CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages.

The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (n = 104) or placebo plus gemcitabine (n = 52).

Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma.

Unlabelled: The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition.

Sympathetic neuropathology is revealed in muscles affected by amyotrophic lateral sclerosis.

The anatomical substrate of skeletal muscle autonomic innervation has remained underappreciated since it was described many decades ago. As such, the structural and functional features of muscle sympathetic innervation are largely undetermined in both physiology and pathology, mainly due to methodological limitations in the histopathological analysis of small neuronal fibers in tissue samples. Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease which mainly targets motor neurons, and despite autonomic symptoms occurring in a significant fraction of patients, peripheral sympathetic neurons (SNs) are generally considered unaffected and, as such, poorly studied.

Towards a clearer view of sympathetic innervation of cardiac and skeletal muscles.

It is well appreciated that autonomic neurons have a central role in the homeostatic regulation of organs and systems and participate to the pathogenesis of several disease conditions. As such, the function and signalling pathways activated by sympathetic neurons (SNs) in different cell types and organs have become a matter of intense investigation throughout the years of modern biomedical research. This review is focused on the methods used to address sympathetic innervation of cardiac and skeletal muscles which, quite surprisingly, has remained incompletely understood, mainly due to the technical limitations of the traditional methodologies.

Postnatal Development and Distribution of Sympathetic Innervation in Mouse Skeletal Muscle.

Vertebrate neuromuscular junctions (NMJs) have been conceived as tripartite synapses composed of motor neuron, Schwann cell, and muscle fiber. Recent work has shown the presence of sympathetic neurons in the immediate vicinity of NMJs and experimental and clinical findings suggest that this plays an eminent role in adult NMJ biology. The present study examined the postnatal development and distribution of sympathetic innervation in different muscles using immunofluorescence, confocal microscopy, and Western blot.