Polyfluoroalkyl Tag Decoration Enables Significantly Enhanced Tumor Penetration Ability of a PTK7 Targeting Aptamer.

Aptamers are widely used molecular recognition tools in targeted therapy, but their ability to effectively penetrate deep into solid tumors remains a significant challenge, leading to suboptimal treatment efficacy. Here, we developed a polyfluoroalkyl (PFA) decoration strategy to enhance aptamer recognition, cell internalization, and solid tumor penetration. Our results indicate that PFA with around 11 fluorine atoms significantly improves aptamer internalization both in vitro and in vivo settings. However, we also observed that the use of PFA tags containing 19 and 23 fluorine atoms on aptamers resulted in nonspecific cell anchoring in control cell lines, affecting the specificity of aptamers. Overall, we found that using a chemical modification strategy could enhance the deep tumor penetration ability of aptamers and validate their effectiveness in vivo. This approach has significant practical applications in targeted drug delivery for cancer treatment.

Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models.

Neuropathic pain (NP) resulting from a lesion or disease of the somatosensory system can lead to loss of function and reduced life quality. Neuroinflammation plays a vital role in the development and maintenance of NP. Exercise as an economical, effective, and nonpharmacological treatment, recommended by clinical practice guidelines, has been proven to alleviate chronic NP. Previous studies have shown that exercise decreases NP by modifying inflammation; however, the exact mechanisms of exercise-mediated NP are unclear. Therefore, from the perspective of neuroinflammation, this review mainly discussed the effects of exercise on inflammatory cytokines in different parts of NP conduction pathways, such as the brain, spinal cord, dorsal root ganglion, sciatic nerve, and blood in rat/mice models. Results suggested that exercise training could modulate neuroinflammation, inhibit astrocyte glial cell proliferation and microglial activation, alter the macrophage phenotype, reduce the expression of proinflammatory cytokines, increase anti-inflammatory cytokine levels, and positively modulate the state of the immune system, thereby relieving NP.

Associations Between Physical Activity and the Incidence of Cerebrovascular Disease or All-Cause Mortality Among 146,742 Older Adults: A 13-Year Prospective Cohort Study.

OBJECTIVES: Although studies have indicated that physical activity (PA) is related to cardiovascular disease, the specific association between PA and incident cerebrovascular disease (CBVD) remains uncertain. The current study aimed to investigate the associations between PA levels and the CBVD incidence or all-cause mortality. DESIGN: Prospective cohort study. SETTINGS AND PARTICIPANTS: Older participants (age >60 years) from the UK Biobank. METHODS: The baseline PA was classified as total, light, moderate, and vigorous PA based on the metabolic equivalent-minutes per week (MET-min/wk) and considered as exposures, whereas CBVD incidence and all-cause mortality were considered as the outcomes. Cox proportional hazards were used to calculate the hazard ratios (HRs) and 95% CIs for the influence of the association between PA and CBVD incidence and all-cause mortality. RESULTS: A total of 146,742 participants aged 60 years and older were included. During a median follow-up period of 13.5 years (interquartile range of 12.8-14.2), 9338 older individuals developed CBVD and 3033 death were recorded (including 767 CBVD-related deaths). High volumes of PA were consistently associated with lower risks of CBVD and all-cause mortality. The lowest risk of CBVD incidence was observed at 2001-2500 MET-min/wk of total PA (HR 0.61, 95% CI 0.53-0.70), and the lowest risk of all-cause mortality was observed at 2501-5000 MET-min/wk (HR 0.52, 95% CI 0.43-0.63) in older adults. Total PA at 2001-2500 MET-min/wk significantly reduced the CBVD incidence in older women (HR 0.57, 95% CI 0.46-0.71), which was more pronounced than that in older men (HR for 2001-2500 MET-min/wk: 0.64, 95% CI 0.50-0.77). CONCLUSIONS AND IMPLICATIONS: Total PA at 2001-2500 MET-min/wk significantly reduced the risk of incident CBVD and all-cause mortality in adults aged >60 years, although the extents of risk reduction vary in men and women.

Ni-Catalyzed Csp2 and Csp3 Coupling for Divergent Bisboronic Ester Synthesis.

Bisboronic esters are critical compounds in various research fields, including drug discovery, chemical biology, and material sciences. Currently, the bisboronic esters with reactive functional groups are difficult to synthesize; this is partially due to the lack of a robust method to produce these products with diverse structures and various functional groups at specific locations. To overcome this issue, this study introduced a Ni-catalysis approach to produce bisboronic esters efficiently via cross-coupling and homocoupling using readily available halogenated boronic esters as the starting material under mild reaction conditions. This newly developed strategy enables Csp2-Csp2, Csp3-Csp3, and Csp2-Csp3 couplings, demonstrating a broad substrate scope and excellent compatibility with various functional groups.

Associations between back pain incidence, and physical activity and sedentary behaviours: A prospective cohort study with data from over 365,000 participants.

OBJECTIVE: To examine the associations between (i) various types of physical activity and the risk of back pain incidence, and (ii) the influence of substituting sedentary behaviours with physical activities on back pain incidence. DESIGN: A prospective cohort study. METHODS: We analyzed UK Biobank data collected from 365,307 participants who were free of back pain at baseline. The exposures were total, light, moderate and vigorous physical activity, and sedentary behaviours. The outcome was back pain incidence. The main statistical models were the Cox proportional hazard model and the isotemporal substitution model. RESULTS: In the follow-up time (median, 12.97 years; inter-quartile range, 12.10-13.71), 25,189 individuals developed back pain. The associations between all types of physical activity and incident back pain were significantly non-linear (p < 0.001) among the general population and other subgroups. High physical activity was associated with a decreased risk of back pain compared with no physical activity. The lowest risk occurred in the 1801-2400 MET-min/week subgroup of total physical activity (HR 0.64, 95% CI 0.59-0.69), approximately consisting of 1200, 600, and 600 MET-min/week of light, moderate and vigorous physical activity, respectively. Extremely high vigorous physical activity was related to high risk, specifically in males (HR 1.13, 95% CI 1.02-1.25). Replacing 1 hour/day of sedentary behaviours with an equal time of physical activity reduced the risk of incident back pain by 2%-8% (p < 0.05). CONCLUSION: Physical activity was related to a reduced risk of back pain incidence (except over-high vigorous physical activity). Substituting sedentary behaviours with physical activities reduced the risk of future back pain.

Demographic and clinical characteristics associated with failure of physical therapy in chronic low back pain: a secondary analysis from a randomized controlled trial.

BACKGROUND: The effect of physical therapy on pain and disability alleviation in patients with chronic low back pain (cLBP) has been demonstrated, but the risk factors for treatment failure remain unknown. AIM: To explore the associations of baseline demographic and clinical characteristics with treatment failure after physical therapy intervention for cLBP. DESIGN: A secondary analysis of a single-blind randomized clinical trial. SETTING: A rehabilitation hospital. POPULATION: A total of 98 patients with cLBP completed the 12-month measurement. METHODS: Patients were randomly grouped into 3-month therapeutic aquatic exercise or physical therapy modalities. The primary outcome was treatment failure, which was defined as a decrease in the numeric rating scale to less than 2.0 points at 12-month follow-up. Associations between baseline demographic and clinical characteristics with risk of treatment failure were assessed by logistic regressions. RESULTS: The pain intensity in the failure cases was alleviated after 3-month intervention but continuously increased at 6- and 12-month follow-up (P<0.05). Old age was significantly associated with an increased risk of treatment failure (adjusted OR 3.26, 95% CI 1.11-9.60). Compared with those receiving physical therapy modalities, the patients receiving therapeutic aquatic exercise had less risk of treatment failure (adjusted OR 0.19, 95% CI 0.08-0.47), and age (P=0.022) was a modifier for this association. CONCLUSIONS: Compared with younger ones, older patients with cLBP had a higher risk of treatment failure after physical therapy and gained a stronger benefit of long-term pain alleviation from therapeutic aquatic exercise. CLINICAL REHABILITATION IMPACT: Therapeutic aquatic exercise is an effective therapy for cLBP and more helpful for preventing treatment failure than physical therapy modalities, especially for older patients.

Physical therapy for acute and sub-acute low back pain: A systematic review and expert consensus.

OBJECTIVE: To review the effectiveness of different physical therapies for acute and sub-acute low back pain supported by evidence, and create clinical recommendations and expert consensus for physiotherapists on clinical prescriptions. DATA SOURCES: A systematic search was conducted in PubMed and the Cochrane Library for studies published within the previous 15 years. REVIEW METHODS: Systematic review and meta-analysis, randomized controlled trials assessing patients with acute and sub-acute low back pain were included. Two reviewers independently screened relevant studies using the same inclusion criteria. The Physiotherapy Evidence Database and the Assessment of Multiple Systematic Reviews tool were used to grade the quality assessment of randomized controlled trials and systematic reviews, respectively. The final recommendation grades were based on the consensus discussion results of the Delphi of 22 international experts. RESULTS: Twenty-one systematic reviews and 21 randomized controlled trials were included. Spinal manipulative therapy and low-level laser therapy are recommended for acute low back pain. Core stability exercise/motor control, spinal manipulative therapy, and massage can be used to treat sub-acute low back pain. CONCLUSIONS: The consensus statements provided medical staff with appliable recommendations of physical therapy for acute and sub-acute low back pain. This consensus statement will require regular updates after 5-10 years.

Mechanisms of transcranial direct current stimulation (tDCS) for pain in patients with fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a recurrent pain condition that can be challenging to treat. Transcranial direct current stimulation (tDCS) has become a promising non-invasive therapeutic option in alleviating FMS pain, but the mechanisms underlying its effectiveness are not yet fully understood. In this article, we discuss the most current research investigating the analgesic effects of tDCS on FMS and discuss the potential mechanisms. TDCS may exert its analgesic effects by influencing neuronal activity in the brain, altering cortical excitability, changing regional cerebral blood flow, modulating neurotransmission and neuroinflammation, and inducing neuroplasticity. Overall, evidence points to tDCS as a potentially safe and efficient pain relief choice for FMS by multiple underlying mechanisms. This article provides a thorough overview of our ongoing knowledge regarding the mechanisms underlying tDCS and emphasizes the possibility of further studies to improve the clinical utility of tDCS as a pain management tool.

High Contrast Bioimaging of Tumor and Inflammation with a Bicyclic Dioxetane Chemiluminescent Probe.

The link between inflammation and the evolution of cancer is well established. Visualizing and tracking both tumor proliferation and the associated inflammatory response within a living organism are vital for dissecting the nexus between these two processes and for crafting precise treatment modalities. We report the creation and synthesis of an advanced NIR chemiluminescence probe that stands out for its exceptional selectivity, extraordinary sensitivity at nanomolar concentrations, swift detection capabilities, and broad application prospects. Crucially, this probe has been successfully utilized to image endogenous ONOO- across different inflammation models, including abdominal inflammation triggered by LPS, subcutaneous inflammatory conditions, and tumors grafted onto mice. These findings highlight the significant promise of chemiluminescence imaging in enhancing our grasp of the intricate interplay between cancer and inflammation and in steering the development of potent, targeted therapeutic strategies.

Reliability and Validity of the Star Excursion Balance Test for Evaluating Dynamic Balance of Upper Extremities.

BACKGROUND: Upper extremity (UE) dynamic balance is a significant physical fitness ability, which includes high-level neuromuscular proprioception, joint mobility, force, and coordination. The evaluation methods of UE dynamic balance are insufficient and lack experimental support. The Star Excursion Balance Test (SEBT) is a reliable assessment of dynamic balance and injury risk of the lower extremity. HYPOTHESIS: The UE-SEBT is a reliable and reproducible approach for evaluating dynamic balance of UEs. STUDY DESIGN: Observational study. LEVEL OF EVIDENCE: Level 4. METHODS: This cross-sectional study recruited 65 healthy adults. All participants were required to complete UE-SEBT, UE Y-balance test (UE-YBT), maximal voluntary isometric contraction (MVIC) of UE, closed kinetic chain UE stability test (CKCUEST), trunk flexor endurance test (TFET), trunk extensor endurance test (TEET), and lateral trunk endurance test (LTET). Intra- and inter-rater reliability and the correlation of UE-SEBT with other outcomes were measured. RESULTS: Among the participants, the intra- and interoperator reliability of UE-SEBT in all directions and composite score achieved a moderate-to-excellent (intraclass correlation coefficients [ICC], 0.729-0.946) reliability. For validity, the UE-SEBT had a moderate to very strong correlation with UE-YBT (r = 0.315-0.755, P < 0.01) and a strong correlation with CKCUEST (r = 0.4-0.67, P < 0.01). Furthermore, the UE-SEBT performance showed weak-to-strong correlations with MVIC (r = 0.26-0.43, P < 0.05). UE-SEBT was also correlated with LTET, TEET, and TFET to varying degrees. CONCLUSION: UE-SEBT has good reliability and validity to assess UE dynamic balance compared with other tests. CLINICAL RELEVANCE: UE-SEBT can be used as a clinical assessment method to evaluate UE dynamic balance and injury prevention.

Association of persistent musculoskeletal pain with dementia risk score in adults aged 45 years or older: The China health and retirement longitudinal study.

BACKGROUND: Recent studies have confirmed an association between pain and dementia. Whether musculoskeletal pain in the spine, upper limbs, and lower limbs is associated with dementia risk remains unclear. The longitudinal effect of musculoskeletal pain on dementia risk also remains unclear. AIMS: This work aimed to investigate the association between musculoskeletal pain and dementia risk score. METHODS: We conducted cross-sectional and longitudinal analyses using data from the China Health and Retirement Longitudinal Study. Participants aged 45 years or older were recruited in 2011. A total of 10,759 participants with complete pain information at baseline were eligible for the cross-sectional analysis, and 5,855 were eligible for the longitudinal analyses. We utilized the Rotterdam Study Basic Dementia Risk Model (BDRM) to assess dementia risk. Generalized estimating equations were used to investigate the associations. RESULTS: Compared with participants without persistent musculoskeletal pain, those with persistent musculoskeletal pain (standardized, ß = 0.83; 95 % CI: 0.06, 1.61, p = 0.036), multisite pain (sites≧5; ß = 1.52; 95 % CI: 0.13, 2.91, p = 0.032), neck pain (ß = 2.33; 95 % CI: 0.41, 4.25, p = 0.018), back pain (ß = 2.12; 95 % CI: 0.43, 3.82, p = 0.014), waist pain (ß = 1.09; 95 % CI: 0.07, 2.11, p = 0.037), shoulder pain (ß = 1.74; 95 % CI: 0.46, 3.02, p = 0.008), wrist pain (ß = 2.72; 95 % CI: 0.42, 5.02, p = 0.021), and knee pain (ß = 1.91; 95 % CI: 0.70, 3.13, p = 0.002) had a higher BDRM score during 4 years of follow-up. CONCLUSIONS: Promoting the management of musculoskeletal pain may be beneficial in reducing the dementia risk score.

Association between smoking and incident back pain: A prospective cohort study with 438 510 participants.

Background: Although smoking is a known potential contributor to back pain, there is still a lack of quantitative studies on the effects of different doses on back pain (BP) occurrence, including a lack of a longitudinal cohorts. To address this gap, we aimed to investigate the association between various smoking-related exposures and back pain incidence to advance global efforts toward smoking cessation and guide primary prevention of BP. Methods: In this prospective cohort study, we retrieved data on 438 510 patients from the UK Biobank who were free of back pain and who were recruited in 2006-2010, and followed them up from baseline through 1 April 2022. We extracted data on smoking-related exposures, including smoking status (SS), number of cigarettes smoked daily (CPD), and pack-years of own smoking (PY) and examined back pain incidence as an outcome. We used a Cox proportional hazard model adjusted for several covariates, multiple imputation methods, and population attribution fraction. Results: During the median follow-up of 12.98 years, 31 467 participants developed BP, with incidence rates in former and current smokers of 1.13 (95% confidence interval (CI) = 1.10-1.16, P < 0.000) and 1.50 (95% CI = 1.45-1.56, P < 0.000), respectively. The hazard ratios (HRs) of participants who smoked more than 30 CPD and those with more than 30 PY were 1.45 (95% CI = 1.36-1.55, P < 0.000) and 1.45 (95% CI = 1.40-1.50, P < 0.000), respectively. Relative to male, female smokers were at more risk of developing BP. Not smoking, quitting smoking, and reducing CPD and PY could lower the BP risk by 7.8%, 5.4%, 9.8%, and 18.0%, respectively. Conclusions: Ever smoking, higher cigarette consumption daily, and increased smoking intensity were associated with an increased BP risk. This association was stronger in female smokers. Not smoking, smoking cessation, and reducing smoking volume and intensity were effective measures to prevent BP occurrence.

Regulating the properties of XQ-2d for targeted delivery of therapeutic agents to pancreatic cancers.

Enhanced recognition ability, cell uptake capacity, and biostability are characteristics attributed to aptamer-based targeted anticancer agents, and are possibly associated with increased accumulation at the tumor site, improved therapeutic efficacy and reduced negative side effects. Herein, a phosphorothioate backbone modification strategy was applied to regulate the biomedical properties of pancreatic cancer cell-targeting aptamer for efficient in vivo drug delivery. Specifically, the CD71- targeting aptamer XQ-2d was modified into a fully thio-substituted aptamer S-XQ-2d, improving the plasma stability of S-XQ-2d and mitomycin C (MMC)-functionalized S-XQ-2d (MFSX), thus considerably prolonging their half-life in mice. Moreover, the binding and uptake capacities of S-XQ-2d were significantly enhanced. MFSX showed the same level of cytotoxicity as that of MMC against targeted cancer cells, but lower toxicity to non-targeted cells, highlighting its specificity and biosafety. Brief mechanistic studies demonstrated that XQ-2d and S-XQ-2d had different interaction modes and internalization pathways with the targeted cells.

Spinal posture assessment and low back pain.

Postural assessment can help doctors and therapists identify risk factors for low back pain and determine appropriate follow-up treatment. Postural alignment is not perfectly symmetrical, and small asymmetries can instead represent norms and criteria for postural evaluation. It is necessary to comprehensively observe patients' posture in all directions and analyze the factors related to posture evaluation. The results of reliability show that in general intra-rater reliability is higher than inter-rater reliability, and inclinometers are being more reliable than other instrumentations. Some common postural problems can cause lumbar discomfort, and prolonged poor posture is a potential risk factor for lumbar spine injuries. On the basis of previous studies on posture evaluation, a unified standardized method for posture evaluation must be established in future research.

Lumbar joint position sense measurement of patients with low back pain.

Lumbar position sense can be assessed by measurement instruments including the goniometer, isokinetic dynamometry, and electronic motion monitoring equipment, which have demonstrated relatively high reliability. This literature provides a comprehensive overview of influencing factors of lumbar position sense measurement, including repositioning method, fatigue degree, and posture during the reposition. It highlights the significant role of muscle proprioception, which contributes to greater accuracy in active reposition compared to passive reposition. The differences in lumbar position sense with different measurement positions may be explained by the presence of mechanoreceptors in the load-bearing structures of the lumbar spine, especially in the facet joint capsules. These mechanoreceptors play a crucial role in providing sensory feedback and proprioceptive information pertaining to the position and movement of the lumbar spine. Individuals with low back pain (LBP) demonstrate alterations in lumbar position sense compared to those without LBP. The auto motor sensory feedback transmission mechanism of patients with non-specific LBP was more unstable than that of healthy people. These findings suggest that lumbar position sense may play a potential role in the development and perpetuation of LBP. At present, the commonly used clinical assessment methods for determining position sense include both active and passive repositioning. However, neither method exhibits high sensitivity and specificity, leading to the poor comparability of relevant studies and posing challenges for clinical application.

Emission Wavelength-Tunable Bicyclic Dioxetane Chemiluminescent Probes for Precise In Vitro and In Vivo Imaging.

Chemiluminescent probes have become increasingly popular in various research areas including precise tumor imaging and immunofluorescence analysis. Nevertheless, previously developed chemiluminescence probes are mainly limited to studying oxidation reaction-associated biological events. This study presents the first example of bioimaging applicable bicyclic dioxetane chemiluminescent probes with tunable emission wavelengths that range from 525 to 800 nm. These newly developed probes were able to detect the analytes of ß-Gal, H2O2, and superoxide with high specificity and a limit of detection of 77 mU L-1, 96, and 28 nM, respectively. The bioimaging application of the probes was verified in ovarian and liver cancer cells and macrophage cells, allowing the detection of the content of ß-Gal, H2O2, and superoxide inside the cells. The high specificity allowed us to image the xenografted tumor in mice. We expect that our probes will receive extensive applications in recording complex biomolecular events using noninvasive imaging techniques.

Chemical Tailoring of Aptamer Glues with Significantly Enhanced Recognition Ability for Targeted Membrane Protein Degradation.

Cell membrane proteins play a crucial role in the development of early cancer diagnosis strategies and precision medicine techniques. However, the application of aptamers in cell membrane protein-based biomedical research is limited by their inherent drawbacks, such as sensitivity to the recognition environment and susceptibility to enzymatic degradation, which leads to the loss of recognition ability. To address these challenges, this study presents a subzero-temperature-enabled molecule stacking strategy for the on-demand tailoring of aptamer glues for the precision recognition and efficient degradation of membrane protein. Mechanistic studies revealed that nucleic acid molecule stacking occurred during the freezing and melting processes, facilitating a rapid click reaction by bringing two reactive groups together. In vitro investigations demonstrated that the strategy confers aptamer glues with significantly enhanced specific recognition ability and binding affinity, allowing the distinction of a targeted cell line from a nontargeted cell line. Moreover, the engineered aptamer glue exhibited impressive targeted cell membrane protein degradation ability; around 74% of the c-Met protein was degraded in 24 h. These findings hold great potential for advancing cancer diagnosis and targeted therapy through the development of more stable and reliable aptamer probes.

Ni-Catalyzed Protecting Group Free Diphenic Acid Analog Synthesis.

Severe side effects and drug resistance are major drawbacks of Pt-based chemotherapy in clinical practice, leading to the search for new Pt-based drugs through the tuning of coordination ligands. Therefore, seeking appropriate ligands has attracted significant interest in this area. In this study, we report a Ni-catalyzed coupling strategy for the divergent synthesis of diphenic acid derivatives and the application of these newly prepared acids in Pt(II) agent synthesis.