Mechanical stretch induces myelin protein loss in oligodendrocytes by activating Erk1/2 in a calcium-dependent manner

Myelin loss in the brain is a common occurrence in traumatic brain injury (TBI) that results from impact-induced acceleration forces to the head. Fast and abrupt head motions, either resulting from violent blows and/or jolts, cause rapid stretching of the brain tissue, and the long axons within the white matter tracts are especially vulnerable to such mechanical strain. Recent studies have shown that mechanotransduction plays an important role in regulating oligodendrocyte progenitors cell differentiation into oligodendrocytes. However, little is known about the impact of mechanical strain on mature oligodendrocytes and the stability of their associated myelin sheaths. We used an in vitro cellular stretch device to address these questions, as well as characterize a mechanotransduction mechanism that mediates oligodendrocyte responses. Mechanical stretch caused a transient and reversible myelin protein loss in oligodendrocytes. Cell death was not observed. Myelin protein loss was accompanied by an increase in intracellular Ca²⁺ and Erk1/2 activation. Chelating Ca²⁺ or inhibiting Erk1/2 activation was sufficient to block the stretch-induced loss of myelin protein. Further biochemical analyses revealed that the stretch-induced myelin protein loss was mediated by the release of Ca²⁺ from the endoplasmic reticulum (ER) and subsequent Ca²⁺-dependent activation of Erk1/2. Altogether, our findings characterize an Erk1/2-dependent mechanotransduction mechanism in mature oligodendrocytes that de-stabilizes the myelination program.     

An open‐label phase I/II study of cyclophosphamide,bortezomib, pegylated liposomal doxorubicin,and dexamethasone in newly diagnosed myeloma

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6–8 cycles of CVDD at four dose levels. There were no dose‐limiting toxicities. The MPD was cyclophosphamide 750 mg/m² IV on day 1, bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m² IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21‐d cycle). Forty‐nine patients were treated at the MPD of which 22% had high‐risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard‐risk, and 100% and 58% in high‐risk cohort, respectively. After a median follow‐up of 34 months, the median progression‐free survival was 31.3 months. The 2‐yr overall survival was 91.1% in the standard‐risk and 88.9% in the high‐risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.     

Autoreactive B‐lymphocytes in SLE and RA patients: Isolation and characterisation using extractable nuclear and citrullinated antigens bound to immunobeads

Systemic lupus erythematosus and rheumatoid arthritis are autoimmune diseases characterised by B‐cell hyperactivation and production of autoantibodies (AutoAbs) against various self‐antigens, including extractable nuclear antigens and citrullinated peptides. Therefore, B lymphocytes and antibody‐secreting cells are considered relevant targets for therapies. However, isolation and characterisation of auto‐reactive specific B lymphocytes are limited, primarily due to technical issues. In this work, we purified extractable nuclear antigen‐specific and citrullinated peptide‐specific auto‐reactive B lymphocytes by magnetic selection with ENA‐ and citrullinated peptide‐bound immunobeads. We obtained blood auto‐reactive B lymphocytes from most patients. Their nature was primarily naïve B cells, some of them in an active status, with low levels of somatic hypermutations in the immunoglobulin heavy‐chain variable regions. Their presence correlated with serum levels of autoAb. Auto‐reactive B lymphocytes were able to differentiate into auto‐reactive antibody‐secreting cells under conditions of stimulation. In addition, based on the presence of circulating auto‐reactive B cells and/or antibody‐secreting cells, four different profiles were described in lupus patients. Thus, tracking auto‐reactive B cells and/or antibody‐secreting cells in patient blood could represent a biomarker for deciding whether to use therapies blocking either B cells, plasma cells or both, as well as a new tool for monitoring minimal residual autoimmune disease in patients.     

One- or two-stage bilateral total hip replacement.

It is not clear whether bilateral hip replacement should be done in 1 or 2 stages. The total number of total hip replacements (THRs) done in our center between 1989 and 1995 was approximately 4,000. The number of hips that were bilateral was 404, or 9% of the total number of THRs performed during this time period. Of these bilateral hip replacements, 190 (95 patients) were done as a 1-stage procedure, whereas 214 (107 patients) were done in 2 stages with 2 to 24 months in between the operations. In contrast to previous studies, there were no significant preoperative differences between the 2 groups of patients having 1-stage or 2-stage THRs, and, in particular, the comorbidity assessed by the American Society of Anesthesiologists (ASA) grade was not significantly different. Our results demonstrate that, in our patient population, bilateral THR was equally safe whether performed as a 1-stage or 2-stage procedure. This was the case in the low-risk (ASA 1 and 2) and high-risk (ASA 3 and 4) patient subgroups. One-stage bilateral THR is cheaper and involves less time in the hospital.     

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer

Background

Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC.

Methods

This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression.

Results

The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001–1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2.

Conclusion

Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

     

HDAC1 and HDAC2 are differentially expressed in endometriosis

Epigenetic mechanisms have been ascribed important roles in endometriosis. Covalent histone modifications at lysine residues have been shown to regulate gene expression and thus contribute to pathological states in many diseases. In endometriosis, histone deacetylase inhibition (HDACi) resulted in reactivation of E-cadherin, attenuation of invasion, decreased proliferation of endometriotic cells, and caused lesion regression in an animal model. This study was conducted to assess basal and hormone-regulated gene expression levels of HDAC1 and HDAC2 (HDAC1/2) in cell lines and protein expression levels in tissues. Basal and steroid hormone-regulated HDAC1/2 gene expression levels were determined by quantitative polymerase chain reaction in cell lines and tissues. Protein levels were measured by immunohistochemistry (IHC) in tissues on an endometriosis tissue microarray (TMA). Basal HDAC1/2 gene expression levels were significantly higher in endometriotic versus endometrial stromal cells, which was confirmed by Western blot analysis. Estradiol (E2) and progesterone (P4) significantly downregulated HDAC1 expression in endometrial epithelial cells. Levels of HDAC2 were upregulated by E2 and downregulated by E2?+?P4 in endometrial stromal cells. Hormone modulation of HDAC1/2 gene expression was lost in the endometriotic cell line. Immunohistochemistry showed that HDAC1/2 proteins were expressed in a substantial proportion of lesions and endometrium from patients, and their expression levels varied according to lesion localization. The highest proportion of strong HDAC1 immunostaining was seen in ovarian, skin, and gastrointestinal lesions, and of HDAC2 in skin lesions and endometrium from patients with endometriosis. These studies suggest that endometriosis etiology may be partially explained by epigenetic regulation of gene expression due to dysregulations in the expression of HDACs.     

Effects of Risperidone in Autistic Children and Young Adults: A Systematic Review and Meta-Analysis

There are several studies investigating the effects of risperidone on autism, but many of these studies are contradictory or inconclusive. This systematic review and meta-analysis investigated the effects of risperidone on five domains of the Aberrant Behaviour Checklist (ABC) scale on Autism Spectrum Disorder (ASD), as well as weight gain and waist circumference. The protocol for the present systematic review and meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO). For this study, we analysed articles (2,459), selecting them according to the PICOS strategy (Population, Intervention, Comparison, Outcome, Study design). Although risperidone is effective for the treatment of lethargy and inadequate speech, concerns about the association between weight gain, waist circumference and risperidone require a need for evaluation of the risk-benefit ratio in its use. There was a significant association between weight gain, waist circumference and risperidone. In conclusion, it was possible to suggest the efficacy of risperidone for the treatment of lethargy and inadequate speech. Finally, we emphasize that the risk-benefit in its use should be evaluated (Protocol number CRD42019122316).