A core of kinase-regulated interactomes defines the neoplastic MDSC lineage

Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a “kinase signature” and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.     

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressing acute lymphoblastic leukemia.     

Altered electromyographic responses to emotional and pain information in awake bruxers: case–control study

Objectives

This study aims to investigate how emotional information and pain-related information affect the activity of the masticatory muscles in participants with awake bruxism and controls.

Material and methods

Different videos and texts, with positive, negative, and neutral valence or related to pain, were presented to a sample of university students, while their electromyographic (EMG) activity around the masseter muscle and their skin conductance were recorded. Two groups were selected, with 24 subjects each: one group of subjects with definitive awake bruxism (confirmed by posterior EMG activity) who also suffered from moderate jaw discomfort, and another group of subjects without bruxism.

Results

The results demonstrated that the subjects with definitive awake bruxism displayed greater muscular activity when presented videos and texts with negative valence, especially when related to pain, than the non-bruxist group.

Conclusions

This study supports the idea that persons with bruxism who also suffer moderate levels of jaw discomfort present greater bruxism activity when watching pain-related stimuli, and to a lesser extent when watching negative stimuli.

Clinical relevance

The increased muscular activity induced by negative and pain-related information might contribute to pain exacerbation and perpetuation in persons with bruxism who suffer from discomfort.

     

NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case−control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.     

Effectiveness of rotavirus vaccines in preventing cases and hospitalizations due to rotavirus gastroenteritis in Navarre, Spain

Two rotavirus vaccines have been available since 2006. This study evaluates the effectiveness of these vaccines using a test-negative case-control design in Navarre, Spain. We included children 3-59 months of age who sought medical care for gastroenteritis and for whom stool samples were taken between January 2008 and June 2011. About 9% had received the pentavalent vaccine (RotaTeq) and another 8% received the monovalent vaccine (Rotarix). Cases were the 756 children with confirmed rotavirus and controls were the 6036 children who tested negative for rotavirus. Thirty-five percent of cases and 9% of controls had required hospitalization (p < 0.0001). The adjusted effectiveness of complete vaccination was 78% (95% CI: 68-85%) in preventing rotavirus gastroenteritis and 83% (95% CI: 65-93%) in preventing hospitalization for rotavirus gastroenteritis. No differences between the two vaccines were detected (p = 0.4523). Both vaccines were highly effective in preventing cases and hospital admissions in children due to rotavirus gastroenteritis.     

New perspectives in the management of small cell lung cancer

The treatment of small cell lung cancer (SCLC) is a challenge for all specialists involved. New treatments have been added to the therapeutic armamentarium in recent months, but efforts must continue to improve both survival and quality of life. Advances in surgery and radiotherapy have resulted in prolonged survival times and fewer complications, while more careful patient selection has led to increased staging accuracy. Developments in the field of systemic therapy have resulted in changes to clinical guidelines and the management of patients with advanced disease, mainly with the introduction of immunotherapy. In this article, we describe recent improvements in the management of patients with SCLC, review current treatments, and discuss future lines of research.     

Advances and controversies in the management of early stage non-small cell lung cancer

Complete resection continues to be the gold standard for the treatment of early-stage lung cancer. The landmark Lung Cancer Study Group trial in 1995 established lobectomy as the minimum intervention necessary for the management of early-stage non-small cell lung cancer, as it was associated with lower recurrence and metastasis rates than sublobar resection and lower postoperative morbidity and mortality than pneumonectomy. There is a growing tendency to perform sublobar resection in selected cases, as, depending on factors such as tumor size, histologic subtype, lymph node involvement, and resection margins, it can produce similar oncological results to lobectomy. Alternative treatments such as stereotactic body radiotherapy and radiofrequency ablation can also produce good outcomes in inoperable patients or patients who refuse surgery.     

Megalencephalic leukoencephalopathy with subcortical cysts: A personal biochemical retrospective

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by dysfunction of the role of glial cells in controlling brain fluid and ion homeostasis. Patients affected by MLC present macrocephaly, cysts and white matter vacuolation, which lead to motor and cognitive impairments. To date, there is no treatment for MLC, only supportive care. MLC is caused by mutations in the MLC1 and GLIALCAM genes. MLC1 is a membrane protein with low identity to the Kv1.1 potassium channel and GlialCAM belongs to an adhesion molecule family. Both proteins form a complex with an as-yet-unknown function that is expressed mainly in the astrocytes surrounding the blood–brain barrier and in Bergmann glia. GlialCAM also acts as an auxiliary subunit of the chloride channel ClC-2, thus regulating its localization at cell–cell junctions and modifying its functional properties by affecting the common gate of ClC-2. Recent studies in Mlc1-, GlialCAM- and Clcn2-knockout mice or Mlc1-knockout zebrafish have provided fresh insight into the pathophysiology of MLC and further details about the molecular interactions between these three proteins. Additional studies have shown that GlialCAM/MLC1 also regulates other ion channels (TRPV4, VRAC) or transporters (Na⁺/K⁺-ATPase) in a not-understood manner. Furthermore, it has been shown that GlialCAM/MLC1 may influence signal transduction mechanisms, thereby affecting other proteins not related with transport such as the EGF receptor. Here, we offer a personal biochemical retrospective of the work that has been performed to gain knowledge of the pathophysiology of MLC, and we discuss future strategies that may be used to identify therapeutic solutions for MLC patients.     

Medium-term outcomes of the S-ROM modular femoral stem in revision hip replacement

Introduction

The objective of this study was to analyse results achieved with the S-ROM modular stem in revision surgery.

Materials and methods

A retrospective observational study was conducted from 2007 to 2015 including 51 patients who had a follow-up of ≥?2 years and complete medical history. The mean age was 66.5 years old (34–87). The main reason for revision was aseptic loosening (38 cases, 74.5%), followed by infection (10, 19.6%), instability (2, 3.9%) and an adverse reaction associated with a metal-on-metal hip implant (1, 2%). Using the Paprosky classification, there were 22 cases of type I (43.1%), 27 of type II (52.9%) and 2 of type IIIA (4%). At the end of the follow-up, radiological parameters were assessed using Engh’s criteria. Pre- and postoperative clinical status was assessed using the Harris Hip Score, a visual analogue scale and the Merle D’Aubigné score.

Results

The mean follow-up period was 5.7 years (2–10). The mean Harris Hip Score improved from 45.5 points (22–65) to 85.8 (55–100) (p?<?0.001), and the final mean Merle D’Aubigné scores were 5.2, 4.6 and 5.6 for pain, ability to walk and mobility, respectively. Osseointegration was confirmed in all except one patient with fibrous non-union. No aseptic loosening has been recorded. Postoperative complications were deep infection in four cases (7.8%) and dislocation in three (5.9%).

Conclusion

This study indicates good medium-term outcomes using a modular hip replacement system with porous-coated proximal sleeves in revision surgery in patients with Paprosky type I and II defects.