This systematic review and meta-analysis aim to provide scientific evidence regarding the effects of training on respiratory muscle training’s impact with the PowerBreath®. A systematic analysis ...based on the PRISMA guides and a conducted research structured around the bases of Web of Science, Scopus, Medline/PubMed, SciELO y Cochrane Library Plus. Six articles published before January 2021 were included. The documentation and quantification of heterogeneity in every meta-analysis were directed through Cochran’s Q test and the statistic I2; additionally, a biased publication analysis was made using funnel plots, whose asymmetry was quantified Egger’s regression. The methodological quality was assessed through McMaster’s. PowerBreath® administering a ≥ 15% resistive load of the maximum inspiratory pressure (PIM) achieves significant improvements (54%) in said pressure within 4 weeks of commencing the inspiratory muscle training. The maximal volume of oxygen (VO2max) considerable enhancements was achieved from the 6 weeks associated with the maximum inspiratory pressure ≥ 21.5% post inspiratory muscle training onwards. Conversely, a significant blood lactate concentration decrement occurred from the 4th week of inspiratory muscle training, after a maximum inspiratory pressure ≥ 6.8% increment. PowerBreath® is a useful device to stimulate sport performance and increase pulmonary function.
Upregulation of a cyclin D gene determined by expression microarrays is an almost universal event in multiple myeloma (MM), but this finding has not been properly confirmed at the protein level. For ...this reason, we carried out a quantitative analysis of cyclin D proteins using a capillary electrophoresis nanoimmunoassay in newly diagnosed MM patients. Exclusive expression of cyclin D1 and D2 proteins was detected in 54 of 165 (33%) and 30 of 165 (18%) of the MM patients, respectively. Of note, cyclin D1 or D2 proteins were undetectable in 41% of the samples. High levels of cyclin D1 protein were strongly associated with the presence of t(11;14) or 11q gains. Cyclin D2 protein was detected in all the cases bearing t(14;16), but in only 24% of patients with t(4;14). The presence of cyclin D2 was associated with shorter overall survival (hazard ratio =2.14; P=0.017), although patients expressing cyclin D2 protein, but without 1q gains, had a favorable prognosis. In conclusion, although one of the cyclins D is overexpressed at the mRNA level in almost all MM patients, in approximately half of the patients this does not translate into detectable protein. This suggests that cyclins D could not play an oncogenic role in a proportion of patients with MM (clinicaltrials gov. identifier: NCT01916252).
Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is ...undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (
,
,
,
,
,
,
,
and
) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb;
< 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of
(rs79662648),
(rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354),
(rs251796 and rs344152214), and
(rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.
Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high ...risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P<0.03). When plasma cells from high-risk smoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235).
PD1 expression in CD4
and CD8
T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as ...consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43,
= 0.007; 1.12 vs. 0.86,
= 0.02). In the early progressors, a significantly lower expression of PD1 in CD8
effector memory T cells (MFI 1327 vs. 926,
= 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.
Summary
Biallelic inactivation of TP53 has been included in the definition of double‐hit (DH) multiple myeloma (MM), which entails an ominous prognosis. However, this condition, or even the presence ...of high‐risk cytogenetic abnormalities, cannot accurately capture the 15%–20% of the MM population with a median overall survival below 24 months. This prompted us to look for other MM patients who might have transcriptional characteristics similar to those with DH‐TP53. In the present study, we analysed RNA‐seq, whole‐genome and whole‐exome sequencing data from 660 newly diagnosed MM (NDMM) patients from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study to characterize the transcriptional signature of TP53 double‐hit (DH‐TP53) MM. We found 78 genes that were exclusively deregulated in DH‐TP53 patients. A score based on these genes identified a group of 50 patients who shared the same transcriptional profile (DH‐TP53‐like group) whose prognosis was particularly unfavourable median overall survival (OS) < 2 years, despite not harbouring the biallelic inactivation of TP53. The prognostic value of the DH‐TP53 score was externally validated using gene expression data from 850 NDMM patients analysed by microarrays. Furthermore, our DH‐TP53 score refined the traditional prognostic stratification of MM patients according to the cytogenetic abnormalities and International Staging System (ISS).
Sports performance in athletes can be limited by respiratory factors, so it is understandable to propose that inspiratory muscle training (IMT) can improve respiratory function and exercise ...performance. Power-Breathe
(PwB) is a sectorized respiratory muscle training tool that uses a resistive load to train IMT. There is currently a growing interest in respiratory muscle training, so we set out to systematically assess the effects of IMT with PwB on respiratory parameters and athletic performance in physically active, healthy adults. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, the Cochrane and PEDro scales to assess methodological quality, effect size using the Rosenthal formula, and the Cochrane tool for estimation of risk of bias, studies searchable in Medline, Web of Science, and Cochrane. In addition, for the performance of the meta-analysis, the documentation and quantification of the heterogeneity in each meta-analysis were directed through the Cochran's Q test and the I2 statistic; in addition, a publication bias analysis was performed using funnel plots. Of the total of 241 studies identified in the search, 11 studies for the systematic review and nine for the meta-analysis met the exclusion and/or inclusion criteria. IMT, with PwB, showed significant improvements in maximal inspiratory pressure (MIP) and substantial improvements in forced vital capacity (FVC) in the meta-analysis results. Also, sports performance was significantly increased by IMT with PwB. In conclusion, the use of PwB is an IMT tool that improves respiratory and sports performance.
Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic ...gene combinations.
To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs).
The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient.
Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.
Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily ...pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several
and
models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed
,
, and
synergy with pomalidomide plus dexamethasone treatment. Importantly, the
synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients.
PDF
