Is more always better? Effectiveness of constraint-induced movement therapy in children with high-risk or unilateral cerebral palsy (0-6 years): Systematic review and meta-analysis.

BACKGROUND: While constraint-induced movement therapy is strongly recommended as an intervention for infants with unilateral cerebral palsy, the optimal dosage remains undefined. This systematic review aims to identify the most effective level of intensity of constraint-induced movement therapy to enhance manual function in infants at high risk of asymmetric brain lesions or unilateral cerebral palsy diagnosis. METHODS: This systematic review with meta-analysis encompassed a comprehensive search across four electronic databases to identify articles that met the following criteria: randomised controlled trials, children aged 0-6 with at high risk or with unilateral cerebral palsy, and treatment involving constraint-induced movement therapy for upper limb function. Studies with similar outcomes were pooled by calculating the standardised mean difference score for each subgroup, and subgroups were stratified every 30 h of total intervention dosage (30-60, 61-90, >90 h). Risk of bias was assessed with Cochrane Collaboration's tool. RESULTS: Seventeen studies were included. Meta-analyses revealed significant differences among subgroups. The 30-60 h subgroup showed a weak effect for spontaneous use of the affected upper limb during bimanual performance, grasp function, and parents' perception of how often children use their affected upper limb. Additionally, this subgroup demonstrated a moderate effect for the parents' perception of how effectively children use their affected upper limb. CONCLUSIONS: Using a dosage ranging from 30 to 60 h when applying a constraint-induced movement therapy protocol holds promise as the most age-appropriate and cost-effectiveness approach for improving upper limb functional outcomes and parent's perception.

Short-Term Effects of Vestibular Training on Gross Motor Function in Children and Youth with Cerebral Palsy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

AIMS: To review the literature on the effects of vestibular training on motor function and balance in children and youth with cerebral palsy. METHODS: Eight databases (MEDLINE-PubMed, PEDro, Cochrane Library, OTSeeker, Web of Science, Scopus Database, CINAHL and SPORTDiscus.) were searched up to May 15th, 2023. Studies comparing vestibular training with other types of interventions. The DerSimonian and Laird method was employed using random effects models to calculate the pooled estimate of the effect size with confidence intervals of 95%. The risk of bias was assessed with the Cochrane Collaboration's tool and the Grading of Recommendations Assessment, Development and Evaluation approach was used to judge the certainty of the evidence for all outcomes. RESULTS: Eight studies were included comprising 226 participants with cerebral palsy. The meta-analyses demonstrated significant standardized mean differences in favor of vestibular training program compared to other technique(s) for Gross Motor Function Measure (-0.471; 95% confidence intervals: -0.919 to -0.023) and balance (-0.546; 95% confidence intervals: -0.916 to -0.176). CONCLUSIONS: Vestibular training has potential benefits in the short-term as a therapeutic approach for improving gross motor function and the balance in children and youth with cerebral palsy, but further research is needed.

Electrical microcurrent stimulation therapy for wound healing: A meta-analysis of randomized clinical trials.

BACKGROUND: Electrical microcurrent therapy (EMT) consists of the application of low intensity (µA) currents that are similar to endogenous electric fields generated during wound healing. AIMS: To examine the effectiveness and safety of EMT for improving wound healing and pain in people with acute or chronic wounds. METHOD: Randomized clinical trials (RCTs) assessing the effectiveness of EMT in wound healing published up to August 1st, 2020 were included. The main outcomes were wound surface area, healing time, and number of wounds healed. Secondary outcomes were pain perception and adverse events. A quantitative analysis was conducted using the inverse variance and Mantel-Haenszel methods. RESULTS: Eight RCTs were included in the qualitative summary and seven in the quantitative analysis (n = 337 participants). EMT plus standard wound care (SWC) produced a greater decrease in wound surface [mean difference (MD) = -8.3 cm2; CI 95%: -10.5 to -6.0] and healing time (MD = -7.0 days; CI 95%: -11.9 to -2.1) that SWC alone, showing moderate and low certainty in the evidence, respectively. However, no differences were observed in the number of healed wounds [risk ratio = 2.0; CI 95%: 0.5 to 9.1], with very low quality of evidence. EMT decreased perceived pain (MD = -1.4; CI 95%: -2.7 to -0.2), but no differences in adverse effects were noted between groups (risk difference = 0.05; CI 95%: -0.06 to 0.17). CONCLUSIONS: EMT is an effective, safe treatment for improving wound area, healing time, and pain. Further clinical trials that include detailed intervention parameters and protocols should be designed to lower the risk of bias.

The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation.

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.

Cancer cell plasticity: Impact on tumor progression and therapy response.

Most tumors exhibit intra-tumor heterogeneity, which is associated with disease progression and an impaired response to therapy. Cancer cell plasticity has been proposed as being an important mechanism that, along with genetic and epigenetic alterations, promotes cancer cell diversity and contributes to intra-tumor heterogeneity. Plasticity endows cancer cells with the capacity to shift dynamically between a differentiated state, with limited tumorigenic potential, and an undifferentiated or cancer stem-like cell (CSC) state, which is responsible for long-term tumor growth. In addition, it confers the ability to transit into distinct CSC states with different competence to invade, disseminate and seed metastasis. Cancer cell plasticity has been linked to the epithelial-to-mesenchymal transition program and relies not only on cell-autonomous mechanisms, but also on signals provided by the tumor microenvironment and/or induced in response to therapy. We provide an overview of the dynamic transition for cancer cell states, the mechanisms governing cell plasticity and their impact on tumor progression, metastasis and therapy response. Understanding the mechanisms involved in cancer cell plasticity will provide insights for establishing new therapeutic interventions.

Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.

The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.

Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis.

Receptor Activator of NF-kappa B (RANK) pathway controls mammary gland development in mice but its role in mammary stem cell fate remains undefined. We show that constitutive RANK signaling expands luminal and basal mammary compartments including mammary stem and luminal progenitor cell pools and interferes with the generation of CD61+ and Sca1+ luminal cells and Elf5 expression. Impaired mammary cell commitment upon RANK overexpression leads to the accumulation of progenitors including K14+K8+ bipotent cells and the formation of heterogeneous tumors containing hyperplastic basal, luminal, and progenitor cells. RANK expression increases in wild-type mammary epithelia with age and parity, and spontaneous preneoplastic lesions express RANK and accumulate K14+K8+ cells. In human breast tumors, high RANK expression levels are also associated with altered mammary differentiation. These results suggest that increased RANK signaling interferes with mammary cell commitment, contributing to breast carcinogenesis.

Telomere lengthening early in development.

Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.

XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer.

TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.

Higher adherence to the Mediterranean Diet is associated with better academic achievement in Spanish university students: A multicenter cross-sectional study.

The objective was to assess the association of the overall score and different items of the Mediterranean Diet Adherence Screener (MEDAS) questionnaire with academic achievement in Spanish university students. We hypothesized that university students with greater adherence to the Mediterranean Diet (MedDiet) would have better academic achievement. A cross-sectional study was performed involving 266 first-year students from the University of Castilla-La Mancha, Spain, during the 2017-2018 academic year. Adherence to the Mediterranean diet was evaluated with the 14-item MEDAS questionnaire. As an indicator variable for academic achievement, the average marks of the examinations required for access to Spanish universities were used. A total of 63 participants (23.6%) adhered to MedDiet recommendations. Analysis of covariance models showed that participants with higher adherence to the MedDiet had significantly higher scores on academic achievement than their peers with low adherence (P < .001) after controlling for potential confounders. Additionally, the evaluation of each item of the MEDAS questionnaire showed that a diet rich in olive oil, vegetables, fruits, legumes, fish and shellfish, and a low consumption of sweets and carbonated beverages were positively associated with academic achievement; nevertheless, wine intake was inversely associated. This study showed that Spanish university students had a low prevalence of good adherence to the MedDiet. Additionally, our results suggested that higher adherence to the MedDiet is associated with better academic achievement in Spanish university students. From a public health perspective and because of low adherence, it is important to continue to focus on promoting adherence to the MedDiet as part of a healthy lifestyle pattern to improve the academic performance of young university students.

Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma.

Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.

Case Report: Hemophagocytic Lymphohistiocytosis Secondary to Plasmodium ovale wallikeri Infection.

We report the first known case of hemophagocytic lymphohistiocytosis (HLH) secondary to imported Plasmodium ovale wallikeri infection in a 58-year-old white woman. A delayed diagnosis of malaria and HLH was made after protracted fever and pancytopenia failed to respond adequately to antimalarial treatment, which required intravenous methylprednisolone and gamma-globulin therapy to resolve.

The effect of therapeutic exercise in the prevention of lymphoedema secondary to breast cancer: a systematic review.

Introduction: One of the most frequent complications of breast cancer treatment is lymphoedema (LE), with lymphadenectomy and radiotherapy being the main triggers of this pathology in developed countries. The aim of the study was to determine the efficacy of therapeutic exercise in the prevention of upper limb (UL) lymphoedema evaluated through cirtometry, volumetry, or bioimpedance spectroscopy (BIS) in women after breast cancer removal surgery. Material and methods: The Pubmed, PEDro, and Cochrane databases were consulted up to May 2020, including randomised clinical trials (RCTs) on therapeutic physical exercise as a possible preventive measure against breast cancer-related lymphoedema (BCRL). The studies were requested to have participants with UL lymphoedema and a control group. Results: A total of 304 articles were found, of which 9 were included (stand-alone studies). A therapeutic exercise program (strength and/or aerobic training) in women who had been surgically intervened for breast cancer may prevent lymphedema, compared to a regular care. Conclusions: A therapeutic exercise program (strength and/or aerobic training) in women operated on for breast cancer contributes to reducing the number of cases that could obtain a greater difference in volume in their upper limbs, compared to a regular care program. However, further research is necessary to affirm that therapeutic physical exercise prevents BCRL.

Effect of Vitamin D Supplementation on Fatigue in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Vitamin D supplementation has been considered a possible treatment to reduce the risk of disease activity and progression in people with multiple sclerosis (MS). However, its effect on disease symptoms remains unclear. The aim of this meta-analysis was to conduct a systematic review to assess the effect of vitamin D on fatigue in this population. The systematic review was conducted using the MEDLINE, Cochrane Library, Embase and Web of Science databases from inception to May 2023. Randomized controlled trials (RCTs) reporting pre-post changes in fatigue after vitamin D supplementation were included. Pooled effect sizes and 95% confidence intervals (95% CIs) were calculated by applying a random effects model with Stata/SE (Version 16.0; StataCorp., College Station, TX, USA). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A total of five studies with 345 individuals (271 females; age range: 25.4-41.1 years) were included. A significant reduction in fatigue was perceived when vitamin D supplementation was compared with a control group: -0.18 (95% CI: -0.36 to -0.01; I2 = 0%). Thus, our findings show that the therapeutic use of vitamin D on fatigue in people with MS could be considered. Nevertheless, due to the lack of agreement on the dose to be applied, it is recommended to use it under medical prescription.

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.

Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc(-/-)) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.

Blockade of novel immune checkpoints and new therapeutic combinations to boost antitumor immunity.

Immunotherapy has emerged as a promising strategy for boosting antitumoral immunity. Blockade of immune checkpoints (ICs), which regulate the activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells has proven clinical benefits. Antibodies targeting CTLA-4, PD-1, and PD-L1 are IC-blockade drugs approved for the treatment of various solid and hematological malignancies. However, a large subset of patients does not respond to current anti-IC immunotherapy. An integrative understanding of tumor-immune infiltrate, and IC expression and function in immune cell populations is fundamental to the design of effective therapies. The simultaneous blockade of newly identified ICs, as well as of previously described ICs, could improve antitumor response. We review the potential for novel combinatory blockade strategies as antitumoral therapy, and their effects on immune cells expressing the targeted ICs. Preclinical evidence and clinical trials involving the blockade of the various ICs are reported. We finally discuss the rationale of IC co-blockade strategy with respect to its downstream signaling in order to improve effective antitumoral immunity and prevent an increased risk of immune-related adverse events (irAEs).

Effectiveness of Microcurrent Therapy for Treating Pressure Ulcers in Older People: A Double-Blind, Controlled, Randomized Clinical Trial.

The aim of this study was to assess the effectiveness of microcurrent therapy for healing pressure ulcers in aged people. A multicentric, randomized clinical trial was designed with a sham stimulation control. The experimental group received an intervention following a standardized protocol for curing ulcers combined with 10 h of microcurrent therapy daily for 25 days. The sham group received the same curing protocol plus a sham microcurrent stimulation. The studied healing-related variables were the Pressure Ulcer Scale for Healing (PUSH) and the surface, depth, grade, and number of ulcers that healed completely. Three evaluations were conducted: pre-intervention (T1), 14 days following the start of the intervention (T2), and 1 day after the intervention was completed (T3). In total, 30 participants met the inclusion criteria (n = 15 in each group). The improvement in the PUSH at T2 and T3 was 16.8% (CI95% 0.5-33.1) and 25.3% (CI95% 7.6-43.0) greater in the experimental group versus the sham control, respectively. The reduction in the wound area at T2 and T3 was 20.1% (CI95% 5.2-35.0) and 28.6% (CI95% 11.9-45.3) greater in the experimental group versus the control, respectively. Microcurrent therapy improves the healing of pressure ulcers in older adults, both quantitatively and qualitatively.

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation.

The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.

The type of exercise most beneficial for quality of life in people with multiple sclerosis: A network meta-analysis.

BACKGROUND: There is overwhelming evidence regarding the beneficial effects of exercise on the management of symptoms, functionality and health-related quality of life (HRQoL) of people with multiple sclerosis (MS). However, few analyze have compared different types of exercise. OBJECTIVE: The aim of this network meta-analysis (NMA) was to assess which type of physical exercise has the greatest positive effect on HRQoL in people with MS. METHODS: MEDLINE, Cochrane Library, Embase, Web of Science, Physiotherapy Evidence Database and SPORTDiscus databases were searched from inception to June 2021 to identify randomized controlled trials (RCTs) examining the effect of physical exercise on HRQoL in people with MS. The NMA included pairwise and indirect comparisons. We ranked the effect of interventions calculating the surface under the cumulative ranking (SUCRA). RESULTS: We included 45 RCTs in this NMA (2428 participants; 76% women; mean age 45 years). Five types of physical exercises were ranked. Sensorimotor training had the highest effect size (0.87, 95% confidence interval [CI] 0.60; 1.15) and the highest SUCRA (87%) for total HRQoL. The highest effect size and SUCRA for physical and mental HRQoL were for aerobic exercise (0.85, 95% CI 0.28; 1.42) (89%) and mind-body exercises (0.54, 95% CI 0.03; 1.06) (89%). Sensorimotor training was the best exercise for mild disease and aerobic exercise for severe disease for total HRQoL. CONCLUSIONS: Sensorimotor training seems the most effective exercise to improve HRQoL and aerobic and mind-body exercises to improve physical and mental HRQoL, respectively.