Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.

Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.

Stage-dependent survival in patients treated with neoadjuvant chemotherapy and radical cystectomy.

BACKGROUND: The aim of this study is to investigate the differential stage-dependent outcomes of patients undergoing radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). METHODS: We performed a retrospective analysis of 1422 patients with cT2-4N0 MIBC treated with RC, with/without cisplatin-based NAC, from our multicenter cooperation program (treated period: 1992-2021). Patients were stratified according to their pathologic stage at RC. Cancer-specific survival (CSS) and overall survival (OS) were calculated using mixed-effects Cox analysis. RESULTS: Analysis was conducted on 761 patients treated with NAC followed by RC and 661 treated with RC only (median follow-up 19 months). Of 337 (24%) patients who died, 259 (18%) died of bladder cancer. On univariable analyses, increased pathologic stage was significantly associated with worse CSS (HR=1.59, 95% CI 1.46-1.73; P<0.01) and OS (HR=1.58, 95% CI 1.47-1.71; P<0.001). On multivariable mixed-effects model, patients after RC only had significantly worse CSS with stage pT≥3/N1-3 and OS with stage pT≥2/N0-3 compared to those with stage pT≤1N0. Patients after RC and NAC had significantly worse CSS and OS already at stage ypT≥2/N0-3 compared to those with ypT≤1N0. On subgroup analyses, CSS (HR=4.26; 95% CI 2.03-8.95; P<0.001) but not OS (HR=1.1; 95% CI 0.5-2.4; P=0.81) was worse for pT2N0 patients after NAC versus no-NAC. This difference was not maintained on multivariable analysis. CONCLUSIONS: NAC improves pathologic stage at the time of RC. Patients with residual MIBC after NAC have worse survival outcomes compared to those with the same pathologic stage who did not receive NAC, suggesting a need for better adjuvant therapy in these patients.

En-bloc resection of non-muscle invasive bladder cancer: does it really make a difference?

PURPOSE OF REVIEW: Transurethral resection of bladder tumour (TURBT) followed by pathology investigation of the obtained specimens is the initial step in the management of urinary bladder cancer (UBC). By following the basic principles of oncological surgery, en-bloc resection of bladder tumour (ERBT) aims to overcome the limitations associated with conventional transurethral resection, and to improve the quality of pathological specimens for a better decision making. The current bulk of evidence provides controversial results regarding the superiority of one technique over the other. The aim of this article is to summarize the recent data and provide evidence on this unanswered question. RECENT FINDINGS: Despite heterogeneous and controversial data, ERBT seems to have a better safety profile and deliver higher quality pathologic specimens. However, the recent evidence failed to support the hypothesized oncological potential benefits of ERBT in the initial surgical treatment of patients with UBC. SUMMARY: ERBT has gained increasing interest globally in the past decade. It continues to represent a promising strategy with a variety of features intended to solve the inherent limitations of TURBT. However, the current quality of evidence does not allow solid conclusions to be drawn about its presumed superiority compared with the conventional technique.

Secondary bladder amyloidosis due to Crohn's disease: a case report and literature review.

The presence of amyloid deposits in bladder walls is a rare histological finding. It can be linked to primary (limited to bladder) or secondary (systemic, associated with chronic inflammatory disorders) amyloidosis. Secondary bladder involvement is very uncommon; it usually presents with gross hematuria, which is challenging to manage, due to frail bladder mucosa and/or necrosis. We present a case of 54-year old man with secondary bladder amyloidosis due to Crohn's disease, that caused gross hematuria and severe anemia, which was managed conservatively by endoscopic transurethral resection, diatermocoagulation, clot evacuation and urinary drainage by bilateral percutaneous nephrostomy, with spontaneous resolution. Secondary bladder amyloidosis is a rare condition that presents with severe hematuria, difficult to control with standard management. Owing to chronic nature of the disease, treatment should be aimed to a conservative approach whenever possible. In case of failure, invasive procedures should be considered as salvage therapies.

Gut Microbiota-Derived Propionate Regulates the Expression of Reg3 Mucosal Lectins and Ameliorates Experimental Colitis in Mice.

BACKGROUND AND AIMS: Regenerating islet-derived protein type 3 [Reg3] lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via interleukin-22- or Toll-like receptor signalling. In addition to antimicrobial effects, tissue protection is hypothesized, but has been poorly investigated in the gut. METHODS: We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate [DSS] colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro. RESULTS: First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short-chain fatty acids [SCFAs], and knock-out [KO] mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA-producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4. CONCLUSIONS: Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signalling. We also provide evidence that the Reg3-propionate axis may be an important mediator of gut epithelial regeneration in colitis.

Congenital pulmonary malformations: metabolomic profile of lung phenotype in infants.

BACKGROUND: The main hydrosoluble metabolites in three different human congenital pulmonary malformations are described by nuclear magnetic resonance (NMR) spectroscopy. METHODS: Bronchogenic cyst (BC), congenital lobar emphysema (CLE) and intrapulmonary sequestration (IPS), were analyzed with respect to a control sample. The extracted metabolites were submitted to high-resolution (1)H NMR-spectroscopy. RESULTS: Congenital lung malformations showed free choline, phosphocoline and myoinositol high levels. IPS and CLE were found increased in lactic acid/glucose ratio. Lactic acid and glucose values resulted to be more elevated in control sample. CONCLUSIONS: Congenital lung lesions showed different metabolomic profiles useful for early diagnosis.

A "twist box" code of p53 inactivation: twist box: p53 interaction promotes p53 degradation.

Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.

Effectiveness of different substrate materials for in vitro sunscreen tests.

BACKGROUND: In vitro measurements of sunscreen products are used to assess their reliability in terms of photoprotection and photo-stability. OBJECTIVE: In this study, several substrates have been fully characterized for in vitro sunscreen testing. METHODS: The following different substrates have been utilised in the study: roughened PMMA plates, Transpore, Vitro-Skin, roughened quartz plate and a laboratory prepared roughened PTFE plate. The suitability of these substrates for SPF evaluation has been investigated by performing total absorbance measurements of seven sunscreen products with different SPF values produced by the same manufacturer. RESULTS AND CONCLUSIONS: Application of sunscreen products on Transpore, roughened quartz plate, PMMA, PTFE and Vitro-Skin was performed efficiently. With regard to photo-stability of the substrate materials, only PMMA plate, PTFE and roughened quartz plate showed to be photo-stable after UV irradiation. With regard to SPF tests, our results indicate that Transpore, roughened quartz plate and Vitro-Skin are preferable to assess SPF values because of a better correlation between in vitro and in vivo measurements. Our study also confirms that an initial calibration must be performed for sunscreen products labelled with different SPF values. Finally, the results of our measurements demonstrate that, although a correlation between in vitro and in vivo SPF results can be established, it is never exactly 1:1.

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers.

BRCA1-associated tumors are characterized by an elevated genomic instability and peculiar expression profiles. Nevertheless, tailored treatments for BRCA1 mutation carriers have only been partially investigated up to now. The implementation of therapeutic strategies specific for these patients has been in part hindered by the paucity of proper preneoplastic and neoplastic BRCA1-deficient tumor cell models. In this study, we took advantage of the RNA interference technology to generate a series of partially transformed (HBL100) and tumorigenic (MCF7 and T47D) breast cancer cell lines in which BRCA1 expression was silenced at different levels. These cell models were probed by clonogenic assay for their response to several DNA-damaging agents commonly used in cancer therapy (mitomycin C, cisplatin, doxorubicin, and etoposide). Our models confirmed the peculiar sensitivity to interstrand cross-link inducers associated with BRCA1 deficiency. Intriguingly, the increased sensitivity to these compounds displayed by BRCA1-defective cells was not correlated with the extent of apoptotic cell death but rather associated to an increased fraction of growth-arrested, enlarged, multinucleated beta-galactosidase-positive senescent cells. Overall, our results support a role for BRCA1 in the regulation of interstrand cross-link-induced premature senescence and suggest a reconsideration of the therapeutic power of mitomycin/platinum-based treatments in BRCA1 carriers. Moreover, our data further prompt the setup of strategies for the imaging of the senescence response in vivo.

Topical tacrolimus in the treatment of lichen planus in a child.

Lichen planus is a relatively common mucocutaneous disease in adult patients, but it is more rare in children. Topical corticosteroids are the first line of treatment in most pediatric patients with a localized classic form of lichen planus. We report the case of a child with cutaneous lichen planus who did not respond to topical steroids but showed complete resolution once switched to 0.03% tacrolimus ointment.