Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche(1,2). Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor alpha (PPAR-alpha)(3), and lowered PPAR-a activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.Peer reviewe

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomicmethods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system

The ABCD rule of dermatoscopy. High prospective value in the diagnosis of doubtful melanocytic skin lesions

BACKGROUND: The difficulties in accurately assessing pigmented skin lesions are ever present in practice. The recently described ABCD rule of dermatoscopy (skin surface microscopy at x10 magnification), based on the criteria asymmetry (A), border (B), color (C), and differential structure (D), improved diagnostic accuracy when applied retrospectively to clinical slides. OBJECTIVE: A study was designed to evaluate the prospective value of the ABCD rule of dermatoscopy in melanocytic lesions. METHODS: In 172 melanocytic pigmented skin lesions, the criteria of the ABCD rule of dermatoscopy were analyzed with a semiquantitative scoring system before excision. RESULTS: According to the retrospectively determined threshold, tumors with a score higher than 5.45 (64/69 melanomas [92.8%]) were classified as malignant, whereas lesions with a lower score were considered as benign (93/103 melanocytic nevi [90.3%]). Negative predictive value for melanoma (True-Negative divided by [True-Negative+False-Negative]) was 95.8%, whereas positive predictive value (True-Positive divided by [True-Positive+False-Positive]) was 85.3%. Diagnostic accuracy for melanoma (True-Positive divided by [True-Positive+False-Positive+False-Negative]) was 80.0%, compared with 64.4% by the naked eye. Melanoma showed a mean final dermatoscopy score of 6.79 (SD, +/- 0.92), significantly differing from melanocytic nevi (mean score, 4.27 +/- 0.99; p < 0.01, U test). CONCLUSION: The ABCD rule can be easily learned and rapidly calculated, and has proven to be reliable. It should be routinely applied to all equivocal pigmented skin lesions to reach a more objective and reproducible diagnosis and to obtain this assessment preoperatively

Basal Cell Carcinoma and World War II-Era Cathode Ray Oscilloscope Exposure

There is a high prevalence of skin cancer in World War II servicemen stationed in the Pacific theater as a result of various risk factors such as exposure to ultraviolet radiation and genetic predisposition. We sought to describe whether a possible association exists between basal cell carcinoma (BCC) development and the use of high-voltage cathode ray tube (CRT) oscilloscopes manufactured around 1940 to 1955, which were a source of X-radiation. We present a case series of 9 men aged 65 to 93 years who presented with similar head and neck distributions of BCC and a history of extensive use of early CRT oscilloscopes during and shortly after the World War II era. The patients were interviewed and their medical records reviewed to determine CRT exposure times and BCC location, subtype, and treatment. Representative BCC histologic sections were reviewed. A total of 230 BCCs of the head and neck region were identified and mapped. Questionnaires determined a minimum exposure of 600 (range, 624-9600) hours within a 60-cm distance of early CRT screens in all patients. The average number of aggressive histologic subtypes was 23.5%. The average number of Mohs micrographic surgery layers required to obtain negative margins was 1.99 compared with 1.63 in the control group treated by the same Mohs micrographic surgeon (P \u3c. 002). This descriptive study is the first to suggest that ionizing radiation from early CRT oscilloscopes may be a factor in the development of multiple BCCs of the head and neck with increased subclinical spread

Legislative Documents

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Proteome-Wide Reactivity Profiling Identifies Diverse Carbamate Chemotypes Tuned for Serine Hydrolase Inhibition

Serine hydrolases are one of the largest and most diverse enzyme classes in Nature. Inhibitors of serine hydrolases are used to treat many diseases, including obesity, diabetes, cognitive dementia, and bacterial and viral infections. Nonetheless, the majority of the 200+ serine hydrolases in mammals still lack selective inhibitors for their functional characterization. We and others have shown that activated carbamates, through covalent reaction with the conserved serine nucleophile of serine hydrolases, can serve as useful inhibitors for members of this enzyme family. The extent to which carbamates, however, cross-react with other protein classes remains mostly unexplored. Here, we address this problem by investigating the proteome-wide reactivity of a diverse set of activated carbamates <i>in vitro</i> and <i>in vivo</i>, using a combination of competitive and click chemistry (CC)-activity-based protein profiling (ABPP). We identify multiple classes of carbamates, including <i>O</i>-aryl, <i>O</i>-hexafluoroisopropyl (HFIP), and <i>O</i>-<i>N</i>-hydroxysuccinimidyl (NHS) carbamates that react selectively with serine hydrolases across entire mouse tissue proteomes <i>in vivo</i>. We exploit the proteome-wide specificity of HFIP carbamates to create <i>in situ</i> imaging probes for the endocannabinoid hydrolases monoacylglycerol lipase (MAGL) and α-β hydrolase-6 (ABHD6). These findings, taken together, designate the carbamate as a privileged reactive group for serine hydrolases that can accommodate diverse structural modifications to produce inhibitors that display exceptional potency and selectivity across the mammalian proteome