Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Biologics for inherited disorders of keratinisation: A systematic review.

BACKGROUND/OBJECTIVES: Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of existing literature on treatment outcomes of inherited keratinisation disorders treated with biologics. METHODS: Eligible records were retrieved through searches of the electronic databases MEDLINE, Embase, PubMed and Scopus. Databases were searched from inception to July 2023 for eligible records. A snowballing method was employed to search the references of the retrieved records for the identification of potentially relevant articles. RESULTS: One hundred and four eligible studies consisting of a total of 166 patients with an inherited disorder of keratinisation were included. Patients had a median age of 19 years (range: 0.5 to 70 years). The most common disorders were Netherton syndrome (n = 63; 38%), autosomal recessive congenital ichthyoses (n = 27; 16%), CARD14-associated papulosquamous eruptions (n = 17; 10%) and familial pityriasis rubra pilaris (PRP) (n = 15; 9%).Of the 207 times biologics were employed, the three most frequently employed biologics were secukinumab (n = 47; 23%), dupilumab (n = 44; 21%) and ustekinumab (n = 37; 18%). Complete remission was observed in 10 (5%) instances, partial remission in 129 (62%), no or limited response to biologic therapy in 68 (32%) cases, and results are still pending in one case. A total of 33 adverse events were reported. CONCLUSIONS: Whilst biologics may be considered in cases of inherited keratinisation disorders recalcitrant to standard therapy, definitive conclusions are prohibited by the low-level of evidence and substantial heterogeneity in methodology across the included studies. Establishment of consensus definitions, and randomised clinical trials may help ascertain the efficacy and safety of biologic therapy in this context and establish the best agent and dosing protocol for each disorder.

Cost-Utility Analysis of Rituximab vs Mycophenolate Mofetil for the Treatment of Pemphigus Vulgaris.

Importance: There is an increasing body of literature that supports the use of rituximab as a first-line steroid-sparing agent in pemphigus vulgaris. However, the cost of rituximab is substantial compared with conventional agents, and there are limited health economic data to justify its use. Objective: To evaluate the cost-effectiveness of rituximab biosimilars relative to mycophenolate mofetil as a first-line steroid-sparing agent for moderate to severe pemphigus vulgaris. Design, Setting, and Participants: A cost-utility analysis over a 24-month time horizon was conducted from the perspective of the Australian health care sector using a modeled cohort of treatment-naive adult patients with moderate to severe pemphigus vulgaris. A Markov cohort model was constructed to simulate disease progression following first-line treatment with rituximab biosimilars or mycophenolate mofetil. The simulated cohort transitioned between controlled disease, uncontrolled disease, and death. Efficacy and utility data were obtained from available published literature. Cost data were primarily obtained from published government data. One-way and probabilistic sensitivity analyses were performed to assess uncertainty. Primary outcomes were the changes in cost and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over the 24 months. Interventions: Rituximab biosimilars and mycophenolate mofetil. Results: The simulated cohort of treatment-naive patients had a mean age of 50.8 years, a female-to-male ratio of 1.24, and moderate to severe disease as classified by the Harman criteria. First-line rituximab biosimilars were associated with a cost reduction of AU$639 and an improvement of 0.07 QALYs compared with mycophenolate mofetil, resulting in an ICER of -AU$8818/QALY. Rituximab biosimilars were therefore more effective and less costly compared with mycophenolate mofetil. Sensitivity analyses demonstrated that rituximab biosimilars remained cost-effective across a range of values for cost, utility, and transition probability input parameters and willingness-to-pay thresholds. Conclusions and Relevance: In this cost-utility analysis, rituximab biosimilars were cost-effective compared with mycophenolate mofetil for moderate to severe pemphigus vulgaris. Further investigation into its cost-effectiveness over a longer time horizon is necessary, but the favorable results of this study suggest that the high acquisition costs of rituximab biosimilars may be offset by its effectiveness and provide economic evidence in support of its listing on the Pharmaceutical Benefits Scheme for pemphigus vulgaris.

Rare Mimic of a Myxofibrosarcoma: Cutaneous Myxoid Spindle Cell Squamous Cell Carcinoma as a Complication of Chronic Osteomyelitis.

ABSTRACT: Myxoid spindle cell squamous cell carcinoma is a rare variant of squamous cell carcinoma that can pose diagnostic challenges because of its unusual morphology. In this article, we report the case of a 68-year-old man who presented with a slow-growing, fungating mass on the right tibia at the site of his long-standing draining sinus tract. Biopsy revealed a malignant spindle cell tumor with prominent myxoid stroma and areas containing thin-walled blood vessels with a curvilinear appearance. The immunohistochemical profile indicated that the neoplastic cells were positive for a variety of keratins (MNF116, Cam 5.2, AE1/AE3, 34ßE12, and CK5/6) and transcriptional markers classically expressed in squamous cell carcinomas (p63 and p40). The tumor cells were negative for melanocytic and mesenchymal markers smooth muscle antibody, S100, caldesmon-h, desmin and CD34. Together, the clinical history, histologic appearance, and immunohistochemical panel was diagnostic of a myxoid spindle cell squamous cell carcinoma. The main differential diagnosis was myxofibrosarcoma. In addition to this clinical case, we also outline the current state of knowledge on this rare entity and discuss the importance of recognizing a Marjolin ulcer in this scenario.

Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects.

Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.