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Nature Communications Jun 2024Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we...
Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.
Topics: Animals; Exodeoxyribonucleases; Humans; Phosphoproteins; Mice; DNA Damage; Recombinational DNA Repair; Phenotype; Mutation; Drosophila; Aging; Female; Drosophila melanogaster; Male; Retinal Diseases; Vascular Diseases; Hereditary Central Nervous System Demyelinating Diseases
PubMed: 38824133
DOI: 10.1038/s41467-024-49066-7 -
Scientific Reports May 2024Pleomorphic dermal sarcomas are infrequent neoplastic skin tumors, manifesting in regions of the skin exposed to ultraviolet radiation. Diagnosing the entity can be...
Pleomorphic dermal sarcomas are infrequent neoplastic skin tumors, manifesting in regions of the skin exposed to ultraviolet radiation. Diagnosing the entity can be challenging and therapeutic options are limited. We analyzed 20 samples of normal healthy skin tissue (SNT), 27 malignant melanomas (MM), 20 cutaneous squamous cell carcinomas (cSCC), and 24 pleomorphic dermal sarcomas (PDS) using mass spectrometry. We explored a potential cell of origin in PDS and validated our findings using publicly available single-cell sequencing data. By correlating tumor purity (TP), inferred by both RNA- and DNA-sequencing, to protein abundance, we found that fibroblasts shared most of the proteins correlating to TP. This observation could also be made using publicly available SNT single cell sequencing data. Moreover, we studied relevant pathways of receptor/ligand (R/L) interactions. Analysis of R/L interactions revealed distinct pathways in cSCC, MM and PDS, with a prominent role of PDGFRB-PDGFD R/L interactions and upregulation of PI3K/AKT signaling pathway. By studying differentially expressed proteins between cSCC and PDS, markers such as MAP1B could differentiate between these two entities. To this end, we studied proteins associated with immunosuppression in PDS, uncovering that immunologically cold PDS cases shared a "negative regulation of interferon-gamma signaling" according to overrepresentation analysis.
Topics: Humans; Skin Neoplasms; Proteomics; Melanoma; Fibroblasts; Sarcoma; Carcinoma, Squamous Cell; Female; Male; Melanoma, Cutaneous Malignant; Immune Evasion; Middle Aged; Signal Transduction; Aged
PubMed: 38822058
DOI: 10.1038/s41598-024-62927-x -
Archives of Dermatological Research May 2024Voriconazole exposure is associated with skin cancer, but it is unknown how the full spectrum of its metabolizer phenotypes impacts this association. We conducted a...
Voriconazole exposure is associated with skin cancer, but it is unknown how the full spectrum of its metabolizer phenotypes impacts this association. We conducted a retrospective cohort study to determine how variation in metabolism of voriconazole as measured by metabolizer status of CYP2C19 is associated with the total number of skin cancers a patient develops and the rate of development of the first skin cancer after treatment. There were 1,739 organ transplant recipients with data on CYP2C19 phenotype. Of these, 134 were exposed to voriconazole. There was a significant difference in the number of skin cancers after transplant based on exposure to voriconazole, metabolizer phenotype, and the interaction of these two (p < 0.01 for all three). This increase was driven primarily by number of squamous cell carcinomas among rapid metabolizes with voriconazole exposure (p < 0.01 for both). Patients exposed to voriconazole developed skin cancers more rapidly than those without exposure (Fine-Grey hazard ratio 1.78, 95% confidence interval 1.19-2.66). This association was similarly driven by development of SCC (Fine-Grey hazard ratio 1.83, 95% confidence interval 1.14-2.94). Differences in voriconazoles metabolism are associated with an increase in the number of skin cancers developed after transplant, particularly SCC.
Topics: Humans; Voriconazole; Skin Neoplasms; Retrospective Studies; Male; Female; Middle Aged; Antifungal Agents; Carcinoma, Squamous Cell; Cytochrome P-450 CYP2C19; Aged; Organ Transplantation; Adult
PubMed: 38819581
DOI: 10.1007/s00403-024-03135-5 -
Alternative Therapies in Health and... May 2024This study explicitly demonstrates the roles of natural killer (NK) cells in different types of kidney transplantation.
OBJECTIVE
This study explicitly demonstrates the roles of natural killer (NK) cells in different types of kidney transplantation.
METHODS
We'd done the whole study from October 2022 to October 2023. To further explore the significance of NK cells during renal transplantation, we provide a theoretical basis for clinically overcoming immune rejection after renal transplantation by developing new anti-rejection drugs. We selected twelve male mice and divided them into three groups (Syngeneic transplant group allograft transplant group allograft transplant (priming) group) by random. Initially, the morphological and histopathological changes in the kidney transplantation graft model of mice in different groups are observed. Further, the DSA-IgG levels in peripheral blood and C3d and IgG deposition in mice are detected by ELISA and immunohistochemical staining. Then, the Banff 2015 score is recorded to screen a suitable AMR mouse model. Finally, the expression of NK cells in different rejection modes is detected by flow cytometry, and the expressions of various cytokines (INF-γ, perforin, granzyme B, TNF-α) in peripheral blood are detected by enzyme-linked immunosorbent assay (ELISA).
RESULTS
In the allogeneic transplantation (priming) group, peritubular capillary inflammatory cell infiltration, moderate endarteritis, and small arterial fibrinoid necrosis are evident. The Banff score showed that the allogeneic transplantation (pre-sensitized) group is significantly higher than the syngeneic and allogeneic transplantation groups. The C3H→C57BL/6 mice are pre-sensitized by skin transplantation, and then kidney transplantation is performed to establish the antibody-mediated rejection (AMR) model. After kidney transplantation, the expression levels of NK cells in the peripheral blood, spleen, and transplanted kidney tissue of mice in the pre-sensitized group are significantly higher than in the allogeneic transplantation and control groups. In the C3H→C57BL/6 mouse model of AMR, NK cells and the related cytokines in the peripheral blood are highly expressed after kidney transplantation, proving that NK cells play an essential role in the occurrence of AMR.
CONCLUSION
Our study proved the significance of NK cells in the occurrence of AMR by systematically monitoring the expression of NK cell-related cytokines in different types, which provided some ideas for the clinical treatment of AMR.
PubMed: 38819183
DOI: No ID Found -
Archives of Dermatological Research May 2024Progesterone is used for hormone replacement therapy through various routes of administration. This study was conducted to (a) evaluate the stability of progesterone in...
Progesterone is used for hormone replacement therapy through various routes of administration. This study was conducted to (a) evaluate the stability of progesterone in a proprietary anhydrous permeation-enhancing base (APEB) and the efficiency of its skin permeation, and (b) determine the appropriateness of mass spectrometry as a method of analysis for permeated progesterone. Using a proven stability-indicating ultra-performance liquid chromatographic method, the compounded hormone (100 mg progesterone/g APEB gel) was determined to be physically and chemically stable at room temperature for six months. Skin permeation analysis using the Franz skin finite dose model and mass spectrometry imaging showed an optical density of 1699 for the permeated progesterone compounded in APEB and 550 for the permeated progesterone in a water containing VBC, which is a statistically significant different (P = 0.029). The study suggests that APEB can be used as a compounding base for effective skin permeation of progesterone, and mass spectrometry is a reliable method for visualization and quantitative analysis of permeated progesterone.
Topics: Progesterone; Skin Absorption; Mass Spectrometry; Skin; Humans; Administration, Cutaneous; Permeability; Drug Stability; Animals; Chromatography, High Pressure Liquid; Drug Compounding
PubMed: 38814486
DOI: 10.1007/s00403-024-03040-x -
Transplant International : Official... 2024The current gold standard for preserving vascularized composite allografts (VCA) is 4°C static cold storage (SCS), albeit muscle vulnerability to ischemia can be...
The current gold standard for preserving vascularized composite allografts (VCA) is 4°C static cold storage (SCS), albeit muscle vulnerability to ischemia can be described as early as after 2 h of SCS. Alternatively, machine perfusion (MP) is growing in the world of organ preservation. Herein, we investigated the outcomes of oxygenated acellular subnormothermic machine perfusion (SNMP) for 24-h VCA preservation before allotransplantation in a swine model. Six partial hindlimbs were procured on adult pigs and preserved for 24 h with either SNMP ( = 3) or SCS ( = 3) before heterotopic allotransplantation. Recipient animals received immunosuppression and were followed up for 14 days. Clinical monitoring was carried out twice daily, and graft biopsies and blood samples were regularly collected. Two blinded pathologists assessed skin and muscle samples. Overall survival was higher in the SNMP group. Early euthanasia of 2 animals in the SCS group was linked to significant graft degeneration. Analyses of the grafts showed massive muscle degeneration in the SCS group and a normal aspect in the SNMP group 2 weeks after allotransplantation. Therefore, this 24-h SNMP protocol using a modified Steen solution generated better clinical and histological outcomes in allotransplantation when compared to time-matched SCS.
Topics: Animals; Organ Preservation; Perfusion; Swine; Vascularized Composite Allotransplantation; Graft Survival; Hindlimb; Composite Tissue Allografts; Models, Animal; Transplantation, Homologous; Allografts
PubMed: 38813393
DOI: 10.3389/ti.2024.12338 -
Journal of Medicine and Life Feb 2024Post-combustion alopecia presents a complex medical challenge with implications spanning dermatological and psychiatric disorders. The use of hair transplantation has...
Post-combustion alopecia presents a complex medical challenge with implications spanning dermatological and psychiatric disorders. The use of hair transplantation has proven to be a significant improvement for this condition. However, the current management involves various techniques, each with advantages and disadvantages. Progressive skin expansions, surgical scar reduction, and skin grafts containing hair follicles yield unsatisfactory aesthetic outcomes and have limited applicability as a first-line treatment for fire victims. So far, follicular unit extraction (FUE) has proven to be one of the most versatile procedures in such cases, having the potential to restore a natural anatomical profile closely resembling the pre-traumatic appearance that led to the traumatic alopecia. Additionally, it contributes to the improvement of associated psychiatric comorbidities, facilitating proper social reintegration and enhancing overall quality of life. This report focuses on a case of post-combustion alopecia and severe facial distortion due to third-degree burns resulting in severe psychiatric comorbidities, which benefited from a proper social reintegration and improvement of the quality of life after three consecutive sessions of FUE for scalp and eyebrow hair.
Topics: Humans; Alopecia; Scalp; Skin Transplantation; Plastic Surgery Procedures; Quality of Life; Adult; Male; Hair; Hair Follicle; Female; Face; Burns
PubMed: 38813359
DOI: 10.25122/jml-2023-0492 -
Clinical Kidney Journal May 2024hydrochlorothiazide (HCTZ) diuretics were correlated with an increased risk of non-melanoma skin cancer (NMSC) and melanoma in the general population. Information is a...
BACKGROUND
hydrochlorothiazide (HCTZ) diuretics were correlated with an increased risk of non-melanoma skin cancer (NMSC) and melanoma in the general population. Information is a scarce regarding this effect in kidney transplant recipients who are at increased risk of skin malignancies under immunosuppression.
METHODS
Single-center retrospective analysis of adult kidney transplant recipients between 1 January 2010 and 31 December 2015. The primary outcome of the study was the first diagnosis of skin cancer that was removed and pathologically analyzed. Exposure to thiazides was defined as HCTZ use daily for at least one year at a dose of 12.5 mg.
RESULTS
Among 520 kidney transplant recipients, 50 (9.4%) were treated with HCTZ. During a median follow-up of 9.8 years, 67 patients underwent surgical removal and pathological analysis of at least one skin cancer. Exposure to HCTZ during the 3 years following transplantation was associated with an increased risk of skin cancer ( = 0.004). In a multivariate model, there was a significant association between HCTZ exposure and NMSC (HR 2.54, 95%CI 1.26-5.15, = 0.007). There was a higher rate of basal cell carcinoma with HCTZ exposure, according to both univariate and multivariate analyses (HR 2.61, 95%CI 1.06-6.43, = 0.037) and (HR 3.03, 95%CI 1.22-7.55, = 0.017, respectively). However, no significant association was observed between HCTZ exposure and squamous cell carcinoma.
CONCLUSIONS
These findings suggest a benefit of increased frequency of dermatologist inspection in kidney transplant recipients receiving HCTZ especially in increased ultraviolet exposure area.
PubMed: 38812910
DOI: 10.1093/ckj/sfae126 -
Frontiers in Allergy 2024The concept of pre-diabetes has led to provision of measures to reduce disease progression through identification of subjects at risk of diabetes. We previously... (Review)
Review
The concept of pre-diabetes has led to provision of measures to reduce disease progression through identification of subjects at risk of diabetes. We previously considered the idea of pre-asthma in relation to allergic asthma and considered that, in addition to the need to improve population health via multiple measures, including reduction of exposure to allergens and pollutants and avoidance of obesity, there are several possible specific means to reduce asthma development in those most at risk (pre- asthma). The most obvious is allergen immunotherapy (AIT), which when given for allergic rhinitis (AR) has reasonable evidence to support asthma prevention in children (2) but also needs further study as primary prevention. In this second paper we explore the possibilities for similar actions in late onset eosinophilic asthma.
PubMed: 38812719
DOI: 10.3389/falgy.2024.1404735 -
Journal of Pharmaceutical Analysis May 2024The "gut-skin" axis has been proved and is considered as a novel therapy for the prevention of skin aging. The antioxidant efficacy of oligomannonic acid (MAOS) make it...
The "gut-skin" axis has been proved and is considered as a novel therapy for the prevention of skin aging. The antioxidant efficacy of oligomannonic acid (MAOS) make it an intriguing target for use to improve skin aging. The present study further explored whereby MAOS-mediated gut-skin axis balance prevented skin aging in mice. The data indicated the skin aging phenotypes, oxidative stress, skin mitochondrial dysfunction, and intestinal dysbiosis (especially the butyrate and HIF-1α levels decreased) in aging mice. Similarly, fecal microbiota transplantation (FMT) from aging mice rebuild the aging-like phenotypes. Further, we demonstrated MAOS-mediated colonic butyrate-HIF-1α axis homeostasis promoted the entry of butyrate into the skin, upregulated mitophagy level and ultimately improving skin aging via HDAC3/PHD/HIF-1α/mitophagy loop in skin of mice. Overall, our study offered a better insights of the effectiveness of alginate oligosaccharides (AOS), promised to become a personalized targeted therapeutic agents, on gut-skin axis disorder inducing skin aging.
PubMed: 38807706
DOI: 10.1016/j.jpha.2023.12.001