Pathogenesis and New Pharmacological Approaches to Noise-Induced Hearing Loss: A Systematic Review.

Noise-induced hearing loss (NIHL) is responsible for significant adverse effects on cognition, quality of life and work, social relationships, motor skills, and other psychological aspects. The severity of NIHL depends on individual patient characteristics, sound intensity, and mainly the duration of sound exposure. NIHL leads to the production of a reactive oxygen (ROS) inflammatory response and the activation of apoptotic pathways, DNA fragmentation, and cell death.

Sex Differences in Chronic Postsurgical Pain after Open Thoracotomy.

Study Objective: To determine the incidence of chronic postsurgical pain (CPSP) in women after open thoracotomy. Secondary objectives were to compare relevant patient and procedural variables between women and men.

Design: Observational cohort study.

XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells.

Unlabelled: Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors.

Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis.

The eukaryotic translation initiation factor eIF4E reprograms alternative splicing.

Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice-factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1.

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL.

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6.

Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma.

Unlabelled: Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVβ3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene.

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of K1.3 Channel Blockade.

Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation.

Histamine H4 Receptor Agonism Induces Antitumor Effects in Human T-Cell Lymphoma.

The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78).

The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.

Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients.

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma.

P38MAPK inhibition in aged astrocytes decreases reactive astrocytes, inflammation and increases nutritive capacity after oxygen-glucose deprivation.

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined.

Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood.

The eukaryotic translation initiation factor eIF4E elevates steady-state mG capping of coding and noncoding transcripts.

Methyl-7-guanosine (mG) "capping" of coding and some noncoding RNAs is critical for their maturation and subsequent activity. Here, we discovered that eukaryotic translation initiation factor 4E (eIF4E), itself a cap-binding protein, drives the expression of the capping machinery and increased capping efficiency of ∼100 coding and noncoding RNAs. To quantify this, we developed enzymatic (cap quantification; CapQ) and quantitative cap immunoprecipitation (CapIP) methods.

Neuroprotective effect of indomethacin in normal perfusion pressure breakthrough phenomenon.

Loss of cerebral autoregulation in normal perfusion pressure breakthrough (NPPB) phenomenon has been reported in other Central Nervous System diseases such as neonatal intraventricular haemorrhage. Several studies have demonstrated that low-dose indomethacin prevents this latter condition. A previous rat model was used to resemble NPPB phenomenon.

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Objective: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.

Glial Factors Regulating White Matter Development and Pathologies of the Cerebellum.

The cerebellum is a brain region that undergoes extremely dynamic growth during perinatal and postnatal development which is regulated by the proper interaction between glial cells and neurons with a complex concert of growth factors, chemokines, cytokines, neurotransmitters and transcriptions factors. The relevance of cerebellar functions for not only motor performance but also for cognition, emotion, memory and attention is increasingly being recognized and acknowledged. Since perturbed circuitry of cerebro-cerebellar trajectories can play a role in many central nervous system pathologies and thereby contribute to neurological symptoms in distinct neurodevelopmental and neurodegenerative diseases, is it the aim with this mini-review to highlight the pathways of glia-glia interplay being involved.

Evidence of nuclear transport mechanisms in the protozoan parasite Giardia lamblia.

Nuclear-cytoplasmic trafficking of proteins is a highly regulated process that modulates multiple biological processes in eukaryotic cells. In Giardia lamblia, shuttling has been described from the cytoplasm to nuclei of proteins during the biological cell cycle of the parasite. This suggests that a mechanism of nucleocytoplasmic transport is present and functional in G.

Neuronal p38α mediates age-associated neural stem cell exhaustion and cognitive decline.

Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age.

Ischemic stroke in neonatal and adult astrocytes.

The objective of this paper is to review current information regarding astrocytes function after a stroke in neonatal and adult brain. Based on the current literature, there are some molecular differences related to blood brain barrier (BBB) homeostasis disruption, inflammation and reactive oxygen species (ROS) mediated injury between the immature and mature brain after an ischemic event. In particular, astrocytes, the main glial cells in brain, play a different role in neonatal and adult brain after stroke, as time course of glial activation is strongly age dependent.