Patient-Specific Vascularized Tumor Model: Blocking TAM Recruitment with Multispecific Antibodies Targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, with the infiltration of monocyte-derived tumor-associated macrophages (TAMs) associated with poor prognosis in diverse cancers. Targeting TAMs holds potential against solid tumors, but effective immunotherapies require testing on immunocompetent human models prior to clinical trials. Here, we develop an in vitro model of microvascular networks that incorporates tumor spheroids or patient tissues. By perfusing the vasculature with human monocytes, we investigate monocyte trafficking into the tumor and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via TAM-produced CCL7 and CCL2, mediated by CSF-1R. Additionally, we assess a novel multispecific antibody targeting CCR2, CSF-1R, and neutralizing TGF-ß, referred to as CSF1R/CCR2/TGF-ß Ab, on monocytes and macrophages using our 3D models. This antibody repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and effectively blocks monocyte migration. Finally, we show that the CSF1R/CCR2/TGF-ß Ab inhibits monocyte recruitment in patient-specific vascularized tumor models. Overall, this vascularized tumor model offers valuable insights into monocyte recruitment and enables functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment (TME).

Trends and Racial Disparities in the Prevalence of Urinary Incontinence Among Men in the USA, 2001-2020.

BACKGROUND: Male urinary incontinence (UI) affects quality of life and leads to a significant burden to the health care system. However, the contemporary prevalence and recent trends in UI and its subtypes among US men remain unknown. OBJECTIVE: We evaluated 20-yr trends in the prevalence of UI and its subtype in US men aged ≥20 yr. DESIGN, SETTING, AND PARTICIPANTS: A serial, cross-sectional analysis of the US nationally representative data from the National Health and Nutrition Examination Survey among men from 2001 to 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prevalence of any, stress, urgency and overflow UI were derived. The frequency of UI was assessed in four categories: less than one time per month, a few times per month, a few times per week, and every day and/or night. All analyses were conducted using sample weights, stratification, and clustering of the complex sampling design. Sociodemographic and lifestyle correlates of UI over time were identified using multivariable logistic regressions. RESULTS AND LIMITATIONS: Data on 22994 US men (mean age, 46.6 yr [standard error, 0.20]; weighted population, 848642150) were analyzed. The prevalence of any UI increased from 2001-2002 (11.5% [95% confidence interval {CI}, 10.0-13.0]) to 2017-2020 (19.3% [95% CI, 17.2-21.3]), driven by urgency (from 9.0% [95% CI, 7.5-10.4]) to 15.2% [95% CI, 13.4-16.9]) and overflow UI (from 3.3% [95% CI, 2.7-4.0] to 5.5% [95% CI, 4.5-6.4]; all p for trend < 0.01). UI affects 38.5% US men ≥60 yr of age, with increasing trends in urgency and overflow UI and a decreasing trend in stress UI (all p for trend < 0.05). Racial/ethnic disparities were noted, with patterns differed by UI subtype. Compared with non-Hispanic White, non-Hispanic Black men were more likely to report urgency UI (odds ratio [OR], 1.94 [95% CI, 1.71-2.20]). Hispanic men were more likely to report urgency UI (OR, 1.33 [95% CI, 1.14-1.56]), but less likely to report stress (OR, 0.74 [95% CI, 0.56-0.98]) and overflow (OR, 0.75 [95% CI, 0.58-0.98]) UI. Men with higher body mass index and current smokers were more likely to report any, stress, and urgency UI than their counterparts. A higher prevalence of any UI was found in men with low family poverty ratios and chronic diseases, and those who were physically inactive. CONCLUSIONS: From 2001 to 2020, the overall prevalence of UI increased among US men, particularly for urgency and overflow UI. PATIENT SUMMARY: In this report, we looked at the prevalence of urinary incontinence among US men in a nationally representative sample. We found that urinary incontinence increased in the past 20 yr driving by the urgency and overflow urinary incontinence.

Positive Regulation of Interleukin-1ß Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation.

Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1ß positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1ß from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1ß glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.

Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology.

The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ null(c) (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drug-resistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity.