Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targetin

Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients

The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population

Is it still current to talk about first ray hypermobility?

Since the time of D. Morton in clinical evaluation we talked about the concept of hypermobility as a cause of diseases such as hallux valgus. To date, this concept has been deepened in order to better understand the pathological mechanisms that create deformity, in order to identify the most appropriate prevention and correction procedures. Physics introduced the concept of stiffness, a property that also belongs to the podalic structures. Changing the terminology is difficult, but the knowledge of biomechanics requires the elimination of the term hypermobility because it resultsinconsistent with the physics applied to the foot, in favor of the terms stiffness and compliance. These clarifications make it possible to us to deepen even more specific and timely therapeutic choices, thus reducing the risk of iatrogenic complications which follows interventions on the first ray

post operative rehabilitation for surgically resected non small cell lung cancer patients serial pulmonary functional analysis

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potential role of rictor copy number gain cng as a key biomarker of mtor activity a comprehensive preclinical analysis in squamous cell lung cancer sqlc models

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Dysgraphia in patients with primary lateral sclerosis: a speech-based rehearsal deficit?

The present study aims to demonstrate that errors when writing are more common than expected in patients affected by primary lateral sclerosis (PLS) with severe dysarthria or complete mutism, independent of spasticity. Sixteen patients meeting Pringle's et al. [34] criteria for PLS underwent standard neuropsychological tasks and evaluation of writing. We assessed writing abilities in spelling through dictation in which a set of words, non-words and short phrases were presented orally and by composing words using a set of preformed letters. Finally, a written copying task was performed with the same words. Relative to controls, PLS patients made a greater number of spelling errors in all writing conditions, but not in copy task. The error types included: omissions, transpositions, insertions and letter substitutions. These were equally distributed on the writing task and the composition of words with a set of preformed letters. This pattern of performance is consistent with a spelling impairment. The results are consistent with the concept that written production is critically dependent on the subvocal articulatory mechanism of rehearsal, perhaps at the level of retaining the sequence of graphemes in a graphemic buffer. In PLS patients a disturbance in rehearsal opportunity may affect the correct sequencing/assembly of an orthographic representation in the written process

Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients

AbstractAmyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS's pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin–myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin–myosin interaction; this in turn might contribute to the pathogenesis of ALS

Mutational and copy number asset of primary sporadic neuroendocrine tumors of the small intestine

Small intestine neuroendocrine tumors (SI-NETs) represent the most common histotype among small intestine neoplasms, and metastatic disease is usually present at diagnosis. A retrospective series of 52 sporadic primary surgically resected SI-NETs, which were metastatic at diagnosis, was analyzed by high-coverage target sequencing (HCTS) for the mutational status of 57 genes and copy number status of 40 genes selected from recently published genome sequencing data. Seven genes were found to be recurrently mutated: CDKN1B (9.6%), APC and CDKN2C (each 7.7%), BRAF, KRAS, PIK3CA, and TP53 (each 3.8%). Copy number analysis showed frequent allelic loss of 4 genes located on chromosome 18 (BCL2, CDH19, DCC, and SMAD4) in 23/52 (44.2%) and losses on chromosomes 11 (38%) and 16 (15%). Other recurrent copy number variations were gains for genes located on chromosomes 4 (31%), 5 (27%), 14 (36%), and 20 (20%). Univariate survival analysis showed that SRC gene copy number gains were associated with a poorer prognosis (p = 0.047). Recurrent copy number variations are important events in SI-NET and SRC may represent a novel prognostic biomarker for this tumor type

preliminary results of principe predictors of resistance to immunotherapy with nivolumab niv study in advanced pretreated non small cell lung cancer apnsclc investigating the role of an immune genomic signature igs including jak2 jak3 pias4 ptpn2 stat3 ifnar2 alterations

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