observed in low TMB patients. Conclusions We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFNγRes and MacReg had significantly more favorable OS compared to high TMB patients with low IFNγRes and low MacReg. These findings may substantially improve current melanoma prognostic models.

We have completed volume 9 of the Journal of Community Hospital Internal Medicine Perspectives – JCHIMP. In this perspective piece we discuss the many achievements of our journal, including our impact factor, the diversity of institutions publishing, our editorial board, and the importance of our reviewers.

An array-based genotyping approach has been the standard practice for genome-wide association studies (GWASs); however, as sequencing costs plummet over the past years, ultra low-coverage whole-genome sequencing (ulcWGS

In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities and/or efficacy of immunotherapy regimens and overall cancer survival. Despite these highly intriguing indications, the potential of germline genetic factors as personalized biomarkers of immune-checkpoint inhibition (ICI) remains vastly unexplored. Here, we review the rationale for exploring the germline genetic factors as novel biomarkers predictive of IO outcomes, including ICI efficacy, toxicity and survival, and discuss the comprehensive approaches for the identification of such germline genetic indicators. In addressing the current limitations, we highlight a need for large collaborative consortia in these efforts. We also outline possible avenues for incorporating germline genetic factors into emerging multifactorial tools for a more personalized prediction of ICI outcomes.

With this issue, we complete volume 8 of the Journal of Community Hospital Internal Medicine Perspectives – JCHIMP. In this perspective piece we discuss the many achievements of our journal, including the journals our articles have been cited in, the increasing number of downloads, and the importance of our reviewers.

The Nus factor complex regulates rRNA folding and prevents Rho-dependent transcription termination in bacteria. Here, Baniulyte et al. show that it also inhibits translation of one of the Nus factor-encoding genes, suhB, and probably regulates the expression of other genes in diverse bacterial species.

Forty years ago is not ancient history in the medical field. However, being an eye witness to the emergence of three new infectious diseases in the northeastern United States in the 1970s left a deep impression on this author. I will relate a small portion of the amazing events that caught the attention of the medical establishment and the general public in a roughly 5-year period of medical discovery.

Objectives: The objective of this study was to assess communication at the bedside in the emergency room between residents and their patients in order to identify common communication gaps. We also intended to evaluate whether residents for whom English is a second language (ESL residents) communicate less effectively. Methods: A scorable checklist was developed in order to assess and identify communication gaps between the residents and their patients. Medical students observed the internal medicine and family medicine residents while they admitted patients to the medical service in the Emergency Room. Before this, medical students were trained for two weeks with a senior internist. The role of the medical student was not revealed; rather they were self-described as observers of the admission process. Results: Over an 8 week period, 71 observations were made of 27 medicine residents. 71 patient intakes were observed, evaluating 27 residents. In 52.1% of these interactions, the residents used medical acronyms when communicating with the patients. During 66.2% of interactions, technical medical terms or expressions were used during the history taking and in only 27.6% of those cases were the terms explained at least partially. Teach back technique was not observed in any of the interactions evaluated. Data was also analyzed based on whether the doctors were ESL residents or native English speakers. ESL residents tended to use significantly more technical language than the native English speakers, but the native English speakers tended to use more acronyms. Conclusions: How much patients understand of what their doctor says is called “health literacy.” Resident physicians often overestimate their patients’ health literacy, and this leads to communication gaps which have the potential to result in poorer health outcomes for the patients. The checklist developed for this pilot study assessed how well residents tailor their communication to their patients’ health literacy. Our assessment revealed much room for improvement. This checklist can be used as a tool to teach future residents how to better assess and take into consideration their patients’ health literacy level and as a result communicate with patients more effectively.

Leptospirosis is a rare zoonotic disease which occurs in people exposed to contaminated water or/and animal urine. We report two cases of moderate to severe leptospirosis. The first case was a healthy middle-aged biology professor who recently visited his family in Jamaica and presented with multi-organ failure. The second case was a 27-year-old police officer who was admitted for acute liver injury and thrombocytopenia after helping people evacuate during a flood/disaster situation.

Chest pain suggestive of myocardial ischemia or infarction is a common emergency department complaint and a subset of these is associated with cocaine use. It can be difficult to triage patients with chest pain while using cocaine.To assess the reliability of the initial electrocardiogram (ECG) done in the emergency department in current cocaine users suspected of acute coronary syndrome (ACS) in predicting a true event.A total of 218 charts of current cocaine users who presented with chest pain judged as possibly cardiac in nature with an initial ECG from September 2003 to August 2007 were reviewed. Initial ECG was classified into: (1) Category A (inverted T waves in two or more contiguous leads and/or characteristic ST segment elevation or depression indicative of an ischemic event possibly acute); (2) Category B (other ischemic changes but without any ST or T abnormalities such as Q wave, or bundle branch block); or (3) Category C (normal tracing, non-specific ST segment or T wave alterations).Eighteen of 218 (8.3%) were confirmed to have ACS. Ten of 18 confirmed ACS patients were among the 70 cases with ECG classified as Category A. One hundred and one of 218 were Category C ECGs: five of these had ACS (three of the five had significant cardiac history) and 96 did not, consistent with 95% negative predictive value. Patients with Category A ECG characteristics were three times at risk to have ACS compared with a Category C ECG.The initial ECG with a good clinical history can be used effectively to triage patients presenting with chest pain and current use of cocaine in the emergency department.

Education should never be reduced to a single subject. A curriculum should never be reduced to a single field, period or academic discipline. Media Education, likewise, has to be committed to a plurality of approaches and fields of interest. It has to deal with the seemingly trite and the unambiguously significant, whether in relation to fashion, history, science, religion, national and personal identities, gender, age, ethnicity, class and a myriad of other fields of representation. It has also to allow for the critical exploration of the relationships between representation and lived existence. Media Education, initially, has to be about the way things are, the way things are represented, and how the ways in which things are represented have an impact on the way things are. It is a process which requires at least two conditions to be met. The first is that those engaged with Media Education, whether as students, researchers or teachers have to undergo a constant, demanding and open-ended period of skill acquisition, of intellectual development and a willingness to doubt and to act in the world. The second condition is that all involved in Media Education have to recognise and accept that we inhabit a fragile, delightful, horrific, challenging, beautiful, ugly, insecure, contradictory world, and it is the only one we have. That, at least, is a beginning. Acceptance of these conditions does not sit comfortably beside the bureaucratisation of education and the managerialism which sustains the bureaucracy. But these two conditions are, to adopt the language of the planner, prerequisites.

They do say that all ideas have their time, and in media education it seems that it is the time for democracy. Books and papers begin to appear and there are conferences with democracy in their titles to replace a focus on the postmodern, or identity. There seems to be a general consensus that democracy is a ‹good thing›. But, as with most other significant terms which hold centre stage for a while, they need to be interrogated with some care. For some more critical educators democracy takes its place alongside Gandhi’s comment when asked about Western Civilisation – he said it would be a good idea. The ‹practice› of democracy takes on a poignant, ironic, desperate or cynical cloak in the light of recent world events and the rise of terrorism as a political weapon. It depends where you stand. Democracy is not something that thrills the hearts and minds of the vast majority of citizens who live in nations who declare themselves to be democratic. Apathy and cynicism work together against democratic growth. But so do governments whose declared democratic aims pay scant attention to the people they are supposed to represent. And then there are the ‹democratic› exercises which supposedly involve the people in a conversation (‹we are listening› they say) which results in the status quo being implemented by politicians with morally superior physiognomies. After all, they say, we did ask your opinions. We did ask you to participate. And so democracy staggers from crisis to disaster...

Chyloptysis is a relatively rare embodiment of disease that encompasses a lengthy differential and provides many diagnostic and therapeutic challenges. Presented here is the case of a young woman with massive chyloptysis due to a thoracic cavernous lymphangioma arising in the peripartum period. The severity of her condition mandated the use of cardiopulmonary bypass to resect her lymphangioma. We believe that the extent of her symptoms, etiology of disease, and surgical management represent a unique scenario in the literature.