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.

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.

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.

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.

A versatile strategy for convenient circular bivalent functional nucleic acids construction.

Functional nucleic acids (FNAs), such as aptamers, nucleic acid enzymes and riboswitches play essential roles in various fields of life sciences. Tailoring of ingenious chemical moieties toward FNAs can enhance their biomedical properties and/or confer them with exogenic biological functions that, in turn, can considerably expand their biomedical applications, or even improve their clinical translations. Herein, we report the first example of a general chemical tailoring strategy that enables the divergent ligation of DNA sequences. By applying this technology, different types of aptamers and single-stranded nucleic acids of various lengths could be efficiently tailored to deliver the designed circular bivalent aptamers (CBApts) and cyclized DNA sequences with high yields. It is worth noting that CBApts exhibited significantly enhanced nuclease resistance, as well as considerably improved binding, targeting and tumor tissue enrichment abilities, which may pave the way for different investigations for biomedical purposes.

Association Between Smoking and Pain, Functional Disability, Anxiety and Depression in Patients With Chronic Low Back Pain.

Objectives: Chronic low back pain (CLBP) accounts for a majority of the disability associated with LBP, which can produce long-term negative effects. This cross-sectional study aimed to investigate the association between smoking and pain, dysfunction and psychological status in patients with CLBP. Methods: The 54 patients with CLBP were recruited and divided into smoking and non-smoking groups. Their pain, dysfunction, anxiety, depression, fear and quality of life were evaluated. The amount of cigarettes smoked daily was recorded. Results: Significant differences in VAS, ODI, RMDQ and FABQ and the impact of LBP on life and work were found between smoking and non-smoking patients. In addition, a correlation was found between the daily cigarette smoking amount and VASmax, FABQtotal, SDS and FABQ-W. Moreover, a correlation was observed between the amount of cigarettes smoked daily and the degree of impact of low back pain on work. Conclusion: The study found that smoking affected the aggravation of symptoms in patients with CLBP, which indicated that patients with CLBP and people at risk of LBP should be aware of the harm caused by smoking.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.

Exercise for osteoporosis: A literature review of pathology and mechanism.

Osteoporosis (OP) is a disease that weakens bones and has a high morbidity rate worldwide, which is prevalent among the elderly, particularly, women of postmenopausal age. The dynamic balance between bone formation and resorption is necessary for normal bone metabolism. Many factors, including aging, estrogen deficiency, and prolonged immobilization, disrupt normal apoptosis, autophagy, and inflammation, leading to abnormal activation of osteoclasts, which gradually overwhelm bone formation by bone resorption. Moderate exercise as an effective non-drug treatment helps increase bone formation and helps relieve OP. The possible mechanisms are that exercise affects apoptosis and autophagy through the release of exercise-stimulated myohormone and the secretion of anti-inflammatory cytokines via mechanical force. In addition, exercise may also have an impact on the epigenetic processes involved in bone metabolism. Mechanical stimulation promotes bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation by altering the expression of non-coding RNAs. Besides, by reducing DNA methylation, the mechanical stimulus can also alter the epigenetic status of osteogenic genes and show associated increased expression. In this review, we reviewed the possible pathological mechanisms of OP and summarized the effects of exercise on bone metabolism, and the mechanisms by which exercise alleviates the progression of OP, to provide a reference for the prevention and treatment of OP.

Non-invasive Brain Stimulation for Chronic Pain: State of the Art and Future Directions.

As a technique that can guide brain plasticity, non-invasive brain stimulation (NIBS) has the potential to improve the treatment of chronic pain (CP) because it can interfere with ongoing brain neural activity to regulate specific neural networks related to pain management. Treatments of CP with various forms of NIBS, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), using new parameters of stimulation have achieved encouraging results. Evidence of moderate quality indicates that high-frequency rTMS of the primary motor cortex has a clear effect on neuropathic pain (NP) and fibromyalgia. However, evidence on its effectiveness regarding pain relief in other CP conditions is conflicting. Concerning tDCS, evidence of low quality supports its benefit for CP treatment. However, evidence suggesting that it exerts a small treatment effect on NP and headaches is also conflicting. In this paper, we describe the underlying principles behind these commonly used stimulation techniques; and summarize the results of randomized controlled trials, systematic reviews, and meta-analyses. Future research should focus on a better evaluation of the short-term and long-term effectiveness of all NIBS techniques and whether they decrease healthcare use, as well as on the refinement of selection criteria.

Exercise for Osteoarthritis: A Literature Review of Pathology and Mechanism.

Osteoarthritis (OA) has a very high incidence worldwide and has become a very common joint disease in the elderly. Currently, the treatment methods for OA include surgery, drug therapy, and exercise therapy. In recent years, the treatment of certain diseases by exercise has received increasing research and attention. Proper exercise can improve the physiological function of various organs of the body. At present, the treatment of OA is usually symptomatic. Limited methods are available for the treatment of OA according to its pathogenesis, and effective intervention has not been developed to slow down the progress of OA from the molecular level. Only by clarifying the mechanism of exercise treatment of OA and the influence of different exercise intensities on OA patients can we choose the appropriate exercise prescription to prevent and treat OA. This review mainly expounds the mechanism that exercise alleviates the pathological changes of OA by affecting the degradation of the ECM, apoptosis, inflammatory response, autophagy, and changes of ncRNA, and summarizes the effects of different exercise types on OA patients. Finally, it is found that different exercise types, exercise intensity, exercise time and exercise frequency have different effects on OA patients. At the same time, suitable exercise prescriptions are recommended for OA patients.

Long Non-coding RNA and mRNA Expression Change in Spinal Dorsal Horn After Exercise in Neuropathic Pain Rats.

Exercise can help inhibition of neuropathic pain (NP), but the related mechanism remains being explored. In this research, we performed the effect of swimming exercise on the chronic constriction injury (CCI) rats. Compared with CCI group, the mechanical withdrawal threshold of rats in the CCI-Swim group significantly increased on the 21st and 28th day after CCI surgery. Second-generation RNA-sequencing technology was employed to investigate the transcriptomes of spinal dorsal horns in the Sham, CCI, and CCI-Swim groups. On the 28th day post-operation, 306 intersecting long non-coding RNAs (lncRNAs) and 173 intersecting mRNAs were observed between the CCI vs Sham group and CCI-Swim vs CCI groups. Then, the biological functions of lncRNAs and mRNAs in the spinal dorsal horn of CCI rats were then analyzed. Taking the results together, this study could provide a novel perspective for the treatment for NP.

A Dual-Targeting Circular Aptamer Strategy Enables the Recognition of Different Leukemia Cells with Enhanced Binding Ability.

Currently, the broad use of monovalent aptamers in oncology faces challenges, including insufficient recognition and internalization caused by a finite number of receptors on the cell surface, as well as a confined recognition spectrum. Herein, we describe the development of a dual-targeting circular aptamer (DTCA) that can recognize two different biomarkers on living cells to augment aptamer-receptor interactions, thus enhancing recognition of the target cells. This improvement not only boosts binding and internalization abilities, but also expands the recognition spectrum of these aptamers to different leukemia cells. Moreover, the stability of DTCA in serum can be significantly improved by an enzyme-promoted terminal ligation strategy. The chemical incorporation of 5-fluorodeoxyuridine into DTCA resulted in a pharmaceutically functional aptamer that exhibited excellent selectivity, as demonstrated by its high cytotoxicity against target cancer cells, but not to normal cells. The superiority of our newly developed strategy was further highlighted by its precise tumor-imaging capability.

Exercise for Neuropathic Pain: A Systematic Review and Expert Consensus.

Background: Neuropathic pain (NP), a severe and disruptive symptom following many diseases, normally restricts patients' physical functions and leads to anxiety and depression. As an economical and effective therapy, exercise may be helpful in NP management. However, few guidelines and reviews focused on exercise therapy for NP associated with specific diseases. The study aimed to summarize the effectiveness and efficacy of exercise for various diseases with NP supported by evidence, describe expert recommendations for NP from different causes, and inform policymakers of the guidelines. Design: A systematic review and expert consensus. Methods: A systematic search was conducted in PubMed. We included systematic review and meta-analysis, randomized controlled trials (RCTs), which assessed patients with NP. Studies involved exercise intervention and outcome included pain intensity at least. Physiotherapy Evidence Database and the Assessment of Multiple Systematic reviews tool were used to grade the quality assessment of the included RCTs and systematic reviews, respectively. The final grades of recommendation were based on strength of evidence and a consensus discussion of results of Delphi rounds by the Delphi consensus panel including 21 experts from the Chinese Association of Rehabilitation Medicine. Results: Eight systematic reviews and 21 RCTs fulfilled all of the inclusion criteria and were included, which were used to create the 10 evidence-based consensus statements. The 10 expert recommendations regarding exercise for NP symptoms were relevant to the following 10 different diseases: spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, cervical radiculopathy, sciatica, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV/AIDS, and surgery, respectively. The exercise recommended in the expert consensus involved but was not limited to muscle stretching, strengthening/resistance exercise, aerobic exercise, motor control/stabilization training and mind-body exercise (Tai Chi and yoga). Conclusions: Based on the available evidence, exercise is helpful to alleviate NP intensity. Therefore, these expert consensuses recommend that proper exercise programs can be considered as an effective alternative treatment or complementary therapy for most patients with NP. The expert consensus provided medical staff and policymakers with applicable recommendations for the formulation of exercise prescription for NP. This consensus statement will require regular updates after five-ten years.

Crosstalk Between MicroRNAs and Circular RNAs in Human Diseases: A Bibliographic Study.

Background: Crosstalk of circular RNAs (circRNAs) and microRNAs (miRNAs) refers to the communication and co-regulation between them. circRNAs can act as miRNAs sponges, and miRNAs can mediate circRNAs. They interact to regulate gene expression and participate in the occurrence and development of various human diseases. Methods: Publications on the crosstalk between miRNAs and circRNAs in human diseases were collected from Web of Science. The collected material was limited to English articles and reviews. CiteSpace and Microsoft Excel were used for bibliographic analysis. Results: A total of 1,013 papers satisfied the inclusion criteria. The publication outputs and types of researched diseases were analyzed, and bibliographic analysis was used to characterize the most active journals, countries, institutions, keywords, and references. The annual number of publications remarkably increased from 2011 to 2020. Neoplasm was the main research hotspot (n = 750 publications), and Biochemical and Biophysical Research Communications published the largest number of papers (n = 64) on this topic. Nanjing Medical University ranked first among institutions actively engaged in this field by publishing 72 papers, and China contributed 96.84% of the 1,013 papers (n = 981 publications) analyzed. Burst keywords in recent years included glioblastoma, miR-7, skeletal muscle, and non-coding RNA. Conclusion: Crosstalk between miRNAs and circRNAs in human diseases is a popular research topic. This study provides important clues on research trends and frontiers.

Regulating the Anticancer Efficacy of Sgc8-Combretastatin A4 Conjugates: A Case of Recognizing the Significance of Linker Chemistry for the Design of Aptamer-Based Targeted Drug Delivery Strategies.

The unique merits of aptamers, including specificity, high binding affinity, easy cell internalization, and rapid tissue accumulation abilities, have led aptamer-drug conjugates to evolve into one of the most attractive strategies for targeted drug delivery purposes. Nevertheless, the critical role of linkers in regulating anticancer efficacy of these conjugates, especially those engineered by automated modular synthesis techniques, has been rarely explored. In this work, we utilized Sgc8c aptamer and combretastatin A4 to develop three conjugates with either a phosphodiester bond linker, a disulfide bond linker, or a carbamate linker to study their payload release mechanisms and the influence on anticancer efficacy. These investigations allowed us to identify the unique activation pathway of the phosphodiester bond linker that is activated by both nucleophilic attack of glutathione and degradation caused by phosphodiesterase, which is highly associated with the higher cytotoxicity of the conjugate. Importantly, the understanding of the chemistry of phosphodiester bond linker activation allowed us to further design another XQ-2d-CA4 conjugate that can induce pancreatic cancer cells apoptosis in a more efficient manner.

Bibliometric Analysis of Research on the Comorbidity of Cancer and Pain.

BACKGROUND: Pain is the most common symptom in patients with neoplasm. It is a distressing experience that seriously destructs the quality-of-life of patients, with a high prevalence in clinical observations. However, only a few studies have applied bibliometric methods to analyze systematic works on the comorbidity of cancer and pain. PURPOSE: The aim of this work was to conduct a systematic analysis of the scientific studies worldwide on the comorbidity of cancer and pain in 2010-2019. METHODS: The Web of Science databases were searched for publications related to the comorbidity of cancer and pain from 2010 to 2019. RESULTS: A total of 3,423 papers met the inclusion criteria in this research. The increase in the quantity of papers presented a significant growth from 2010 to 2019 (P<0.001) by linear regression analysis. The research subject categories of the 3,423 papers mainly concentrated on oncology (28.57%), clinical neurology (25.62%), and healthcare science services (15.89%). The US had the highest number of published papers, followed by the People's Republic of China, and England. According to scientific statistics, breast cancer (20.36%) was by far the most predominant topic in the papers related to the comorbidity of cancer and pain. CONCLUSION: This bibliometric research provided a framework for visual and quantitative research to management scholars in favor of exploring a potential field related to hot issue and research frontiers.