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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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 Role of Physiotherapy in Pediatric Palliative Care: A Systematic Review.

Pediatric palliative care (PPC) is a set of actions aimed at children who suffer from a severe or life-threatening disease to alleviate the symptoms of the disease and improve the quality of life of both the child and his/her family. One of the tools used to control symptoms is physiotherapy; however, its application in the child population has not been thoroughly studied. The main objective of this study was to gather, analyze, and critically evaluate the available scientific evidence on physiotherapy in children who require palliative care through a systematic review of the studies published in the last 10 years in the following databases: PubMed, Cochrane Library, PEDro, CINAHL, and Scopus. Of a total of 622 studies, the inclusion criteria were only met by seven articles, which were focused on the relationship between physiotherapy and PPC. This study analyzed: (1) the main pathologies treated, with a predominance of cerebral palsy and cancer; (2) the interventions applied, such as respiratory physiotherapy, neurological physiotherapy, therapeutic massage, and virtual reality; (3) the effects achieved in the child and his/her family, highlighting the control of symptoms and the improvement of the quality of life; and (4) the knowledge of the physiotherapists on PPC, observing that most of the professionals had not received training in this scope. The findings of this review indicate a lack of an adequate evidence foundation for physiotherapy in PPC.

Early Intervention in Unilateral Cerebral Palsy: Let's Listen to the Families! What Are Their Desires and Perspectives? A Preliminary Family-Researcher Co-Design Study.

Cerebral palsy (CP) is a clinical diagnosis based on a combination of clinical and neurological signs, which occurs between the ages of 12 and 24 months. Cerebral palsy or a high risk of cerebral palsy can be accurately predicted before 5-6 months, which is the corrected age. This would allow the initiation of intervention at an early stage. Parents must be more involved in the development and implementation of the early therapy, increasing opportunities for parent-child interaction. The aim of this study was to learn from the perspectives of families with children under 12 months with unilateral cerebral palsy (UCP), what ingredients (barriers and facilitators) should be involved in early intervention so that we could co-design (researchers and families) a multidisciplinary guideline for a global intervention addressed to the needs of the child and the family. Semi-structured interviews were conducted at a time and venue convenient for the families. A total of ten families with experience in early intervention were invited to attend the interview with open questions: (1) What components should early intervention have for a baby diagnosed with UCP? (2) What components should early intervention have for the family? (3) What should the involvement of the family be in early intervention? (4) What barriers included in early intervention should be removed? From the data analysis, three key topics emerged and were subsequently named by focus group participants: (1) UCP early intervention components, (2) family involvement in early intervention of UCP, and (3) removing barriers and creating facilitators within early intervention. The participation of the families (mothers) in the co-design of the necessary ingredients within the scope of a multidisciplinary early intervention guide aimed at children with UCP under 12 months allows learning about their reality and not that of the therapist. The following list highlights the present barriers as perceived by the parents: intervention as spectators, therapeutic goals, clinic environment, and lack of empathy, and the possible facilitators determined by the parents during the implementation comprised teamwork, the family's goals, motivation during the intervention, and learning at home. Thus, an early intervention program to improve global functionality should address family involvement through multidisciplinary coaching and the modification of the environment, encouraging family goals and family support through the family-therapist team.

Efficacy of the use of unaffected hand containment in unimanual intensive therapy to increase visuomotor coordination in children with hemiplegia: a randomized controlled pilot study.

BACKGROUND: The capacity of children with hemiplegia to be engaged in anticipatory action planning is affected. There is no balance among spatial, proprioceptive and visual information, thus altering the affected upper limb visuomotor coordination. The objective of the present study was to assess the improvement in visuomotor coordination after the application of a unimanual intensive therapy program, with the use of unaffected hand containment compared with not using unaffected hand containment. METHODS: A simple blind randomized clinical trial was realized. A total of 16 subjects with congenital infantile hemiplegia participated in the study with an age mean of 5.54 years old (SD:1.55). Two intensive protocols for 5 weeks of modified constraint-induced movement therapy (mCIMT) or unimanual therapy without containment (UTWC) were executed 5 days per week (2 h/day). Affected upper limb visuomotor coordination (reaction time, task total time, active range, dynamic grasp) was measured before-after intensive therapy using a specific circuit with different slopes (10°/15°). RESULTS: Statistically significant inter-group differences were found after the intervention, with clinically relevant results for the mCIMT group not seen in UTWC, in the following variables: reaction time 10°slope (p = 0.003, d = 2.44), reaction time 15°slope (p = 0.002, d = 2.15) as well as for the task total time 10°slope (p = 0.002, d = 2.25), active reach 10°slope (p = 0.002, d = 2.7), active reach 15°slope (p = 0.003, d = 2.29) and dynamic grasp 10°/15°slopes (p = <0.001, d = 2.69). There were not statistically significant inter-group differences in the total task time with 15°slope (p = 0.074, d = 1.27). CONCLUSIONS: The use of unaffected hand containment in mCIMT would allow improvements in the affected upper limb's visuomotor coordination. Thus, it would favor clinical practice to make decisions on therapeutic approaches to increase the affected upper limb functionality and action planning in children diagnosed with infantile hemiplegia (4-8 years old).

The "Fat but Fit" Paradigm and Bone Health in Young Adults: A Cluster Analysis.

The fat but fit paradox has suggested that obese individuals with good fitness levels have lower cardiometabolic risk compared to individuals with normal weight but lower fitness levels. This paradigm has not been explored in the context of bone health. The aim of this study was to test whether categories of fat but fit paradigm assessed by body fat percentage and handgrip strength holds up in young adults and to analyze the relationship between fat but fit categories and bone outcomes. Cluster cross-sectional analyses of data from 499 young adults aged 18 to 30 from Toledo and Cuenca, Spain were conducted. Body fat percentage, handgrip strength, bone mineral content (BMC), bone mineral density (BMD), and dietary nutrients such as, proteins, magnesium, calcium, phosphorus, potassium, and vitamin D were assessed. Cluster analysis of body fat percentage and handgrip z scores resulted in a classification of four clusters that could be interpreted according to Fat Unfit (FU), Unfat Unfit (UU), Fat Fit (FF) and Unfat Fit (UF) categories. ANCOVA models showed that young adults in clusters with higher handgrip strength levels (FF, UF) and with higher key bone nutrients levels (UF) had significantly higher total BMC values than their peers in the UU and FU cluster categories, after controlling for sex, age and height. This study provides two novel conclusions in relation to the fat but fit paradigm: first, it confirms the construct of the four clusters of body fat percentage and handgrip strength, and second, it reinforces the predictive validity of the fat but fit paradigm categories, indicating the positive effect, although it may not just be a causal relationship, of muscular strength and key bone nutrients on counteracting the negative effect of obesity on bone health.

FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma.

PURPOSE: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. EXPERIMENTAL DESIGN: We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. RESULTS: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. CONCLUSIONS: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.

Modified Constraint-Induced Movement Therapy at Home-Is It Possible? Families and Children's Experience.

Modified constraint-induced movement therapy (mCIMT) is efficient at improving upper limb non-use. The experiences of families and children with mCIMT could allow researchers to understand how it influences their day-to-day life and to improve the function of the affected upper limb without altering family life and avoiding frustration. In this qualitative study, we aimed to collect the experiences of parents and their children (aged 4-8 years) who did mCIMT at home regarding the application of low-intensity modified constraint-induced movement therapy to improve the affected upper limb functionality in infantile hemiplegia with moderate manual ability. Individual semi-structured interviews were performed to obtain insights into their experience with mCIMT. The experiences of parents and children were described in thematic sections. Eight children with hemiplegia (six years, standard deviation, SD: 1.77) and their parents were asked about their experiences after applying 50 h of mCIMT at home. Three main themes emerged from the children's interview data: (1) the experience of wearing the containment in the modified constraint-induced movement therapy (CIMT) intervention, (2) the reaction to performing the therapy at home with his/her family, and (3) learning of the affected upper limb. In the parents' interview data, there were two main themes: (1) the difficulty of executing an intensive therapy protocol (mCIMT: 50 h) at home and (2) the feeling of not wanting to finish the intervention. The experiences of the parents and their children regarding mCIMT allowed us to understand the facilitators and barriers that affect the execution of mCIMT at home, and this understanding allows us to improve its future application.

Application of Low-Intensity Modified Constraint-Induced Movement Therapy to Improve the Affected Upper Limb Functionality in Infantile Hemiplegia with Moderate Manual Ability: Case Series.

OBJECTIVE: To assess the functionality of the affected upper limb in children diagnosed with hemiplegia aged between 4 and 8 years after applying low-intensity modified Constraint-Induced Movement Therapy (mCIMT). METHODS: Prospective case series study. A mCIMT protocol was applied for five weeks, with two hours of containment per day. The study variables were quality of movement of the upper limb, spontaneous use, participation of the affected upper limb in activities of daily living, dynamic joint position, grasp-release action, grasp strength, supination and extension elbow movements. Four measurements were performed, using the quality of upper extremity test (QUEST) scale, the Shriners Hospital for Children Upper Extremity Evaluation (SHUEE) Evaluation, a hand dynamometer and a goniometer. RESULTS: The sample was composed of eight children with moderate manual ability. Statistically significant differences were detected in all the studied variables (p < 0.05) between the pre-treatment and post-treatment results (Week 0-Week 5), except for upper limb dressing, putting on splints and buttoning up. In the first week, the changes were statistically significant, except for protective extension, grasp strength, grasp-release and all functional variables (level of functionality and participation of the patient's upper limbs) in the SHUEE Evaluation (p > 0.05). The greatest increase occurred in spontaneous use from Assessment 1 to Assessment 4 (p = 0.01), reaching 88.87% active participation in bimanual tasks. The quality of movement of the upper limb exhibited a significant value due to the increase in dissociated movements and grasp (p = 0.01). CONCLUSION: A low dose (50 h) of mCIMT increased the functionality of children diagnosed with congenital hemiplegia between 4 and 8 years of age with moderate manual ability.