A tissue injury sensing and repair pathway distinct from host pathogen defense.

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity.

Author Correction: Extracellular serine controls epidermal stem cell fate and tumour initiation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extracellular serine controls epidermal stem cell fate and tumour initiation.

Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma.

Oncolytic HSV-Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition.

Purpose: To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors.

Experimental Design: Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects .

Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair.

Resistance to genotoxic therapies is a primary cause of treatment failure and tumor recurrence. The underlying mechanisms that activate the DNA damage response (DDR) and allow cancer cells to escape the lethal effects of genotoxic therapies remain unclear. Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair.

The Status of "Nonmotor" Features of the Malady in an Essay on the Shaking Palsy (1817).

This chapter examines the status James Parkinson accorded "nonmotor" features of the malady set out in his 1817 Essay. In reading the Essay through the lens of this recently developed dichotomy I use "nonmotor" to mean the application of a late 20th-century category to a 200 year old account, whereas nonmotor designates application of the concept to contemporary understanding. While Parkinson granted "motor" components of the malady high definitional visibility, the Essay shows he was also attentive to patients' overall well-being and noticed some "nonmotor" aspects of the malady, in particular, constipation, interrupted speech, and difficulties with saliva and swallowing.

Narrative constructs in modern clinical case reporting.

Modern clinical case reporting takes the form of problem-solution narratives that redescribe symptoms in terms of disease categories. Authored almost always by those who have played a part in the medical assessment of the patient, reports historicise the salient details of an individual's illness as a complex effect of identifiable antecedent causes. Candidate hypotheses linking illness to pathological mechanisms are suggested by the patient's experience, and by data that emerge from clinical examination and investigation.

Translation from unconventional 5' start sites drives tumour initiation.

We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared.

Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy.

Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)-expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy.

Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis.

Purpose: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth.

Medical humanities and medical alterity in fiction and in life.

A widely accepted component of any answer to the question 'What is it to do good medical ethics?' is the commitment to benefit people's health, in principlist terminology, 'beneficence'. This paper addresses deliberate maleficence and the cultural otherness with which it is associated, focusing on the activities of the serial killer Dr Harold Shipman. It finds an uncanny 'fit' between the normal operation of healthcare services and this sort of alterity which has attracted little attention from bioethicists but has been addressed by novelists.

Urban observation and sentiment in James Parkinson's Essay on the Shaking Palsy (1817).

James Parkinson’s (1817) has long been considered the foundational text of the disease which now bears the author’s name. This paper shows how the radically re-formulated a diverse array of human dysmobilities as a “species” of disease. Parkinson incorporated medical observation with a clear focus on patient experience and subjectivity in a deeply affecting narrative, fusing clinical and urban case-descriptions within the genre of a sentimental natural history.

Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects.

Background: Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic herpes simplex virus-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for antitumor efficacy.

Experimental Design: The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis.

Medical humanities: lineage, excursionary sketch and rationale.

Medical Humanities the journal started life in 2000 as a special edition of the JME. However, the intellectual taproots of the medical humanities as a field of enquiry can be traced to two developments: calls made in the 1920s for the development of multidisciplinary perspectives on the sciences that shed historical light on their assumptions, methods and practices; refusals to assimilate all medical phenomena to a biomedical worldview. Medical humanities the term stems from a desire to situate the significance of medicine as a product of culture.

Textual practices in crafting bioethics cases.

Bioethics case reports generally treat aspects of moral fathomability, characterised and addressed in different ways. This paper reads the case as a textual model of scenarios and draws attention to its structure, narrative shape, linguistic register, and the effects of tone and temporality on reader expectation and responsiveness. Such textual elements of case composition reflect authorial purpose and influence the interpretation, including moral and ethical interpretation, of bioethics cases.