“If You Seek it Like Silver”: Illness and Poverty as Metaphors for Obligation in Israel Salanter

This article analyzes the role of experiences of illness and poverty in the work of Israel Salanter (1810-1883). It argues that Salanter uses these two experiences, and the emotional responses that they engender, as paradigms for understanding the experience of being obligated to study, and then, change, one’s character. The article shows that obligation played a central role in Salanter’s thought, but that his account of obligation is articulated not against a newly-available form of modern autonomy, but instead, against forms of constraint created by poverty and illness

‘I Will Sing of Love and Justice’: Jewish Responses to the Theological Roots of Contemporary Virtue Ethics

This dissertation puts Jewish philosophy into conversation with contemporary ethical theory in order to develop a novel account of the relationship between moral rules and character development. I begin by showing that anti-Jewish rhetoric that criticized Judaism as overly concerned with rule-following has contributed significantly to the prevailing assumption that virtue ethics and deontology are two mutually exclusive ways to understand ethics. I then use Maimonides, Moses Mendelssohn, and the nineteenth-century Musar thinkers Israel Salanter and Simḥah Zissel Ziv as case studies to show that Jewish thought combines virtue ethics and deontology in ways that contemporary ethical theories have ignored. In the final chapter of the dissertation, I show that the assumed distinction between virtue ethical and deontological moral reasoning hampers moral discourse in the public sphere, especially surrounding issues of race and gender. Using examples including sexual assault and police violence, I show that when someone is accused of committing a moral wrong, they often respond by claiming that they are “a good person,” thereby shifting from a deontological to a virtue ethical mode of analysis. This prevents the actor from doing the moral work of becoming the kind of person who would not have committed the moral wrong. I then use my case studies in Jewish thought to address the moral evasion that these shifts from deontology to virtue ethics (and vice versa) allow

Intralesional therapy for metastatic melanoma

Introduction: Intralesional therapy for metastatic melanoma has some advantages over systemic therapy. Local drug administration allows for delivery of an increased concentration of the agent and reduced systemic exposure, thereby increasing local efficacy and limiting toxicity. Moreover, since in vivo tumor nodules contain the tumor antigens, this tumor tissue may serve as an autologous vaccine to induce systemic immunity. This so-called 'bystander effect', where uninjected distant lesions exhibit a response, has been reported in select intralesional therapy trials. Areas covered: This review will give an overview of the working mechanisms, clinical evidence and side effects for available intralesional and topical therapies and summarize the most recent developments in this field. Expert opinion: The ideal treatment approach for locoregionally advanced melanoma should be multidisciplinary and tailored to the patient, taking into consideration patient-related, tumor-related factors (such as location, tumor burden, mutation status) and previous treatments received. It will likely not be a single therapy, but rather a combination of injectable treatments, regional perfusions and systemic therapies

Developments in Intralesional Therapy for Metastatic Melanoma

Background: Locoregional advanced melanoma poses a complex clinical challenge that requires a multi-disciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing.Methods: The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents.Results: Intralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary.Conclusions: Due to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.</p

Troponin Elevation in Patients Undergoing Percutaneous Hepatic Perfusion for Metastatic Uveal Melanoma

Background Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy. Objective To assess the cardiac safety and subsequent clinically significant sequalae of this therapy. Methods Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution. Results Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. ( P = .042). Conclusion Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia

NF-kappa B signaling in tanycytes mediates inflammation-induced anorexia

Objectives: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1 beta. Methods: IL-1 beta was injected intravenously. To interfere with IL-1 beta signaling, we deleted the essential modulator of NF-kappa B signaling (Nemo) in astrocytes and tanycytes. Results: Systemic IL-1 beta increased the activity of the transcription factor NF-kB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-kappa B signaling, IL-1 beta induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E-2 (PGE(2)) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1 beta-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. Conclusions: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Funding Agencies|Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [GRK1957, T-CRC 134, SPP1629, MU 3743/1-1]; Swedish Research CouncilSwedish Research Council [07879, 20725]; Swedish Brain Foundation; Swedish Cancer Foundation [2016/585]; Agence Nationale de la RechercheFrench National Research Agency (ANR) [ANR-15-CE14-0025-01, ANR-16-CE37-0006-02]; European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programmeEuropean Research Council (ERC) [810331]; Velux Stiftung, Switzerland</p

Selenium inhibits renal oxidation and inflammation but not acute kidney injury in an animal model of rhabdomyolysis

Acute kidney injury (AKI) is a manifestation of rhabdomyolysis (RM). Extracellular myoglobin accumulating in the kidney after RM promotes oxidative damage, which is implicated in AKI. AIM: To test whether selenium (Se) supplementation diminishes AKI and improves renal function. RESULTS: Dietary selenite increased Se in the renal cortex, as demonstrated by X-ray fluorescence microscopy. Experimental RM-stimulated AKI as judged by increased urinary protein/creatinine, clusterin, and kidney injury molecule-1 (KIM-1), decreased creatinine clearance (CCr), increased plasma urea, and damage to renal tubules. Concentrations of cholesterylester (hydro)peroxides and F₂-isoprostanes increased in plasma and renal tissues after RM, while aortic and renal cyclic guanidine monophosphate (cGMP; marker of nitric oxide (NO) bioavailability) decreased. Renal superoxide dismutase-1, phospho-P65, TNFα gene, MCP-1 protein, and the 3-chloro-tyrosine/tyrosine ratio (Cl-Tyr/Tyr; marker of neutrophil activation) all increased after RM. Dietary Se significantly decreased renal lipid oxidation, phospho-P65, TNFα gene expression, MCP-1 and Cl-Tyr/Tyr, improved NO bioavailability in aorta but not in the renal microvasculature, and inhibited proteinuria. However, CCr, plasma urea and creatinine, urinary clusterin, and histopathological assessment of AKI remained unchanged. Except for the Se++ group, renal angiotensin-receptor-1/2 gene/protein expression increased after RM with parallel increases in MEK1/2 inhibitor-sensitive MAPkinase (ERK) activity. INNOVATION: We employed synchrotron radiation to identify Se distribution in kidneys, in addition to assessing reno-protection after RM. CONCLUSION: Se treatment has some potential as a therapeutic for AKI as it inhibits oxidative damage and inflammation and decreases proteinuria, albeit histopathological changes to the kidney and some plasma and urinary markers of AKI remain unaffected after RM.Anu Shanu, Ludwig Groebler, Hyun Bo Kim, Sarah Wood, Claire M. Weekley, Jade B. Aitken, Hugh H. Harris, and Paul K. Wittin

BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma: a potential neoadjuvant strategy

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival