Effects of a 12-week exercise-based intervention on weight management in overweight or obese breast cancer survivors: a randomized controlled trial.

PURPOSE: Breast cancer survivors face dual challenges: long-term sequelae of treatment and the risk of recurrent disease. Furthermore, obesity and a sedentary lifestyle can complicate both challenges. We aimed to assess the effect of a 12-week exercise-based weight-management program in overweight/obese breast cancer survivors. METHODS: A two-arm, single-blinded, randomized controlled trial was conducted among 60 overweight/obese, stage 0-III breast cancer survivors. During the 12-week program, the intervention group received weekly information support, fortnightly exercise prescriptions, including aerobic and resistance exercises to perform at home, and one dietary instruction. The control group received information support about weight management and exercise. Weight, body composition, and physical fitness data were collected at baseline, postintervention, and the 3-month follow-up. RESULTS: The intervention group showed significant improvements in body weight and all adiposity indices, including body mass index, waist circumference, and %body fat, in comparison with baseline (P < 0.001) and the control group (P < 0.05). Both groups showed no significant changes in fat-free mass during the 6-month period (P > 0.05). International Physical Activity Questionnaire scores and left grip strength increased significantly in the intervention group in comparison with the baseline (P < 0.01) and the control group (P < 0.05). Right grip strength, lower-body strength, and aerobic endurance showed no significant intergroup differences (P > 0.05). CONCLUSIONS: A combination of exercise prescription and weight-loss interventions yielded clinically meaningful weight loss in overweight/obese breast cancer survivors. These findings may facilitate the incorporation of home-based exercise and weight management into breast cancer treatment and survivorship care.

Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin.

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.

Effects of Fatigue and Unanticipated Factors on Knee Joint Biomechanics in Female Basketball Players during Cutting.

(1) This study examined the impact of fatigue and unanticipated factors on knee biomechanics during sidestep cutting and lateral shuffling in female basketball players, assessing the potential for non-contact anterior cruciate ligament (ACL) injuries. (2) Twenty-four female basketball players underwent fatigue induction and unanticipated change of direction tests, and kinematic and kinetic parameters were collected before and after fatigue with a Vicon motion capture system and Kistler ground reaction force (GRF) sensor. (3) Analysis using two-way repeated-measures ANOVA showed no significant interaction between fatigue and unanticipated factors on joint kinematics and kinetics. Unanticipated conditions significantly increased the knee joint flexion and extension angle (p < 0.01), decreased the knee flexion moment under anticipated conditions, and increased the knee valgus moment after fatigue (p ≤ 0.05). One-dimensional statistical parametric mapping (SPM1d) results indicated significant differences in GRF during sidestep cutting and knee inversion and rotation moments during lateral shuffling post-fatigue. (4) Unanticipated factors had a greater impact on knee load patterns, raising ACL injury risk. Fatigue and unanticipated factors were independent risk factors and should be considered separately in training programs to prevent lower limb injuries.

Biomechanical Investigation of Lower Limbs during Slope Transformation Running with Different Longitudinal Bending Stiffness Shoes.

BACKGROUND: During city running or marathon races, shifts in level ground and up-and-down slopes are regularly encountered, resulting in changes in lower limb biomechanics. The longitudinal bending stiffness of the running shoe affects the running performance. PURPOSE: This research aimed to investigate the biomechanical changes in the lower limbs when transitioning from level ground to an uphill slope under different longitudinal bending stiffness (LBS) levels in running shoes. METHODS: Fifteen male amateur runners were recruited and tested while wearing three different LBS running shoes. The participants were asked to pass the force platform with their right foot at a speed of 3.3 m/s ± 0.2. Kinematics data and GRFs were collected synchronously. Each participant completed and recorded ten successful experiments per pair of shoes. RESULTS: The range of motion in the sagittal of the knee joint was reduced with the increase in the longitudinal bending stiffness. Positive work was increased in the sagittal plane of the ankle joint and reduced in the keen joint. The negative work of the knee joint increased in the sagittal plane. The positive work of the metatarsophalangeal joint in the sagittal plane increased. CONCLUSION: Transitioning from running on a level surface to running uphill, while wearing running shoes with high LBS, could lead to improved efficiency in lower limb function. However, the higher LBS of running shoes increases the energy absorption of the knee joint, potentially increasing the risk of knee injuries. Thus, amateurs should choose running shoes with optimal stiffness when running.

Application of hyperbaric oxygen therapy in diabetic foot ulcers: A meta-analysis.

Hyperbaric oxygen therapy (HBOT) has been used in patients with diabetic foot ulcers (DFU) for many years, but its clinical efficacy is still controversial. Therefore, this study explored the efficacy of HBOT applied to DFU by means of meta-analysis. PubMed, Cochrane Library, Embase, CNKI and Wanfang databases were searched, from database inception to October 2023, and published randomised controlled trials (RCTs) of HBOT in DFU were collected. Two investigators independently screened the collected literature, extracted relevant data and assessed the quality of the literature. Review Manager 5.4 software was applied for data analysis. Twenty-nine RCTs with 1764 patients were included. According to the combined results, when compared with conventional treatment, HBOT significantly increased the complete healing rate of DFUs (46.76% vs. 24.46%, odds ratio [OR]: 2.83, 95% CI: 2.29-3.51, p < 0.00001) and decreased the amputation rate (26.03% vs. 45.00%, OR: 0.41, 95% CI: 0.18-0.95, p = 0.04), but the incidence of adverse events was significantly higher in patients (17.37% vs. 8.27%, OR: 2.49, 95% CI: 1.35-4.57, p = 0.003), whereas there was no significant difference in the mortality (6.96% vs. 12.71%, OR: 0.52, 95% CI: 0.21-1.28, p = 0.16). Our results suggest that HBOT is effective in increasing the complete healing rate and decreasing the amputation rate in patients with DFUs, but increases the incidence of adverse events, while it has no significant effect on mortality.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.

Adriamycin-loaded exosome with anti-CD20 aptamers selectively suppresses human CD20+ melanoma stem cells.

BACKGROUND: Targeting CD20+ melanoma cancer stem cells (CSCs) subset is essential for treating melanoma. Anti-CD20 aptamer-modified exosomes (ACEXO) loaded with Adriamycin could be a therapeutic strategy for targeting CSCs. MATERIALS AND METHODS: Exosomes loaded with Adriamycin were modified with anti-CD20 aptamer and characterized by size and molecular markers using transmission electron microscope and dynamic light scattering. The uptake of ACEXO into CD20+ cells was checked, and its cytotoxicities in CD20+ melanoma cells, HEK 293T, and 3T3 cells were evaluated. At the same time, the in vivo distribution of ACEXO in the tumor-bearing mice model was determined. RESULTS: The particle size of the exosome is about 80-100 nm. Western blot analysis showed that they expressed the characteristic exosome markers: CD9 and CD63. Quantitative analysis of the mean fluorescence intensity after 4 h incubation showed that ACEXO significantly improved Adriamycin uptake. Notably, the ACEXO killed only CD20+ melanoma cells. In addition, they exhibited good biocompatibility with both 293T and 3T3 cells at all doses. After intravenous injection, exosome distribution data showed that ACEXO's accumulation in the tumor is higher than anti-CD20-modified exosomes (AEXO)'s at all time points, and the accumulation increased as time prolonged. Addition of ACEXO reduces the number of tumorspheres in A375 or WM266-4 cells compared to untreated controls or AEXO-treated group. More important, while treating melanoma tumor-bearing mice, ACEXO-treated group showed the lowest tumor weight without body weight loss. CONCLUSION: ACEXO loaded with Adriamycin could suppress tumor cell growth in vitro and in vivo, probably by targeting CD20+ melanoma CSCs.

Microemulsion-thermosensitive gel composites as in situ-forming drug reservoir for periodontitis tissue repair through alveolar bone and collagen regeneration strategy.

A satisfactory clinical effect in treating periodontitis is often difficult to achieve by conventional non-surgical systemic drug delivery due to the narrow anatomical structure of the periodontal pocket and insufficient drug concentration at lesion sites. In addition, the feasibility of combating periodontal tissue lesions by restoring the alveolar bone and allowing collagen regeneration has not been fully explored. The objective of this study was to prepare a microemulsion integrating the anti-inflammatory and osteogenic active ingredients of baicalin and clove oil (BC-MEs). Then, the composite hydrogel obtained by mixing poloxamer 407 and 188 was used as the thermosensitive gel matrix to load BC-MEs and form a drug reservoir (Gel-BC-MEs) injectable in situ. Gel-BC-MEs exhibited a significant, sustained release of baicalin for 12 h, gelation temperature was 33.4 ± 0.36 °C, and pH was 5.45 ± 0.12. The experiment on a rat periodontitis model demonstrated that Gel-BC-MEs significantly improved periodontal tissue repair by collagen regeneration and osteogenesis by inhibiting osteoclast infiltration. This study proposes a novel strategy for periodontal tissue repair by enhancing the therapeutic potential of a microemulsion using an in situ nano-gel delivery system.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

BACKGROUND: Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

Prevalence, risk, and outcome of deep vein thrombosis in acute respiratory distress syndrome.

BACKGROUND: Few data exist on deep vein thrombosis (DVT) in patients with acute respiratory distress syndrome (ARDS), a group of heterogeneous diseases characterized by acute hypoxemia. STUDY DESIGN AND METHODS: We retrospectively enrolled 225 adults with ARDS admitted to the Beijing Chao-Yang Hospital and the First Affiliated Hospital of Shandong First Medical University between 1 January 2015 and 30 June 2020. We analyzed clinical, laboratory, and echocardiography data for groups with and without DVT and for direct (pulmonary) and indirect (extrapulmonary) ARDS subgroups. RESULTS: Ninety (40.0%) patients developed DVT. Compared with the non-DVT group, patients with DVT were older, had lower serum creatinine levels, lower partial pressure of arterial oxygen/fraction of inspired oxygen, higher serum procalcitonin levels, higher Padua prediction scores, and higher proportions of sedation and invasive mechanical ventilation (IMV). Multivariate analysis showed an association between age, serum creatinine level, IMV, and DVT in the ARDS cohort. The sensitivity and specificity of corresponding receiver operating characteristic curves were not inferior to those of the Padua prediction score and the Caprini score for screening for DVT in the three ARDS cohorts. Patients with DVT had a significantly lower survival rate than those without DVT in the overall ARDS cohort and in the groups with direct and indirect ARDS. CONCLUSIONS: The prevalence of DVT is high in patients with ARDS. The risk factors for DVT are age, serum creatinine level, and IMV. DVT is associated with decreased survival in patients with ARDS.

Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1α/VEGF pathway.

F-box proteins, a type of substrate-recognition complexes consisting of SKP1-cullin 1-F-box protein (SCF) E3 ligase, can critically affect many cellular processes because of the ubiquitylation and subsequent degradation of target proteins. This study investigated the effect of FBXO22 on melanoma angiogenesis, migration, and invasion. Results showed that FBXO22 staining intensity was increased in malignant melanoma (MM) compared with that in skin tissue (P˂0.001). The percentage of high FBXO22 expression in MM (74.3%) was markedly higher than that in paracancerous and skin tissues (0%) (P˂0.001). FBXO22 was also overexpressed in MM tissues compared with that in normal skin tissues. FBXO22 knockdown in vitro inhibited MM cell migration, invasion, and angiogenesis (P < 0.001). In vivo studies confirmed that using nude mice with knocked down FBXO22 reduced the formation of blood vessels and decreased the positive rate of CD31 (P < 0.05). HIF-1α expression varied with FBXO22, indicating that FBXO22 regulated the expression of HIF-1α and VEGFA and that FBXO22 was a regulator of HIF-1α and VEGF for the control of tumor angiogenesis. In conclusion, FBXO22 promoted the migration and invasion of tumor cells and melanoma angiogenesis via HIF-1α upregulation. This study demonstrated that FBXO22 knockdown suppressed tumor progression and metastasis, suggesting that FBXO22 might be developed as a novel target for treating patients with MM.

Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion.

The dyskeratosis congenita 1 (DKC1) gene is located on the X chromosome at Xq28. Dyskerin encoded by the DKC1 gene is associated with the formation of certain small RNAs and the telomerase activity. Inherited mutations in DKC1 inactivate the dyskerin and causes dyskeratosis congenital, which is characterized by skin defects, hematopoiesis failure, and increased susceptibility to cancer. DKC1 reportedly up-regulates in several human cancers, including renal cell carcinoma and prostate cancer. Dyskerin is deregulated in B-chronic lymphocytic leukemia and breast carcinomas, but its expression and function in glioma have hardly been investigated. Hence, we were prompted to collect tissue samples and implement cell experiments. Our study reveals that DKC1 expression is significantly increased in the pathological tissues of glioma compared with that in normal tissues. The increased staining of DKC1 is related to the World Health Organization stages of tumors. DKC1 knockdown also significantly inhibits glioma cell growth by altering the expression of cell cycle-relative molecules to arrest at the G1 phase. In the transwell chamber, DKC1 knockdown glioma cells exhibit low motility. Consistent with classic oncogenic pathways, N-cadherin, HIF-1α, and MMP2 expression levels are lower compared with those of the control group. Therefore, DKC1 up-regulation in gliomas is common and necessary for extensive tumor growth. The phenotype of glioma cell lines after DKC1 down-regulation suggests its use as a valuable clinical treatment strategy.

The requirement of CD8+ T cells to initiate and augment acute cardiac inflammatory response to high blood pressure.

Macrophage infiltration and activation in myocardium are hallmarks of acute cardiac inflammatory response to high blood pressure. However, the underlying mechanisms remain elusive. In this article, we report that CD8(+) T cells are required for cardiac recruitment and activation of macrophages. First, mice with CD8 gene-targeted (CD8 knockout) or CD8(+) T cells depleted by Ab showed significantly reduced cardiac inflammatory response to the elevation of blood pressure after angiotensin II (Ang II) infusion, whereas CD8 knockout mice reconstituted with CD8(+) T cells restored the sensitivity to Ang II. More importantly, CD8(+) T cells were required for macrophage infiltration in myocardium and subsequent activation to express proinflammatory cytokines and chemokines. Furthermore, macrophage activation required direct contact with activated CD8(+) T cells, but with TCR dispensable. TCR-independent activation of macrophages was further confirmed in MHC class I-restricted OVA-specific TCR transgenic mice, which showed a CD8(+) T cell activation and cardiac proinflammatory response to Ang II similar to that of wild-type mice. Finally, only myocardium-infiltrated, but not peripheral, CD8(+) T cells were specifically activated by Ang II, possibly by the cardiac IFN-γ that drove IFN-γR(+) CD8(+) T cell infiltration and activation. Thus, this work identified a TCR-independent innate nature of CD8(+) T cells that was critical in initiating the sterile immune response to acute elevation of blood pressure.

Downregulation of JWA promotes tumor invasion and predicts poor prognosis in human hepatocellular carcinoma.

We previously identified JWA as a novel microtubule-associated protein (MAP), which is implicated in carcinogenesis and tumor progression. The aims of the present study were to investigate the biological action and the prognostic significance of JWA in hepatocellular carcinoma (HCC). Quantitative real-time PCR and Western blot were used to detect JWA mRNA and protein expression, respectively, in stepwise metastatic HCC cell lines and HCC tissues. Short hairpin RNA was used to inhibit JWA expression in HCC cells. The effects of JWA depletion on cell migration, invasion, adhesion and in vivo metastasis were investigated. Immunohistochemistry of JWA was conducted in microarrays with tissue from 314 HCC patients who had undergone surgical resection. Prognostic significance was assessed using the Kaplan-Meier method and log-rank tests. The result showed JWA expression was decreased in the highly metastatic HCC cell lines and HCC tissues. Depletion of JWA caused a notable increase in cell migration, invasion and adhesion in vitro and metastasis in vivo. Furthermore, there was an inverse correlation between JWA expression and FAK expression and phosphorylation, RhoA activation and matrix metalloproteinase-2 (MMP-2) activity in HCC cells. More notably, multivariate analysis revealed that a low level of JWA expression was an independent prognosticator for both recurrence-free and overall survival for HCC patients after surgical resection, especially for AFP-normal HCC patients. Taken together, our data demonstrate that JWA plays a crucial role in HCC progression and suggest JWA may be a potential prognostic biomarker and therapeutic target for HCC.

Effect of orthopedic insoles on lower limb motion kinematics and kinetics in adults with flat foot: a systematic review.

Flatfoot is characterized by the collapse of the medial longitudinal arch, eversion of the rearfoot and abduction of the loaded forefoot. Orthopedic insoles are the frequently recommended treatment to support the arch of the foot, adjust the structure of the foot, reduce pain, improve stability and new techniques have been applied to the design of orthopedic insoles in recent years. However, the effectiveness of orthopedic insoles in different motions is still debated from the perspective of biomechanics. Therefore, this study aimed to explore the impact of orthopedic insoles on the kinematics and kinetics of lower limb motion, and to verify effectiveness and propose possible future research directions. We conducted a literature search across three databases employing Boolean operations and filtered results based on eligibility criteria. A total of 671 relevant literature were searched in this review, and 19 literature meeting the requirements were finally included. The results showed that: 1) orthopedic insoles were effective when patients walk, run and jump from the perspective of biomechanics; 2) orthopedic insoles had different result on the change of ankle sagittal angle, moment and peak pressure in the metatarsal region; 3) Whether the effect of insoles, which uses new techniques such as different 3D printed technologies and adds various accessories, can be further improved remains to be further studied; 4) Follow-up studies can pay more attention to the differences between diverse populations, increase the breadth of running and jumping and other movements research and long-term intervention.

Association of serum ferritin and all-cause mortality in AKI patients: a retrospective cohort study.

Background: Serum ferritin (SF) is clinically found to be elevated in many disease conditions, and our research examines serum ferritin in patients with acute kidney injury (AKI) and its implication on the risk of short-term mortality in AKI. Methods: Data were extracted from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database. Adult patients with AKI who had serum ferritin tested on the first day of ICU admission were included. The primary outcome was 28-day mortality. Kaplan-Meier survival curves and Cox proportional hazards models were used to test the relationship between SF and clinical outcomes. Subgroup analyses based on the Cox model were further conducted. Results: Kaplan-Meier survival curves showed that a higher SF value was significantly associated with an enhanced risk of 28-day mortality, 90-day mortality, ICU mortality and hospital mortality (log-rank test: p < 0.001 for all clinical outcomes). In multivariate Cox regression analysis, high level of SF with mortality was significantly positive in all four outcome events (all p < 0.001). This result remains robust after adjusting for all variables. Subgroup analysis of SF with 28-day mortality based on Cox model-4 showed that high level of SF was associated with high risk of 28-day mortality in patients regardless of the presence or absence of sepsis (p for interaction = 0.730). Positive correlations of SF and 28-day mortality were confirmed in all other subgroups (p for interaction>0.05). Conclusion: High level of SF is an independent prognostic predictor of 28-day mortality in patients with AKI.

Curved carbon-plated shoe may further reduce forefoot loads compared to flat plate during running.

Using a curved carbon-fiber plate (CFP) in running shoes may offer notable performance benefit over flat plates, yet there is a lack of research exploring the influence of CFP geometry on internal foot loading during running. The objective of this study was to investigate the effects of CFP mechanical characteristics on forefoot biomechanics in terms of plantar pressure, bone stress distribution, and contact force transmission during a simulated impact peak moment in forefoot strike running. We employed a finite element model of the foot-shoe system, wherein various CFP configurations, including three stiffnesses (stiff, stiffer, and stiffest) and two shapes (flat plate (FCFP) and curved plate (CCFP)), were integrated into the shoe sole. Comparing the shoes with no CFP (NCFP) to those with CFP, we consistently observed a reduction in peak forefoot plantar pressure with increasing CFP stiffness. This decrease in pressure was even more notable in a CCFP demonstrating a further reduction in peak pressure ranging from 5.51 to 12.62%, compared to FCFP models. Both FCFP and CCFP designs had a negligible impact on reducing the maximum stress experienced by the 2nd and 3rd metatarsals. However, they greatly influenced the stress distribution in other metatarsal bones. These CFP designs seem to optimize the load transfer pathway, enabling a more uniform force transmission by mainly reducing contact force on the medial columns (the first three rays, measuring 0.333 times body weight for FCFP and 0.335 for CCFP in stiffest condition, compared to 0.373 in NCFP). We concluded that employing a curved CFP in running shoes could be more beneficial from an injury prevention perspective by inducing less peak pressure under the metatarsal heads while not worsening their stress state compared to flat plates.

PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2.

BACKGROUND: Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood. METHODS: In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques. RESULTS: Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model. CONCLUSION: Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function.