Citations

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the activated B cell–like subtype (ABC-DLBCL) is associated with particularly poor outcome. Many ABC-DLBCLs harbor gain-of-function mutations that cause inappropriate assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, a cytoplasmic complex that drives downstream NF-κB signaling. MALT1 is the effector protein of the CBM signalosome such that its recruitment to the signalosome via interaction with BCL10 allows it to exert both protease and scaffolding activities that together synergize in driving NF-κB. Here, we demonstrate that a molecular groove located between two adjacent immunoglobulin-like domains within MALT1 represents a binding pocket for BCL10. Leveraging this discovery, we performed an in silico screen to identify small molecules that dock within this MALT1 groove and act as BCL10-MALT1 protein-protein interaction (PPI) inhibitors. We report the identification of M1i-124 as a first-in-class compound that blocks BCL10-MALT1 interaction, abrogates MALT1 scaffolding and protease activities, promotes degradation of BCL10 and MALT1 proteins, and specifically targets ABC-DLBCLs characterized by dysregulated MALT1. Our findings demonstrate that small-molecule inhibitors of BCL10-MALT1 interaction can function as potent agents to block MALT1 signaling in selected lymphomas, and provide a road map for clinical development of a new class of precision-medicine therapeutics.

Background: Breast cancer survivors face a risk of significant psychological distress, which can persist for years after their initial diagnosis. Although numerous guidelines and tools exist to help screen for and measure distress in patients with cancer, additional longitudinal studies are needed to better characterize the trajectory of distress over time. Patients and Methods: We conducted a longitudinal study to evaluate distress and health-related quality of life in patients with breast cancer. Annual assessments included global mental and physical health scores using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10), posttraumatic stress symptoms using the Impact of Event Scale-Revised (IES-R), and depressive symptoms using the Patient Health Questionnaire-2 (PHQ-2). Eligible participants had stage 0–III breast cancer, with baseline surveys administered within 1 year of diagnosis. Annual follow-up surveys were conducted through year 4 after the baseline survey. Only patients who completed the baseline survey and at least one follow-up survey were included in this analysis. Individuals with stage IV or recurrent breast cancer were excluded. Results: A total of 2,140 individuals were included. Over time, global mental health scores declined slightly, with differences in T-scores from baseline ranging from 0.4 to 0.9. In contrast, global physical health scores improved, with differences in T-scores ranging from 0.3 to 0.6. Mean scores remained in the normative range. Depressive symptoms remained stable throughout the study period, while posttraumatic stress symptoms showed improvement over time. Conclusions: This study provides important longitudinal data on distress subtypes in breast cancer survivors with nonmetastatic disease. Although global mental health declined slightly, depression symptoms remained stable, and posttraumatic stress symptoms improved. Investigation of distress subtypes over time merits further study to advance detection of significant distress across the cancer continuum.

ABSTRACT Although lung transplant recipients who develop Ureaplasma- associated hyperammonemia syndrome are treated with Ureaplasma -targeted antibiotics, optimal therapy is incompletely defined, and typically not based on real-time antimicrobial susceptibility testing results. This study compared levofloxacin, azithromycin, and doxycycline prevention and treatment of Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) infections in an immunosuppressed murine lung infection model. For prophylaxis, mice received antibiotics before infection with UP-FS (susceptible to all study antibiotics), UP-AzmR (azithromycin-resistant), UP-LevR (levofloxacin-resistant), or UU-DoxR (doxycycline-resistant), with lung bacterial loads (color changing units [CCUs]) measured 18 hours following infection. For UP-FS, doxycycline was most active (Δ4.84 log 10 CCU/g; P = 0.0006), followed by levofloxacin (Δ2.45 log 10 CCU/g; P = 0.018), with azithromycin yielding a nonsignificant CCU reduction. Doxycycline (Δ1.9 log 10 CCU/g; P = 0.0025) and levofloxacin (Δ1.3 log 10 CCU/g; P = 0.004) showed activity against UP-AzmR. Only doxycycline showed activity against UP-LevR (Δ2.28 log 10 CCU/g; P = 0.0002), and only azithromycin showed activity against UU-DoxR (Δ0.67 log 10 CCU/g; P = 0.0175). For treatment, antibiotics were administered 24 hours following infection; doxycycline significantly reduced bacterial loads of all study isolates, except UU-DoxR. In addition, azithromycin was active against UP-LevR (Δ1.21 log 10 CCU/g reduction; P = 0.0003). In summary, except for doxycycline-resistant UU, doxycycline was active in preventing and treating Ureaplasma lung infection in immunosuppressed mice.

Background: Cervical cancer screening with a self-collected vaginal specimen for human papillomavirus (HPV) testing was approved by the U.S. Food and Drug Administration in May 2024, offering a potential solution to declining screening rates. Objective: We aimed to assess acceptability of clinic-based vaginal specimen self-collection for HPV testing and to evaluate associations between participants’ sociodemographics and their likelihood of choosing self-collection for future screening and the overall acceptability of using the Evalyn® brush device. We also evaluated associations between specific acceptability constructs and reported likelihood to use the device in the future and overall acceptability. Methods: Following self-collection of a vaginal specimen, participants completed an electronic survey that measured constructs from the Theoretical Framework of Acceptability. Associations were assessed using logistic regressions. The study was conducted at a colposcopy clinic in the Gynecology department of a midwestern academic medical center in the United States from November 2022 through July 2023. Results: Participants ( n = 81) reported high likelihood (98% likely or very likely) of choosing in-home self-collection for future screening and unanimity on overall acceptability (100% acceptable or completely acceptable) of using the device. More affirmative responses to measures on instruction understandability, ease of device use, understanding the device is used for cervical cancer screening, and perceiving self-collection improves screening rates were associated with a higher likelihood to choose self-collection for future screenings and overall acceptability of the device (all p values <0.05). Conclusion: Vaginal specimen self-collection for HPV testing was well-received in the studied population, with high acceptability and likelihood of uptake. Implementation efforts should provide user-friendly instructions and emphasize the benefits of self-collection for cervical cancer screening, particularly among people less likely to engage with clinician-collected speculum-based screening.

Abstract Background: Prior research on the associations of p16, COX-2, and Ki67 immunopositivity in ductal carcinoma in situ (DCIS) tissue with the risk of subsequent ipsilateral invasive breast cancer (IBC) is limited. Methods: In a case–control study nested in a cohort of women diagnosed with DCIS, immunostaining for p16, COX-2, and Ki67 was performed on DCIS tissue from those who developed subsequent ipsilateral IBC (cases; n = 146) and on matched subjects who did not develop IBC (controls; n = 273). Conditional logistic regression was used to estimate ORs and 95% confidence intervals for the associations between immunopositivity for p16, COX-2, and Ki67 and the risk of subsequent ipsilateral IBC. Results: There was no association between p16, COX-2, and Ki67 immunopositivity, examined either individually or in combination, and a risk of ipsilateral IBC. Compared with all other groups, the multivariable OR (95% confidence interval) for women who were triple positive for the three markers was 1.16 (0.38–3.54). Conclusions: p16, COX-2, and Ki67 immunopositivity was not associated with altered risk of ipsilateral IBC in women with DCIS. Impact: p16, COX-2, and Ki67 may not be prognostic for ipsilateral IBC in women with DCIS.

Abstract Background: Although colorectal cancer survival rates are improving, the risk of incident type 2 diabetes mellitus (T2D) among Asian, Native Hawaiian, and Pacific Islander (ANHPI) ethnic groups is poorly understood. This study aims to identify high-risk groups and quantify the risk across different periods. Methods: Using the SEER–Medicare database, colorectal cancer survivors who were ANHPI were matched to non-Hispanic White (NHW) survivors at a ratio of 1:3. Multivariable Cox regression models computed HRs and 95% confidence intervals (CI) for incident T2D. Results: The study included 6,463 NHW and 2,901 ANHPI colorectal cancer survivors diagnosed between 2000 and 2017. Among them, 715 NHW and 484 ANHPI developed T2D during 39,097 and 10,769 person-years of follow-up, respectively. ANHPI colorectal cancer survivors had an elevated T2D risk compared with NHW across all follow-up periods (HRoverall: 1.84, 95% CI, 1.51–2.25; HR1–5 years: 1.83, 95% CI, 1.45–2.30). Southeast and East Asians demonstrated the highest T2D risks. Colon cancer was linked to early postdiagnosis T2D risk, whereas rectal cancer was associated with later risk. No significant association was observed for Native Hawaiians and Pacific Islanders. Conclusions: ANHPI colorectal cancer survivors face a greater risk of T2D, particularly among Southeast and East Asians. These findings highlight the need for evidence-based survivorship strategies to prevent T2D and reduce ethnic disparities. Impact: This is the first study to examine T2D risk among ANHPI colorectal cancer survivors, providing critical insights to inform tailored diabetes prevention and survivorship care.