Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation.

Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFß synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.

Formation of an invasion-permissive matrix requires TGFß/SNAIL1-regulated alternative splicing of fibronectin.

BACKGROUND: As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFß, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFß target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses. METHODS: We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis. RESULTS: In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFß-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix  that does not sustain TGFß-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis. CONCLUSIONS: Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment.

Comparative Analysis of Power Consumption between MQTT and HTTP Protocols in an IoT Platform Designed and Implemented for Remote Real-Time Monitoring of Long-Term Cold Chain Transport Operations.

IoT platforms for the transportation industry are portable with limited battery life and need real-time and long-term monitoring operations. Since MQTT and HTTP are widely used as the main communication protocols in the IoT, it is imperative to analyze their power consumption to provide quantitative results that help maximize battery life in IoT transportation systems. Although is well known that MQTT consumes less power than HTTP, a comparative analysis of their power consumption with long-time tests and different conditions has not yet been conducted. In this sense, a design and validation of an electronic cost-efficient platform system for remote real-time monitoring is proposed using a NodeMCU module, in which experimentation is carried out for HTTP and MQTT with different QoS levels to make a comparison and demonstrate the differences in power consumption. Furthermore, we characterize the behavior of the batteries in the systems and compare the theoretical analysis with real long-time test results. The experimentation using the MQTT protocol with QoS 0 and 1 was successful, resulting in power savings of 6.03% and 8.33%, respectively, compared with HTTP, demonstrating many more hours in the duration of the batteries, which could be very useful in technological solutions for the transport industry.

Amygdala stimulation ameliorates memory impairments and promotes c-Fos activity in fimbria-fornix-lesioned rats.

Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.

How Much Is Needed? Comparison of the Effectiveness of Different Pain Education Dosages in Patients with Fibromyalgia.

OBJECTIVE: To assess the effect of different dosages of pain neuroscience education (PNE) programs on central nociceptive processing in patients with fibromyalgia. Second, to compare the effects of different dosages of PNE programs on numerical pain rating scale (NPRS), disability, and psychological variables. DESIGN: Single-blind randomized controlled trial. SETTING: Three fibromyalgia centers in Spain (Valencia, Alcorcón, Alcalá de Henares). SUBJECTS: Seventy-seven patients with fibromyalgia. METHODS: Participants were randomized to four groups of PNE: 1) high-dose PNE (N = 20), 2) low-concentrated dose PNE (N = 20), 3) diluted low-dose PNE (N = 20), and (4) control treatment (N = 17), conducted in two 30-50-minute sessions in groups of four to six participants. Conditioned pain modulation (CPM), temporal summation (TS), and pressure pain thresholds (PPTs) were assessed at baseline and at three-month follow-up. Secondary outcome measures were the Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, and Pain Anxiety Symptoms Scale. RESULTS: There were significant between-group differences for NPRS in favor of the groups receiving high-dose PNE, with a large effect size at three-month follow-up (P < 0.01, η2p = 0.170), but there were no significant differences between groups for the remaining variables (P > 0.05). All groups improved for central nociceptive processing, psychological variables, disability, and pain intensity (NPRS). CONCLUSIONS: In patients with fibromyalgia, higher dosages of PNE produced a larger improvement in pain severity at three-month follow-up than other dosages of PNE and biomedical education. However, PNE was not superior to biomedical education in the central nociceptive processing, disability, or psychological variables in patients with fibromyalgia.

Hip-Joint Posture and Movement Alterations Are Associated With High Interference of Pain in the Life of Patients With Greater Trochanteric Pain Syndrome.

OBJECTIVE: Greater trochanteric pain syndrome (GTPS) is a common condition that can cause lateral hip pain. The single-leg-squat test (SLST) may be used by physicians in primary care environments to evaluate patients' dynamic stability. The aim of this study was to evaluate the dynamic stability and strength of lateral abduction hip movements in primary care patients with GTPS in relation to their perceived pain interference in life. METHODS: A descriptive observational study was carried out in a primary health care center. Fifty-four participants with GTPS were included in this study and divided into lower- and higher-interference groups (n = 30 and 19, respectively) according to the Graded Chronic Pain Scale. Participants were evaluated for their lateral abduction hip strength and the SLST. RESULTS: The SLST showed a statistically significant difference between groups with respect to hip-joint posture and movement level (P = .043) but not for other SLST domains or lateral abduction hip strength (P > .05). CONCLUSION: Patients with GTPS with more pain interference in their lives had poorer dynamic stability with respect to hip-joint posture and movements based on the SLST but did not present impaired lateral hip abduction strength in comparison with those who perceived lower pain interference in life.

Abrogation of myofibroblast activities in metastasis and fibrosis by methyltransferase inhibition.

Myofibroblasts are a population of highly contractile fibroblasts that express and require the activity of the transcription factor Snail1. Cancer-associated fibroblasts (CAFs) correlate with low survival of cancer patients when present in the stroma of primary tumors. Remarkably, the presence of myofibroblastic CAFs (which express Snail1) creates mechanical properties in the tumor microenvironment that support metastasis. However, therapeutic blockage of fibroblast activity in patients with cancer is a double-edged sword, as normal fibroblast activities often restrict tumor cell invasion. We used fibroblasts depleted of Snail1 or protein arginine methyltransferases 1 and 4 (PRMT1/-4) to identify specific epigenetic modifications induced by TGFß/Snail1. Furthermore, we analyzed the in vivo efficiency of methyltransferase inhibitors using mouse models of wound healing and metastasis, as well as fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF). Mechanistically, TGFß-induced Snail1 promotes the epigenetic mark of asymmetrically dimethylated arginine. Critically, we found that inhibitors of methyltransferases prevent myofibroblast activity (but not regular fibroblast activity) in the extracellular matrix, both in cell culture and in vivo. In a mouse breast cancer model, the inhibitor sinefungin reduces both the myofibroblast activity in the tumor stroma and the metastatic burden in the lung. Two distinct inhibitors effectively blocked the exacerbated myofibroblast activity of patient-derived IPF fibroblasts. Our data reveal epigenetic regulation of myofibroblast transdifferentiation in both wound healing and in disease (fibrosis and breast cancer). Thus, methyltransferase inhibitors are good candidates as therapeutic reagents for these diseases.

Pain Expansion and Severity Reflect Central Sensitization in Primary Care Patients with Greater Trochanteric Pain Syndrome.

OBJECTIVES: The aims of this study were twofold: 1) to evaluate the differences in pain sensitivity of patients with greater trochanteric pain syndrome (GTPS) and 2) to examine the association between pain expansion, pain severity, and pain-related central sensitization somatosensory variables in patients with GTPS. STUDY DESIGN: A cross-sectional study. SETTING: Primary health care centers. SUBJECTS: The sample consisted of 49 participants with a mean age of 48.28 ± 8.13 years and included eight males (16.3%) and 41 females (83.7%). METHODS: Conditioned pain modulation (CPM), pain location, temporal summation, pressure pain detection threshold (PPDT), and pain intensity were recorded. Pain severity was determined with the Graded Chronic Pain Scale (GCPS). RESULTS: Several participants (34.7%) showed a negative conditioned pain modulation and a statistically significant negative moderate correlation (P < 0.05; r = -0.316) between conditioned pain modulation and right view percentage of pain location. Temporal summation at the major trochanter showed a statistically significant low negative correlation (P < 0.05; r = -0.298). The GCPS exhibited a statistically significant moderately positive correlation (P < 0.01; r = 0.467) with the PPDT at the trochanter and a significant correlation with the postero-superior iliac spine (P < 0.01; r = 0.515) and epicondyle (P < 0.01; r = 0.566). CONCLUSIONS: Patients with GTPS presented altered CPM, a relationship with more pain areas associated with negative CPM, and a positive association between pain severity and mechanical hyperalgesia at remote sites. Thus, physicians could apply these outcome measurements to assess primary care patients with GTPS and determine the central sensitization presence to prescribe adequate multimodal treatment approaches.

Relationship of Dynamic Balance Impairment with Pain-Related and Psychosocial Measures in Primary Care Patients with Chronic Greater Trochanteric Pain Syndrome.

OBJECTIVE: Subjects with greater trochanteric pain syndrome (GTPS) show an altered physical function while performing static and dynamic tasks. Pain and psychosocial factors are also variables that influence the outcomes of these patients. Thus, the aim of this study was to evaluate the relationship between dynamic balance, pain-related measures, and psychosocial measures in subjects with chronic GTPS. DESIGN: Descriptive cross-sectional study. SETTING: Primary health care center. SUBJECTS: Fifty-one subjects with greater trochanteric pain syndrome were recruited. METHODS: Dynamic balance was evaluated using the Y-Balance Test (YBT), and a self-reported test battery was used to assess the following aspects: pain catastrophizing (Pain Catastrophizing Scale [PCS]), kinesiophobia (Tampa Scale of Kinesiophobia [TSK-11]), pain intensity (visual analog scale [VAS]), disability (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), and self-efficacy (Chronic Pain Self-Efficacy Scale [CPSS]). RESULTS: Correlation analysis showed that YBT was negatively associated with the VAS average, the helplessness subscale of the PCS, and the pain and function subscales and total score of the WOMAC. YBT was positively associated with the pain subscale of the CPSS. The scores of the YBT forward movement were predicted by the VAS average (38.1% of variance) in addition to the WOMAC total score (34.2% of variance) and TSK-11 total score (43.8% of variance). CONCLUSIONS: The findings of this study suggest that kinesiophobia, pain, and physical function are related to dynamic balance in subjects with GTPS. Thus, when diagnosing and planning the treatment of patients with GTPS, psychosocial and physical function factors should be taken into account, in addition to pain management.

Prediction Model for Choosing Needle Length to Minimize Risk of Median Nerve Puncture With Dry Needling of the Pronator Teres.

OBJECTIVE: The aim of this study was to relate forearm anthropometric measures to ultrasound pronator teres depth to determine the necessary needle length to prevent median nerve (MN) injury during pronator teres dry needling. METHODS: We conducted a study employing a diagnostic accuracy prediction model (NCT03308279) at a Spanish university center. The study recruited 65 participants to predict the depth of the MN (measured with ultrasound) in the pronator teres using a decision tree algorithm to reduce the risk of MN puncture using 2 needle lengths (13 mm or 25 mm). The decision tree was developed by automatically selecting a cutoff for body mass index, forearm length and circumference, and pronator teres thickness. RESULTS: For forearm circumferences ≤27.5 cm, the predictive value for the 13-mm needle was 92%. For forearm circumferences >27.5 cm and forearm lengths ≤26.75 cm, the predictive value for the 25-mm needle was 100%. CONCLUSION: Based upon the findings of this study, we suggest that needle length should be selected according to forearm anthropometric measures to prevent MN injury during pronator teres dry needling.

Association between somatosensory, motor and psychological variables by levels of disability in patients with cervicogenic dizziness.

Cervicogenic dizziness is a musculoskeletal disorder mainly characterized by dizziness associated with neck pain. The aim of this study was to assess the association between somatosensory, motor and psychological variables by levels of disability due to dizziness in patients with cervicogenic dizziness. A total of 64 patients were classified into two groups according to the presence of higher and lower levels of disability due to dizziness. The degree of disability due to dizziness, the magnitude of chronic pain, catastrophizing and kinesiophobia were evaluated by self-reports. The cervical active range of motion and the pressure pain thresholds were also assessed. The psychosocial variables showed significant differences. Higher values were found in the group with the highest level of disability due to dizziness (d = 0.80). Regarding motor variables, some differences were found in extension (d = 0.52) and in right rotation cervical movement (d = 0.90), with lower values in the group with greater disability due to dizziness. No differences were observed in the somatosensory variables (p > .05). In the group with lower levels of disability due to dizziness, negative associations were found with the range of cervical motion and positive associations were found with kinesiophobia. Our results suggest that levels of disability due to dizziness could be an important factor to consider in patients with cervicogenic dizziness. The influence of psychological factors and some ranges of cervical movement should be considered clinically.

Subacute Clinical Features After Arthroscopy Surgical Reconstruction of Complete Anterior Cruciate Ligament Rupture: A Case-Control Study.

OBJECTIVE: The purpose of this study was to describe the clinical features in the subacute phase after surgical reconstruction of complete anterior cruciate ligament rupture (ACLR) with respect to healthy participants. METHODS: A case-control observational study was performed. A total sample of 80 participants was recruited from an outpatient clinic and divided into case (n = 40 patients after ACLR reconstruction in subacute phase) and control (n = 40 healthy participants) groups. Outcomes, including pain intensity, range of motion (ROM), stability, and functionality were assessed by the visual analogue scale, universal goniometer, the Star Excursion Balance Test, and the Western Ontario and McMaster Universities Osteoarthritis Index, respectively. RESULTS: There were no statistically significant differences (P > .05) for sex, side, age, and body mass index between patients with ACLR after reconstruction surgery and healthy participants. Statistically significant differences (P < .001) with a large effect size (Rosenthal r) from -0.86 to -0.93 were shown for ROM (median ± interquartile range [IQR], -70.00° ± 10.00°) and Star Excursion Balance Test (mean ± standard deviation, -38.31 cm ± 4.52 cm) reduction, as well as higher visual analogue scale (median ± IQR, 7.00 ± 1.00) and Western Ontario and McMaster Universities Osteoarthritis Index (median ± IQR, 68.77 ± 6.29) scores in favor of the ACLR reconstructed group, with respect to the healthy control group. CONCLUSIONS: Measurable clinical differences of functionality, stability, and ROM should be considered during the evaluation of patients at a subacute period after complete ACLR reconstruction surgery with respect to healthy matched controls.

Transcultural adaptation and psychometric validation of a Spanish-language version of the "Pelvic Girdle Questionnaire".

BACKGROUND: The Pelvic Girdle Questionnaire is the only instrument designed to assess pain and disability specifically in pregnant or postpartum women with pelvic girdle pain. The objective of this study was the adaptation to the Spanish language and analysis of the psychometric properties of the Pelvic Girdle Questionnaire. METHODS: This is a descriptive cross-sectional study divided into two phases. In the first phase, a translation and adaptation process was performed according to international guidelines. Secondly, the analysis of the properties of the Spanish version was conducted using a sample of 125 pregnant or postpartum women suffering from pelvic girdle pain. Participants completed the Spanish version along with five other measurement instruments through an online platform. Internal consistency, construct validity, test-retest reliability, the ceiling and floor effects, responsiveness and discriminatory ability of the Spanish version were analysed. RESULTS: The Spanish version of the Pelvic Girdle Questionnaire showed high internal consistency with Cronbach's alpha = 0.961, and an intraclass correlation coefficient of 0.962. The convergent validity showed high positive correlation with other questionnaires used. ROC curves showed no discriminatory capacity for number of sites of pain or pregnancy/post-partum state. CONCLUSIONS: This article presents the translation, validation and psychometric properties of the Spanish version of the Pelvic Girdle Questionnaire, that has proved to be an appropriate and valid assessment tool of disability due to pelvic girdle pain in pregnant and postpartum women.

Survey of WBSNs for Pre-Hospital Assistance: Trends to Maximize the Network Lifetime and Video Transmission Techniques.

This survey aims to encourage the multidisciplinary communities to join forces for innovation in the mobile health monitoring area. Specifically, multidisciplinary innovations in medical emergency scenarios can have a significant impact on the effectiveness and quality of the procedures and practices in the delivery of medical care. Wireless body sensor networks (WBSNs) are a promising technology capable of improving the existing practices in condition assessment and care delivery for a patient in a medical emergency. This technology can also facilitate the early interventions of a specialist physician during the pre-hospital period. WBSNs make possible these early interventions by establishing remote communication links with video/audio support and by providing medical information such as vital signs, electrocardiograms, etc. in real time. This survey focuses on relevant issues needed to understand how to setup a WBSN for medical emergencies. These issues are: monitoring vital signs and video transmission, energy efficient protocols, scheduling, optimization and energy consumption on a WBSN.

Can a specific biobehavioral-based therapeutic education program lead to changes in pain perception and brain plasticity biomarkers in chronic pain patients? A study protocol for a randomized clinical trial.

BACKGROUND: Chronic pain conditions are complex multifactorial disorders with physical, psychological, and environmental factors contributing to their onset and persistence. Among these conditions, the role of brain-derived neurotrophic factor (BDNF) and the impact of a specific therapeutic education (TE) on pain management have emerged as important areas of research. OBJECTIVE: This study aims to investigate the effects of a specific type of therapeutic education on pain levels and BDNF concentrations. METHODS: In this single-blind, randomized clinical trial, patients will be randomly assigned to one of two groups: one will receive exercise with TE and the other without TE. Assessments will be made at baseline, mid-treatment, post-intervention, and at one and eight months. OUTCOMES: This study will shed light on the effectiveness of a therapeutic education (TE) program in pain management. Additionally, it will provide information on its effects on BDNF levels, a biomarker of brain plasticity, as well as on various psychosocial variables that can influence pain experience. CONCLUSION: By comprehensively addressing the need to quantify brain changes more precisely in individuals with chronic pain during interventions like TE and recognizing the importance of establishing a more structured and comprehensive protocol, this study lays a solid and replicable foundation for future evidence-based treatment developments.

The Spanish Adaptation of the Tampa Scale for Kinesiophobia Heart: Psychometric Evidence in Cardiac Rehabilitation Patients.

BACKGROUND: The factor structure of the Tampa Scale of Kinesiophobia Heart version has rarely been adequately analyzed. We aimed to evaluate the psychometric properties of this scale through a variety of exploratory and confirmatory factorial approaches. AIM: To perform a translation, cross-cultural adaptation, and psychometric evaluation of the Spanish version of the Tampa Scale of Kinesiophobia Heart in patients attending Cardiac Rehabilitation (TSK-SPA). DESIGN: Cross-sectional study. SETTING: A Cardiac Rehabilitation unit. POPULATION: Adults with the principal diagnosis of coronary artery disease (83%) who were referred to Cardiac Rehabilitation (N.=194; mean age, 64.28±9.2; 15% women). METHODS: We performed a translation and a cross-cultural adaptation of the TSK-SPA. The psychometric properties of validity comprising the face, content, and construct validity were then tested. Five factorial models were proposed to analyze the data structure. We examined the validity evidence of the TSK-SPA based on the relationships with other analyzed variables using the SF12 quality of life Questionnaire, the International Physical Activity Questionnaire, the Hospital Anxiety and Depression Scale and the Beck Depression Inventory. The reliability tests included internal consistency and stability over time. RESULTS: The results suggested a four-dimensional structure. Models with more than 1 dimension exhibited undesirable factor loadings or inadequate fit indices. Based on these results, a short version of the scale with 13 items is proposed. In terms of reliability, the TSK-SPA Heart was found internally consistent (α=0.79) and stable over time (test-retest = 0.82). An Exploratory Structural Equation Modeling (ESEM) analysis provided an acceptable fit for a hypothesized 4-factor model with the inclusion of a method factor: the root mean squared error of approximation was <0.05 (RMSEA = 0.046), and the comparative fit indices were >0.95 or close (CFI=0.994, TLI=0.934). Significant positive correlations were observed between the TSK-SPA scores and the measures of anxiety and depression, with correlation coefficients ranging from 0.35 to 0.48. CONCLUSIONS: A best-fitting model was identified, and the proposed 13-item TSK-SPA Heart showed sufficient evidence of validity and reliability for Spanish patients with cardiovascular disease. The scale's overall reliability is deemed acceptable, although the factor reliability could be further enhanced. CLINICAL REHABILITATION IMPACT: Using this questionnaire on fear or avoidance of movement will improve our understanding of cognitive-behavioral factors in patients with cardiovascular disease, aiding their rehabilitation and optimizing their prognosis.

Combination of different noninvasive brain stimulation treatments for upper limb recovery in stroke patients: A systematic review.

We report a review of Pubmed (Medline), CENTRAL, Web of Science, and Scopus to test the effectiveness of the combined application of repetitive transcranial magnetic stimulation and transcranial direct current stimulation in the improvement of different functional variables of the upper limb in people with stroke. Two independent reviewers assessed eligibility and evaluated the quality of the studies. Five articles were included in the final review according to the inclusion criteria: Most show statistically significant differences in motor function improvement in favor of the experimental group, but not in activity. Due to the heterogeneity of the observed studies, the results should be interpreted with caution-more high-quality studies are needed to investigate the effectiveness of these interventions in different stages of stroke patients.

Analyzing the role of cancer-associated fibroblast activation on macrophage polarization.

Snail1 is a transcriptional factor required for cancer-associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) model of murine mammary gland tumors, Snai1 gene deletion, besides increasing tumor-free lifespan, altered macrophage differentiation, with fewer expressing low levels of MHC class II. Snail1 was not expressed in macrophages, and in vitro polarization with interleukin-4 (IL4) or interferon-γ (IFNγ) was not altered by Snai1 gene depletion. We verified that CAF activation modified polarization of naïve bone-marrow-derived macrophages (BMDMΦs). When BMDMΦs were incubated with Snail1-expressing (active) CAFs or with conditioned medium derived from these cells, they exhibited a lower cytotoxic capability than when incubated with Snail1-deleted (inactive) CAFs. Gene expression analysis of BMDMΦs polarized by conditioned medium from wild-type or Snai1-deleted CAFs revealed that active CAFs differentially stimulated a complex combination of genes comprising genes that are normally induced by IL4, downregulated by IFNγ, or not altered during the two canonical differentiations. Levels of RNAs relating to this CAF-induced alternative polarization were sensitive to inhibitors of factors specifically released by active CAFs, such as prostaglandin E2 and TGFß. Finally, CAF-polarized macrophages promoted the activation of the immunosuppressive regulatory T cells (T-regs). Our results imply that an active CAF-rich tumor microenvironment induces the polarization of macrophages to an immunosuppressive phenotype, preventing the macrophage cytotoxic activity on tumor cells and enhancing the activation of T-reg cells.

Effect of Different Physical Therapy Interventions on Brain-Derived Neurotrophic Factor Levels in Chronic Musculoskeletal Pain Patients: A Systematic Review.

OBJECTIVE: The main objectives of this review were, firstly, to study the effect of different physiotherapy interventions on BDNF levels, and, secondly, to analyze the influence of physiotherapy on pain levels to subsequently draw conclusions about its possible relationship with BDNF. BACKGROUND: Based on the theory that neurotrophic factors such as BDNF play a fundamental role in the initiation and/or maintenance of hyperexcitability of central neurons in pain, it was hypothesized that the levels of this neurotrophic factor may be modified by the application of therapeutic interventions, favoring a reduction in pain intensity. METHODS: A literature search of multiple electronic databases (Pubmed, PsycINFO, Medline (Ebsco), Scopus, WOS, Embase) was conducted to identify randomized control trials (RCTs) published without language restrictions up to and including March 2022. The search strategy was based on the combination of medical terms (Mesh) and keywords relating to the following concepts: "pain", "chronic pain", "brain derived neurotrophic factor", "BDNF", "physiotherapy", and "physical therapy". A total of seven papers were included. RESULTS: There were two studies that showed statistically significant differences in pain intensity reduction and an increase in the BDNF levels that used therapies such as rTMS and EIMS in patients with chronic myofascial pain. However, the same conclusions cannot be drawn for the other physical therapies applied. CONCLUSIONS: rTMS and EIMS interventions achieved greater short-term reductions in pain intensity and increased BDNF over other types of interventions in chronic myofascial pain patients, as demonstrated by a moderate amount of evidence. In contrast, other types of physical therapy (PT) interventions did not appear to be more effective in decreasing pain intensity and increasing BDNF levels than placebo PT or minimal intervention, as a low amount of evidence was found.

Visually-Induced Motor Imagery Effects on Motor Adaptation to Reverse Steering Cycling. A Randomized Controlled Trial.

Purpose: First, testing an intervention of neuromodulation based on motor imagery and action observation as a promoter of motor adaptation of a complex motor task involving balance. Second, determining what prior balance factors can affect the motor adaptation task. Methods: A double-blind randomized controlled trial was performed. Forty-eight healthy subjects were recruited. The balance of all participants during gait and standing was assessed before adapting to the complex, multi-limb motor task of riding an inverse steering bicycle (ISB). Two interventions were carried out interleaved among trials of adaptation to the motor task: the experimental group (n = 24) was asked to perform neuromodulation (EN) by watching first-person ISB riding through immersive VR glasses and, simultaneously, mentally mimicking the movements. The control group (CG) was asked to watch a slideshow video of steady landscape images. Results: The results showed that the EN group did not improve the motor adaptation rate and induced higher adaptation times with respect to the CG. However, while the motor adaptation success showed a significant dependence on the prior proprioceptive participation in balance in the CG, the EN group did not present any relationship between the prior balance profile and motor adaptation outcome. Conclusions: Results point to a benefit of the visually guided neuromodulation for the motor adaptation of the subjects with low participation of proprioception in balance. Moreover, the results from the control group would allow to disclose prognostic factors about the success of the motor adaptation, and also prescription criteria for the proposed neuromodulation based on the balance profile.