ROS1 Gene Rearrangements Are Associated With an Elevated Risk of Peridiagnosis Thromboembolic Events

Introduction

This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate.

Hospitalization affects the anticoagulation patterns of patients with atrial fibrillation

Journal of Thrombosis and Thrombolysis - Scarce data are available on the effects of hospitalization on oral anticoagulation (OAC) patterns in patients with atrial fibrillation (AF). This study...     

Development of a rational strategy for integration of lactate dehydrogenase A suppression into therapeutic algorithms for head and neck cancer

Background Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment.Methods We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised ¹³C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation.Results shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved.Conclusions Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.Subject terms: Cancer therapy, Thyroid cancer, Cancer metabolism, Head and neck cancer     

Heterogeneity in reporting venous thromboembolic phenotypes in COVID-19: methodological issues and clinical implications

COVID-19 is associated with increased risk of venous thromboembolic events (VTE). However, there is significant heterogeneity in the thromboembolic phenotypes of COVID-19 patients (deep vein thrombosis, pulmonary embolism/thrombosis). The latter might be partly attributed to the variation in VTE risk factors in COVID-19 patients including: (i) patients’ characteristics; (ii) hospitalization conditions and interventions; and (iii) SARS-CoV-2-specific factors (coagulopathy, endothelial injury/microthrombosis). Furthermore, there is methodological heterogeneity in relation to the assessment of VTE (indications for screening, diagnostic methodology, etc). Physicians should be aware of the increased VTE risk, strongly consider VTE screening, and use thromboprophylaxis in all hospitalized patients.     

Role of autophagy in gastric carcinogenesis

Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.     

Resuscitation after hemorrhagic shock: the effect on the liver—a review of experimental data

The liver is currently considered to be one of the first organs to be subjected to the hypoxic insult inflicted by hemorrhagic shock. The oxidative injury caused by resuscitation also targets the liver and can lead to malfunction and the eventual failure of this organ. Each of the various fluids, vasoactive drugs, and pharmacologic substances used for resuscitation has its own distinct effect(s) on the liver, and the anesthetic agents used during surgical resuscitation also have an impact on hepatocytes. The aim of our study was to identify the specific effect of these substances on the liver. To this end, we conducted a literature search of MEDLINE for all types of articles published in English, with a focus on articles published in the last 12 years. Our search terms were “hemorrhagic shock,” “liver,” “resuscitation,” “vasopressors,” and “anesthesia.” Experimental studies form the majority of articles found in bibliographic databases. The effect of a specific resuscitation agent on the liver is assessed mainly by measuring apoptotic pathway regulators and inflammation-induced indicators. Apart from a wide range of pharmacological substances, modifications of Ringer’s Lactate, colloids, and pyruvate provide protection to the liver after hemorrhage and resuscitation. In this setting, it is of paramount importance that the treating physician recognize those agents that may attenuate liver injury and avoid using those which inflict additional damage.