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International Journal of Molecular... Jun 2024Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the...
Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of , a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of in tooth development. This is the first report showing the association between the variant and congenital insensitivity to pain in humans.
Topics: Humans; Homozygote; Male; Plectin; Female; Pain Insensitivity, Congenital; Child; Pedigree; Mutation, Missense; Exome Sequencing
PubMed: 38928066
DOI: 10.3390/ijms25126358 -
Cancers Jun 2024Chondroblastoma metastasis, though rare, represents a clinically significant and notably important aspect of bone tumors. Understanding its epidemiological... (Review)
Review
Chondroblastoma metastasis, though rare, represents a clinically significant and notably important aspect of bone tumors. Understanding its epidemiological characteristics, pathological features, and treatment modalities, despite its infrequency, is imperative for comprehensive patient management. This review aims to elucidate the epidemiology, molecular mechanisms, diagnostic challenges, and therapeutic strategies associated with chondroblastoma metastasis. The patterns, prognostic factors, and treatment outcomes were explored through an analysis of case studies and clinical reports. Notably, we highlighted emerging therapeutic perspectives aimed at improving patient outcomes. To the best of our knowledge, there has been no previous review addressing these matters cumulatively, highlighting a significant gap in the existing scholarly literature. By shedding light on the nuances of chondroblastoma metastasis, this review contributes to the advancement of knowledge in this field and informs clinical decision-making for improved patient care.
PubMed: 38927987
DOI: 10.3390/cancers16122283 -
Cancers Jun 2024Lung resection represents the main curative treatment in lung cancer; however, this surgical process leads to several disorders in tissues and organs. Previous studies...
Lung resection represents the main curative treatment in lung cancer; however, this surgical process leads to several disorders in tissues and organs. Previous studies have reported cardiovascular, pulmonary, and muscular disturbances that affect the functional capacity of these patients in the short, mid, and long term. However, upper limb impairment has been scarcely explored in the long term, despite the relevance in the independence of the patients. The aim of this study was to characterize the upper limb impairment in survivors of lung cancer one year after pulmonary resection. In this observational trial, patients who underwent lung cancer surgery were compared to control, healthy subjects matched by age and gender. Upper limb musculoskeletal disorders (shoulder range of motion, pain pressure threshold, nerve-related symptoms) and functional capacity (upper limb exercise capacity) were evaluated one-year post-surgery. A total of 76 survivors of lung cancer and 74 healthy subjects were included in the study. Significant differences between groups were found for active shoulder mobility ( < 0.05), widespread hypersensitivity to mechanical pain ( < 0.001), mechanosensitivity of the neural tissue ( < 0.001), and upper limb exercise capacity ( < 0.001). Patients who undergo lung cancer surgery show upper limb musculoskeletal disorders and upper limb functional impairment after a one-year lung resection. This clinical condition could limit the functionality and quality of life of patients with lung cancer.
PubMed: 38927983
DOI: 10.3390/cancers16122279 -
Cancers Jun 2024The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a...
BACKGROUND
The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a set of tumor-suppressing proteins. In this study, we examined the possibility of identifying anticancer peptides (ACPs) from trypsin-digested protein fragments derived from iTSC proteomes.
METHODS
The efficacy of ACPs was examined using an MTT-based cell viability assay, a Scratch-based motility assay, an EdU-based proliferation assay, and a transwell invasion assay. To evaluate the mechanism of inhibitory action, a fluorescence resonance energy transfer (FRET)-based GTPase activity assay and a molecular docking analysis were conducted. The efficacy of ACPs was also tested using an ex vivo cancer tissue assay and a bone microenvironment assay.
RESULTS
Among the 12 ACP candidates, P18 (TDYMVGSYGPR) demonstrated the most effective anticancer activity. P18 was derived from Arhgdia, a Rho GDP dissociation inhibitor alpha, and exhibited inhibitory effects on the viability, migration, and invasion of breast cancer cells. It also hindered the GTPase activity of RhoA and Cdc42 and downregulated the expression of oncoproteins such as Snail and Src. The inhibitory impact of P18 was additive when it was combined with chemotherapeutic drugs such as Cisplatin and Taxol in both breast cancer cells and patient-derived tissues. P18 had no inhibitory effect on mesenchymal stem cells but suppressed the maturation of RANKL-stimulated osteoclasts and mitigated the bone loss associated with breast cancer. Furthermore, the P18 analog modified by N-terminal acetylation and C-terminal amidation (Ac-P18-NH2) exhibited stronger tumor-suppressor effects.
CONCLUSIONS
This study introduced a unique methodology for selecting an effective ACP from the iTSC secretome. P18 holds promise for the treatment of breast cancer and the prevention of bone destruction by regulating GTPase signaling.
PubMed: 38927935
DOI: 10.3390/cancers16122230 -
Bioengineering (Basel, Switzerland) May 2024Cartilage degeneration is a characteristic of osteoarthritis (OA), which is often observed in aging populations. This degeneration is due to the breakdown of articular... (Review)
Review
Cartilage degeneration is a characteristic of osteoarthritis (OA), which is often observed in aging populations. This degeneration is due to the breakdown of articular cartilage (AC) mechanical and tribological properties primarily attributed to lubrication failure. Understanding the reasons behind these failures and identifying potential solutions could have significant economic and societal implications, ultimately enhancing quality of life. This review provides an overview of developments in the field of AC, focusing on its mechanical and tribological properties. The emphasis is on the role of lubrication in degraded AC, offering insights into its structure and function relationship. Further, it explores the fundamental connection between AC mechano-tribological properties and the advancement of its degradation and puts forth recommendations for strategies to boost its lubrication efficiency.
PubMed: 38927777
DOI: 10.3390/bioengineering11060541 -
Bioengineering (Basel, Switzerland) May 2024Genipin polymers are self-forming tensile-load-carrying oligomers, derived from the gardenia fruit, that covalently bond to amines on collagen. The potential therapeutic... (Review)
Review
Genipin polymers are self-forming tensile-load-carrying oligomers, derived from the gardenia fruit, that covalently bond to amines on collagen. The potential therapeutic mechanical benefits of a non-discrete in situ forming mesh of genipin oligomers for degraded spinal discs were first conceived in 1998. Over more than two decades, numerous studies have demonstrated the immediate mechanical effects of this injectable, intra-annular polymeric mesh including an early demonstration of an effect on clinical outcomes for chronic or recurrent discogenic low back pain. This literature review focused on articles investigating mechanical effects in cadaveric animal and human spinal discs, biochemical mechanism of action studies, articles describing the role of mechanical degradation in the pathogenesis of degenerative disc disease, initial clinical outcomes and articles describing current discogenic low back pain treatment algorithms. On the basis of these results, clinical indications that align with the capabilities of this novel injectable polymer-based treatment strategy are discussed. It is intended that this review of a novel nano-scale material-based solution for mechanical deficiencies in biologically limited tissues may provide a helpful example for other innovations in spinal diseases and similarly challenging musculoskeletal disorders.
PubMed: 38927771
DOI: 10.3390/bioengineering11060535 -
Bioengineering (Basel, Switzerland) May 2024Bone marrow edema-like lesions (BMEL) in the knee have been linked to the symptoms and progression of osteoarthritis (OA), a highly prevalent disease with profound...
Bone marrow edema-like lesions (BMEL) in the knee have been linked to the symptoms and progression of osteoarthritis (OA), a highly prevalent disease with profound public health implications. Manual and semi-automatic segmentations of BMELs in magnetic resonance images (MRI) have been used to quantify the significance of BMELs. However, their utilization is hampered by the labor-intensive and time-consuming nature of the process as well as by annotator bias, especially since BMELs exhibit various sizes and irregular shapes with diffuse signal that lead to poor intra- and inter-rater reliability. In this study, we propose a novel unsupervised method for fully automated segmentation of BMELs that leverages conditional diffusion models, multiple MRI sequences that have different contrast of BMELs, and anomaly detection that do not rely on costly and error-prone annotations. We also analyze BMEL segmentation annotations from multiple experts, reporting intra-/inter-rater variability and setting better benchmarks for BMEL segmentation performance.
PubMed: 38927762
DOI: 10.3390/bioengineering11060526 -
Biomedicines Jun 2024The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is... (Review)
Review
The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis, and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being "shared" between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour before considering future directions in the field.
PubMed: 38927506
DOI: 10.3390/biomedicines12061297 -
Antibiotics (Basel, Switzerland) May 2024Improving local antibiotic delivery is a promising approach to improve infection control and potentially shorten systemic treatment in periprosthetic joint infection...
BACKGROUND
Improving local antibiotic delivery is a promising approach to improve infection control and potentially shorten systemic treatment in periprosthetic joint infection (PJI). This study investigates the use of an antibiotic-loaded, mouldable collagen-tricalciumphosphate composite in treatment of hip PJI.
METHODS
124 application cases in 79 patients were included from a referral centre; systemic adverse infects, local complications, and infection control were analysed.
RESULTS
In most cases, either vancomycin or meropenem were used. Pathogens were previously known in 82 (66%) cases with polymicrobial infection in 20 (25%) patients. There were no cases of hypercalcaemia. Acute kidney injure was present in 14 (11%) cases. Chronic kidney failure persisted in two cases. During a mean follow-up of 12 (SD 9.3; range 3-35) months, implant survival was achieved in 73 (92%) patients; revision due to PJI was performed in 19 cases.
CONCLUSION
Mouldable collagen-tricalciumphosphate composite bone substitute as a local antibiotic carrier in revision hip arthroplasty appears to be a valid option for local antibiotic delivery without systemic complications. Implant survival of 92% supports the hypothesis that local antibiotic therapy is an important component in the treatment of PJI.
PubMed: 38927177
DOI: 10.3390/antibiotics13060510 -
Biomolecules May 2024Metabolic syndrome (MetS) is a cluster of metabolic abnormalities affecting ~25% of adults and is linked to chronic diseases such as cardiovascular disease, cancer, and...
Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose-Response Study.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities affecting ~25% of adults and is linked to chronic diseases such as cardiovascular disease, cancer, and neurodegenerative diseases. Oxidative stress and inflammation are key drivers of MetS. Hesperidin, a citrus bioflavonoid, has demonstrated antioxidant and anti-inflammatory properties; however, its effects on MetS are not fully established. We aimed to determine the optimal dose of hesperidin required to improve oxidative stress, systemic inflammation, and glycemic control in a novel mouse model of MetS. Male 5-week-old C57BL/6 mice were fed a high-fat, high-salt, high-sugar diet (HFSS; 42% kcal fat content in food and drinking water with 0.9% saline and 10% high fructose corn syrup) for 16 weeks. After 6 weeks of HFSS, mice were randomly allocated to either the placebo group or low- (70 mg/kg/day), mid- (140 mg/kg/day), or high-dose (280 mg/kg/day) hesperidin supplementation for 12 weeks. The HFSS diet induced significant metabolic disturbances. HFSS + placebo mice gained almost twice the weight of control mice ( < 0.0001). Fasting blood glucose (FBG) increased by 40% ( < 0.0001), plasma insulin by 100% ( < 0.05), and HOMA-IR by 150% ( < 0.0004), indicating insulin resistance. Hesperidin supplementation reduced plasma insulin by 40% at 140 mg/kg/day ( < 0.0001) and 50% at 280 mg/kg/day ( < 0.005). HOMA-IR decreased by 45% at both doses ( < 0.0001). Plasma hesperidin levels significantly increased in all hesperidin groups ( < 0.0001). Oxidative stress, measured by 8-OHdG, was increased by 40% in HFSS diet mice ( < 0.001) and reduced by 20% with all hesperidin doses ( < 0.005). In conclusion, hesperidin supplementation reduced insulin resistance and oxidative stress in HFSS-fed mice, demonstrating its dose-dependent therapeutic potential in MetS.
Topics: Animals; Hesperidin; Oxidative Stress; Insulin Resistance; Metabolic Syndrome; Male; Mice; Citrus; Mice, Inbred C57BL; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Blood Glucose; Diet, High-Fat; Antioxidants
PubMed: 38927040
DOI: 10.3390/biom14060637