The Use of Scrambler Therapy in Treating Chronic Pain Syndromes: A Systematic Review.

BACKGROUND: Scrambler therapy (ST) is a noninvasive method of transcutaneous neuromodulation that has 510(K) clearance from the United States Food and Drug Administration for treating acute pain, postoperative pain, and intractable chronic pain. Since its inception, ST has been used to treat many chronic pain syndromes in a variety of patient populations. We synthesized the available literature for ST to delineate its overall evidence basis. MATERIALS AND METHODS: We performed a systematic review based on conventional Preferred Reporting Items for Systematic Reviews and Meta-Analyses methods by surveying multiple data sources from January 1950 through October 2021. Two review authors, independently and in a standardized, unblinded fashion, conducted a systematic review to identify relevant studies and extract the necessary outcome measures. A conservative search strategy was implemented to identify all ST studies for the treatment of chronic pain syndromes. Primary outcome parameters collected were analgesic benefit, adverse effects, and other metrics such as sensorimotor testing. RESULTS: A total of 21 studies met the final criteria for study inclusion and comprised randomized controlled trials (n = 8), prospective observational studies (n = 10), and retrospective cohort studies (n = 3). Nearly all the reported studies explored the use of ST for the treatment of neuropathic pain, with chemotherapy-induced peripheral neuropathy being the most studied condition. Most studies were limited by small cohorts but reported ST being safe, well tolerated, and providing clinically meaningful pain reduction. The duration of posttreatment follow-up ranged from ten to 14 days (concordant with completion of typical ST protocols) to three months. Secondary benefits such as medication reduction and improvement of sensory and motor symptoms were noted by some studies. CONCLUSIONS: ST is regarded as a safe intervention with potential for significant analgesic benefit for neuropathic pain conditions. Although the available evidence is most robust for treating chemotherapy-induced peripheral neuropathy, ST has also been shown to be effective in treating other neuropathic pain syndromes. Evidence for ST use in nociceptive pain conditions is limited but appears promising. The favorable safety profile and increasing evidence basis for ST warrant more extensive recognition and consideration for use in clinical care.

SATB2: A versatile transcriptional regulator of craniofacial and skeleton development, neurogenesis and tumorigenesis, and its applications in regenerative medicine.

SATB2 (special AT-rich sequence-binding protein 2) is a member of the special AT-rich binding protein family. As a transcription regulator, SATB2 mainly integrates higher-order chromatin organization. SATB2 expression appears to be tissue- and stage-specific, and is governed by several cellular signaling molecules and mediators. Expressed in branchial arches and osteoblast-lineage cells, SATB2 plays a significant role in craniofacial pattern and skeleton development. In addition to regulating osteogenic differentiation, SATB2 also displays versatile functions in neural development and cancer progression. As an osteoinductive factor, SATB2 holds great promise in improving bone regeneration toward bone defect repair. In this review, we have summarized our current understanding of the physiological and pathological functions of SATB2 in craniofacial and skeleton development, neurogenesis, tumorigenesis and regenerative medicine.

Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies.

Throughout human history, infection has been the leading cause of morbidity and mortality, with pain being one of the cardinal warning signs. However, in a substantial percentage of cases, pain can persist after resolution of acute illness, manifesting as neuropathic, nociplastic (eg, fibromyalgia, irritable bowel syndrome), or nociceptive pain. Mechanisms by which acute infectious pain becomes chronic are variable and can include immunological phenomena (eg, bystander activation, molecular mimicry), direct microbe invasion, central sensitization from physical or psychological triggers, and complications from treatment. Microbes resulting in a high incidence of chronic pain include bacteria such as the Borrelia species and Mycobacterium leprae, as well as viruses such as HIV, SARS-CoV-2 and herpeses. Emerging evidence also supports an infectious cause in a subset of patients with discogenic low back pain and inflammatory bowel disease. Although antimicrobial treatment might have a role in treating chronic pain states that involve active infectious inflammatory processes, their use in chronic pain conditions resulting from autoimmune mechanisms, central sensitization and irrevocable tissue (eg, arthropathy, vasculitis) or nerve injury, are likely to cause more harm than benefit. This review focuses on the relation between infection and chronic pain, with an emphasis on common viral and bacterial causes.

Applications of Biocompatible Scaffold Materials in Stem Cell-Based Cartilage Tissue Engineering.

Cartilage, especially articular cartilage, is a unique connective tissue consisting of chondrocytes and cartilage matrix that covers the surface of joints. It plays a critical role in maintaining joint durability and mobility by providing nearly frictionless articulation for mechanical load transmission between joints. Damage to the articular cartilage frequently results from sport-related injuries, systemic diseases, degeneration, trauma, or tumors. Failure to treat impaired cartilage may lead to osteoarthritis, affecting more than 25% of the adult population globally. Articular cartilage has a very low intrinsic self-repair capacity due to the limited proliferative ability of adult chondrocytes, lack of vascularization and innervation, slow matrix turnover, and low supply of progenitor cells. Furthermore, articular chondrocytes are encapsulated in low-nutrient, low-oxygen environment. While cartilage restoration techniques such as osteochondral transplantation, autologous chondrocyte implantation (ACI), and microfracture have been used to repair certain cartilage defects, the clinical outcomes are often mixed and undesirable. Cartilage tissue engineering (CTE) may hold promise to facilitate cartilage repair. Ideally, the prerequisites for successful CTE should include the use of effective chondrogenic factors, an ample supply of chondrogenic progenitors, and the employment of cell-friendly, biocompatible scaffold materials. Significant progress has been made on the above three fronts in past decade, which has been further facilitated by the advent of 3D bio-printing. In this review, we briefly discuss potential sources of chondrogenic progenitors. We then primarily focus on currently available chondrocyte-friendly scaffold materials, along with 3D bioprinting techniques, for their potential roles in effective CTE. It is hoped that this review will serve as a primer to bring cartilage biologists, synthetic chemists, biomechanical engineers, and 3D-bioprinting technologists together to expedite CTE process for eventual clinical applications.

Identification of a prognostic signature based on copy number variations (CNVs) and CNV-modulated gene expression in acute myeloid leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) is caused by multiple genetic alterations in hematopoietic progenitors, and molecular genetic analyses have provided useful information for AML diagnosis and prognostication. This study aimed to integratively understand the prognostic value of specific copy number variation (CNV) patterns and CNV-modulated gene expression in AML. METHODS: We conducted integrative CNV profiling and gene expression analysis using data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) AML cohorts. CNV-related genes associated with survival were identified using the TARGET AML cohort and validated using the TCGA AML cohort. Genes whose CNV-modulated expression was associated with survival were also identified using the TARGET AML cohort and validated using the TCGA AML cohort, and patient bone marrow samples were then used to further validate the effects of CNV-modulated gene expression on survival. CNV and mRNA survival analyses were conducted using proportional hazards regression models (Cox regression) and the "survminer" and "survival" packages of the R Project for Statistical Computing. Genes belonging to the Kyoto Encyclopedia of Genes and Genomes (KEGG) cancer panel were extracted from KEGG cancer-related pathways. RESULTS: One hundred two CNV-related genes (located at 7q31-34, 16q24) associated with patient survival were identified using the TARGET cohort and validated with the TCGA AML cohort. Among these 102 validated genes, three miRNA genes (MIR29A, MIR183, and MIR335) were included in the KEGG cancer panel. Five genes (SEMA4D, CBFB, CHAF1B, SAE1, and DNMT1) whose expression was modulated by CNVs and significantly associated with clinical outcomes were identified, and the deletion of SEMA4D and CBFB was found to potentially exert protective effects against AML. The results of these five genes were also validated using patient marrow samples. Additionally, the distribution of CNVs affecting these five CNV-modulated genes was independent of the risk group (favorable-, intermediate-, and adverse-risk groups). CONCLUSIONS: Overall, this study identified 102 CNV-related genes associated with patient survival and identified five genes whose expression was modulated by CNVs and associated with patient survival. Our findings are crucial for the development of new modes of prognosis evaluation and targeted therapy for AML.

Stem Cell-Friendly Scaffold Biomaterials: Applications for Bone Tissue Engineering and Regenerative Medicine.

Bone is a dynamic organ with high regenerative potential and provides essential biological functions in the body, such as providing body mobility and protection of internal organs, regulating hematopoietic cell homeostasis, and serving as important mineral reservoir. Bone defects, which can be caused by trauma, cancer and bone disorders, pose formidable public health burdens. Even though autologous bone grafts, allografts, or xenografts have been used clinically, repairing large bone defects remains as a significant clinical challenge. Bone tissue engineering (BTE) emerged as a promising solution to overcome the limitations of autografts and allografts. Ideal bone tissue engineering is to induce bone regeneration through the synergistic integration of biomaterial scaffolds, bone progenitor cells, and bone-forming factors. Successful stem cell-based BTE requires a combination of abundant mesenchymal progenitors with osteogenic potential, suitable biofactors to drive osteogenic differentiation, and cell-friendly scaffold biomaterials. Thus, the crux of BTE lies within the use of cell-friendly biomaterials as scaffolds to overcome extensive bone defects. In this review, we focus on the biocompatibility and cell-friendly features of commonly used scaffold materials, including inorganic compound-based ceramics, natural polymers, synthetic polymers, decellularized extracellular matrix, and in many cases, composite scaffolds using the above existing biomaterials. It is conceivable that combinations of bioactive materials, progenitor cells, growth factors, functionalization techniques, and biomimetic scaffold designs, along with 3D bioprinting technology, will unleash a new era of complex BTE scaffolds tailored to patient-specific applications.