Citations

ABSTRACT Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic β-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role β-cell senescence in diabetes progression. In contrast, β-cell senescence also promotes immune surveillance, promoting β-cell survival and function. Thus, a better understanding of senescent cells’ phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent β-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21 Cip1 ) and Cdkn2a (encoding p16 Ink4a ) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a -expressing β-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a + cells was sufficient to induce secondary senescence and β-cell dysfunction in vitro . JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored β-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT

PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.

ImportanceMetastatic cutaneous Crohn disease (MCD) is a rare condition for which there are currently no published diagnostic criteria. Formal MCD diagnostic criteria will expand clinical care and research by enabling future diagnostic code validation, crystallizing a more uniform disease entity for the purposes of translational research, and allowing the development of more formalized outcome measures aimed at treatment response.ObjectiveTo define a set of criteria for the diagnosis of MCD.Evidence ReviewIn this consensus statement, a panel of experts on MCD and related conditions was assembled. Their opinions were gathered regarding the clinical and histologic findings that are sufficient, necessary, and highly suggestive of MCD through serial survey. Subsequent surveys were continued until consensus was achieved. Sufficient was defined as a feature that, if noted, would enable diagnosis of MCD without any other signs, symptoms, or testing. Necessary was defined as a feature that must be present to establish a diagnosis of MCD. Highly suggestive referred to any other features that were indicative of MCD but did not qualify as sufficient or necessary to diagnose MCD.FindingsOf 24 experts invited, 19 agreed to participate, with a 79% to 100% response rate across 5 rounds conducted. Five patients were also invited to participate, but none opted to participate, citing lack of clinical expertise and time concerns. The experts were all from the US; 5 (26%) have practiced medicine for 0 to 5 years, 5 (26%) practiced for 6 to 10 years, 6 (32%) practiced for 11 to 15 years, and 3 (16%) practiced for more than 20 years. A total of 18 experts (95%) worked in an academic practice setting. There was consensus agreement that MCD could present as oral disease, genital disease, or, rarely, in another location. Consensus was achieved on 2 major and 5 minor criteria for genital/other subtypes of MCD and 5 minor criteria for oral MCD. There was consensus that, while there are some pathological findings that are highly suggestive of MCD, histologic criteria are not necessary for diagnosis.Conclusions and RelevanceA panel of experts reached consensus on the diagnostic criteria for MCD described in this study. These criteria include major and minor clinical criteria, along with histopathological criteria for the diagnosis of genital and oral MCD. This consensus is a crucial step in the diagnosis of and future treatment development for MCD, a rare and clinically understudied condition.

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.