Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections.

Urinary tract infection (UTI) is a pervasive health problem worldwide. Patients with a history of UTIs suffer increased risk of recurrent infections, a major risk of antibiotic resistance. Here, we show that bladder infections induce expression of Ezh2 in bladder urothelial cells. Ezh2 is the methyltransferase of polycomb repressor complex 2 (PRC2)-a potent epigenetic regulator. Urothelium-specific inactivation of PRC2 results in reduced urine bacterial burden, muted inflammatory response, and decreased activity of the NF-κB signaling pathway. PRC2 inactivation also facilitates proper regeneration after urothelial damage from UTIs, by attenuating basal cell hyperplasia and increasing urothelial differentiation. In addition, treatment with Ezh2-specific small-molecule inhibitors improves outcomes of the chronic and severe bladder infections in mice. These findings collectively suggest that the PRC2-dependent epigenetic reprograming controls the amplitude of inflammation and severity of UTIs and that Ezh2 inhibitors may be a viable non-antibiotic strategy to manage chronic and severe UTIs.

Inequalities in Cancer Stage at Diagnosis Among Incarcerated Individuals Undergoing Radiation Therapy at a Large Safety-Net Hospital.

INTRODUCTION: There is a dearth of data on cancer care in the incarcerated population, despite being the leading cause of illness-related death in United states' prisons. We retrospectively reviewed the demographic and clinicopathologic characteristics of incarcerated individuals who received radiation therapy at a large safety-net hospital. METHODS: Following IRB approval, we identified 80 incarcerated patients who presented for radiation therapy between January 2003 and May 2019. Descriptive statistics on the patients, tumor types and stage, treatment factors, and follow-up rates were analyzed. RESULTS: 80 individuals with 82 cancer diagnoses presented for radiation oncology consultation over the study period. The median age was 54 years (range, 46-64). Patients of White, Black, and "other" races comprised 61.3% (n=49), 28.8% (n=23), and 10% (n=8), respectively. Most patients were male (n=75, 93.8%) and English speakers (n=76, 95%). Moreover, 50% (n=40) had a substance use disorder history and 75% (n=60) had a smoking history. The three most common cancer types were prostate (n=12, 14.6%), gastrointestinal (n=14, 17.1%), thoracic (n=17, 20.7%), and head and neck (n=21, 25.6%). The distribution of tumor stage (AJCC) was I (n=12, 14.6%), II (n=12, 14.6%), III (n=14, 17.1%), IV (n=38, 46.3%), and unknown/unavailable (n=6, 7.3%). Of the cohort, 65 patients with 66 cancers (80.5%) received radiation. Among them, the 6-month, 1-year, and 5-year follow-up rates were 41.5%, 27.7%, and 3.1%, respectively. Subset analysis limited to stage I-III patients (n=30) revealed 6-month, 1-year and 5-year follow-up rates of 41.9%, 22.6%, and 3.2%, respectively. CONCLUSIONS: This study highlights inequalities in cancer stage at diagnosis among a vulnerable patient population that is largely excluded from clinical research. Majority of the incarcerated patients presented with stage III & IV cancers and have poor follow up rates even among those with early-stage disease. Efforts to understand and mitigate persistent health inequalities among incarcerated patients are warranted.

Mechanism of Sex Differences in Bladder Cancer: Evident and Elusive Sex-biasing Factors.

Bladder cancer incidence is drastically higher in males than females across geographical, racial, and socioeconomic strata. Despite potential differences in tumor biology, however, male and female bladder cancer patients are still clinically managed in highly similar ways. While sex hormones and sex chromosomes have been shown to promote observed sex differences, a more complex story lies beneath these evident sex-biasing factors than previously appreciated. Advances in genomic technology have spurred numerous preclinical studies characterizing elusive sex-biasing factors such as epigenetics, X chromosome inactivation escape genes, single nucleotide polymorphism, transcription regulation, metabolism, immunity, and many more. Sex-biasing effects, if properly understood, can be leveraged by future efforts in precision medicine based on a patient's biological sex. In this review, we will highlight key findings from the last half century that demystify the intricate ways in which sex-specific biology contribute to differences in pathogenesis as well as discuss future research directions.

Oral cancer patients achieve comparable survival at high safety-net burden hospitals.

PURPOSE: To evaluate the impact of hospital safety-net burden and social demographics on the overall survival of patients with oral cavity squamous cell carcinoma. MATERIALS AND METHODS: We identified 48,176 oral cancer patients diagnosed between the years 2004 to 2015 from the National Cancer Database and categorized treatment facilities as no, low, or high safety-net burden hospitals based on the percentage of uninsured or Medicaid patients treated. Using the Kaplan Meier method and multivariate analysis, we examined the effect of hospital safety-net burden, sociodemographic variables, and clinical factors on overall survival. RESULTS: Of the 1269 treatment facilities assessed, the median percentage of uninsured/Medicaid patients treated was 0% at no, 11.6% at low, and 23.5% at high safety-net burden hospitals and median survival was 68.6, 74.8, and 55.0 months, respectively (p < 0.0001). High safety-net burden hospitals treated more non-white populations (15.4%), lower median household income (<$30,000) (23.2%), and advanced stage cancers (AJCC III/IV) (54.6%). Patients treated at low (aHR = 0.97; 95% CI = 0.91-1.04, p = 0.405) and high (aHR = 1.05; 95% CI = 0.98-1.13, p = 0.175) safety-net burden hospitals did not experience worse survival outcomes compared to patients treated at no safety-net burden hospitals. CONCLUSION: High safety-net burden hospitals treated more oral cancer patients of lower socioeconomic status and advanced disease. Multivariate analysis showed high safety-net burden hospitals achieved comparable patient survival to lower burden hospitals.

Arid1a regulates bladder urothelium formation and maintenance.

Epigenetic regulation of gene expression plays a central role in bladder urothelium development and maintenance. ATPase-dependent chromatin remodeling is a major epigenetic regulatory mechanism, but its role in the bladder has not been explored. Here, we show the functions of Arid1a, the largest subunit of the SWI/SNF or BAF chromatin remodeling ATPase complex, in embryonic and adult bladder urothelium. Knockout of Arid1a in urothelial progenitor cells significantly increases cell proliferation during bladder development. Deletion of Arid1a causes ectopic cell proliferation in the terminally differentiated superficial cells in adult mice. Consistently, gene-set enrichment analysis of differentially expressed genes demonstrates that the cell cycle-related pathways are significantly enriched in Arid1a knockouts. Gene-set of the polycomb repression complex 2 (PRC2) pathway is also enriched, suggesting that Arid1a antagonizes the PRC2-dependent epigenetic gene silencing program in the bladder. During acute cyclophosphamide-induced bladder injury, Arid1a knockouts develop hyperproliferative and hyperinflammatory phenotypes and exhibit a severe loss of urothelial cells. A Hallmark gene-set of the oxidative phosphorylation pathway is significantly reduced in Aria1a mutants before injury and is unexpectedly enriched during injury response. Together, this study uncovers functions of Arid1a in both bladder progenitor cells and the mature urothelium, suggesting its critical roles in urothelial development and regeneration.

Disparities in Laryngeal Cancer Treatment and Outcomes: An Analysis by Hospital Safety-Net Burden.

OBJECTIVES/HYPOTHESIS: To analyze the impact of hospital safety-net burden on survival outcomes for laryngeal squamous cell carcinoma (LSCC) patients. STUDY DESIGN: Retrospective cohort study. METHODS: From 2004 to 2015, 59,733 LSCC patients treated with curative intent were identified using the National Cancer Database. Low (LBH) <25th, medium (MBH) 25th-75th, and high (HBH) >75th safety-net burden hospitals were defined by the percentage quartiles (%) of uninsured/Medicaid-insured patients treated. Social and clinicopathologic characteristics and overall survival (using Kaplan-Meier survival analysis) were evaluated. Crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed using Cox regression modeling. RESULTS: There were 324, 647, and 323 hospitals that met the criteria as LBH, MBH, and HBH, respectively. The median follow-up was 38.6 months. A total of 27,629 deaths were reported, with a median survival of 75.8 months (a 5-year survival rate of 56.6%). Median survival was 83.2, 77.8, and 69.3 months for patients from LBH, MBH, and HBH, respectively (P < .0001). The median % of uninsured/Medicaid-insured patients treated among LBH, MBH, and HBH were 3.6%, 14.0%, and 27.0%, respectively. Patients treated at HBH were significantly more likely to be young, Black, Hispanic, of low income, and present with more advanced disease compared to LBH and MBH. Survival was comparable for LBH and MBH (HR = 1.02; 95% CI = 0.97-1.07, P = .408) on multivariate analysis. HBH, compared to LBH patients, had inferior survival (HR = 1.07; 95% CI = 1.01-1.13, P = .023). CONCLUSIONS: High burden safety-net hospitals receive disproportionately more patients with advanced-stage and low socioeconomic status, yielding inferior survival compared to low burden hospitals. LEVEL OF EVIDENCE: 3 (individual cohort study) Laryngoscope, 131:E1987-E1997, 2021.

A national cancer database analysis on stereotactic body radiation therapy of head and neck cancers.

BACKGROUND: To evaluate demographic, clinicopathological, treatment factors including biological effective radiation dose (BED) that influence overall survival in head and neck cancer (HNC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Between 2004 and 2015, 591 SBRT-treated HNC patients were identified from the National Cancer Data Base. A BED using an alpha/beta ratio of 10 (BED10), was used to compare dose fractionation of different SBRT regimens. Overall survival was estimated using the Kaplan Meier method, and log-rank tests were used to determine statistical significance. Cox regression modeling was used to compute crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Median follow-up was 11.9 (interquartile range, 5.5 to 26.7) months. The 5-year overall survival rate was 15.5%. On multivariate analysis, older age, Charlson-Deyo comorbidity score ≥ 1, history of cancer, tumor, nodal and metastatic stage, and receiving treatment at academic/research program were associated with poor survival. Compared to SBRT alone, superior survival was observed with SBRT with chemotherapy, surgery with SBRT, but not surgery with SBRT and chemotherapy. Improved survival was observed with aa BED10 of ≥59.5 Gy (adjusted HR 0.57, 95% CI 0.46-0.70, P < 0.0001). CONCLUSIONS: Factors affecting associated with worse survival in HNC patients treated with SBRT included older age, patient comorbidities, advanced tumor stage, cancer history, and lower biological effective SBRT dose. LEVEL OF EVIDENCE: 2b (individual cohort study).

Sex Differences in Bladder Cancer Immunobiology and Outcomes: A Collaborative Review with Implications for Treatment.

CONTEXT: Urothelial carcinoma of the bladder (UCB) exhibits significant sexual dimorphism in the incidence, etiology, and response to intravesical immunotherapy. Environmental factors such as tobacco use and clinical management issues such as delayed presentation have widely been associated with sex differences in UCB outcomes. Emerging findings from immune checkpoint blockade trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in the way immune system functions and responds to pathogenic insults are well established. As such, an in-depth understanding of the genetic and epigenetic factors contributing to sex-associated differences in response to immunomodulatory therapies is needed urgently for improved management of UCB. OBJECTIVE: To review the associations between patient sex and clinical outcomes, with a focus on the incidence, host intrinsic features, and response to therapies in UCB. EVIDENCE ACQUISITION: Using the PubMed database, this narrative review evaluates published findings from mouse model-based and clinical cohort studies to identify factors associated with sex and clinical outcomes in bladder cancer. A scoping review of the key findings on epidemiology, genetic, hormonal, immune physiology, and clinical outcomes was performed to explore potential factors that could have implications in immunomodulatory therapy design. EVIDENCE SYNTHESIS: Sex-associated differences in UCB incidence and clinical outcomes are influenced by sex hormones, local bladder resident immune populations, tumor genetics, and bladder microbiome. In the context of therapeutic outcomes, sex differences are prominent in response to bacillus Calmette-Guérin immunotherapy used in the treatment of non-muscle-invasive bladder cancer. Similarly, with respect to tumor molecular profiles in muscle-invasive bladder cancer, tumors from females show enrichment of the basal subtype. CONCLUSIONS: Among proposed tumor/host intrinsic factors that may influence response to immune-based therapies, patient sex remains a challenging consideration that deserves further attention. Evidence to date supports a multifactorial origin of sexual dimorphism in the incidence and outcomes of UCB. PATIENT SUMMARY: In this review, we highlight the sex-associated host and tumor intrinsic features that may potentially drive differential disease progression and therapeutic response in urothelial carcinoma of the bladder.

Current and future molecular diagnostics of gastric cancer.

Introduction: Gastric cancer (GC) is the fifth most common cancer and confers the second-highest mortality among other cancers. Improving the survival rates of GC patients requires prompt and accurate diagnosis and effective treatment which is often preceded by the poorly understood pathogenic mechanisms. Area covered: This literature review aims to summarize current understanding of genetic and molecular alterations that promote carcinogenesis including (1) activation of oncogenes, (2) overexpression of growth factors, receptors and matrix metalloproteinases, (3) inactivation of tumor suppressor genes, DNA repair genes, and cell adhesion molecules and (4) alterations of cell-cycle regulators that regulate biological characteristics of cancer cells. Moreover, the significance of molecular biomarkers such as micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) and advanced molecular techniques including droplet digital polymerase chain reaction (ddPCR), quantitative PCR (qPCR) and next-generation sequencing (NGS) are also discussed. Expert opinion: A GC-specific panel of biomarkers based on the NGS or ddPCR has the potential for diagnosis, prognosis, and monitoring treatment response in GC patients. Despite the requirements for validation in larger population in clinical studies, race-specific differences in the gene panel have also to be examined by performing the clinical trials in subjects with different races.

Mommy, speak clearly: induced hearing loss shapes vowel hyperarticulation.

Talkers hyperarticulate vowels when communicating with listeners that require increased speech intelligibility. Vowel hyperarticulation is said to be motivated by knowledge of the listener's linguistic needs because it typically occurs in speech to infants, foreigners and hearing-impaired listeners, but not to non-verbal pets. However, the degree to which vowel hyperarticulation is determined by feedback from the listener is surprisingly less well understood. This study examines whether mothers' speech input is driven by knowledge of the infant's linguistic competence, or by the infant's feedback cues. Specifically, we manipulated (i) mothers' knowledge of whether they believed their infants could hear them or not, and (ii) the audibility of the speech signal available to the infant (full or partial audibility, or inaudible). Remarkably, vowel hyperarticulation was completely unaffected by mothers' knowledge; instead, there was a reduction in the degree of hyperarticulation such that vowels were hyperarticulated to the greatest extent in the full audibility condition, there was reduced hyperarticulation in the partially audible condition, and no hyperarticulation in the inaudible condition. Thus, while it might be considered adaptive to hyperarticulate speech to the hearing-impaired adult or infant, when these two factors (infant and hearing difficulty) are coupled, vowel hyperarticulation is sacrificed. Our results imply that infant feedback drives talker behavior and raise implications for intervention strategies used with carers of hearing-impaired infants.

Maternal interactions with a hearing and hearing-impaired twin: similarities and differences in speech input, interaction quality, and word production.

PURPOSE: This study examined a mother's speech style and interactive behaviors with her twin sons: 1 with bilateral hearing impairment (HI) and the other with normal hearing (NH). METHOD: The mother was video-recorded interacting with her twin sons when the boys were 12.5 and 22 months of age. Mean F0, F0 range, duration, and F1/F2 vowel space of the corner vowels /i/, /u/, and /a/ were compared in her infant-directed (ID) and adult-directed (AD) speech. The interactions were also coded for emotional availability, and vocabulary size was collected at 17 and 22 months. RESULTS: Acoustic analyses revealed no difference among mean F0, F0 range, and duration between the twins. In contrast, when the corner vowels were plotted in F1/F2 vowel space, the results showed a diminished vowel space in speech to the HI twin compared to the NH twin. Ratings of emotional availability were lower for the HI than the NH twin, but the HI twin had a larger expressive vocabulary on both occasions, albeit in the lower percentile. CONCLUSIONS: The mother appears more focused on maintaining the attention of the HI infant using the typical ID exaggerations to prosody and overlooking linguistic features such as the hyperarticulation of her vowels. The results have implications for early intervention strategies.

Age-Specific Preferences for Infant-Directed Affective Intent.

This study examined the developmental course of infants' attentional preferences for 3 types of infant-directed affective intent, which have been shown to be commonly used at particular ages in the first year of life. Specifically, Kitamura and Burnham (2003) found mothers' tone of voice in infant-directed speech is most comforting between birth and 3 months, most approving at 6 months, and most directive at 9 months. Thus, the aim of this study was to assess whether there is a relation between the type of affective intent used by mothers at each age point, and infants' affective intent preferences. Each infant group, 3-, 6-, and 9-month-olds, was played the 3 types of affective intent alternating across a single test session. When analyzed across age, the interactions revealed the predicted developmental trajectory; that is, infant preferences transformed between 3 and 6 months from comforting to approving, and between 6 and 9 months, from approving to directive. However, when analyzed separately by age, it was shown that 3-month-olds preferred comforting to other types; 6-month-olds preferred approving to directive, but listened equally to approving and comforting; and 9-month-olds showed no preference for any type of affective intent. Because it was possible that 9-month-olds were more focused on phonetic and phonotactic information, a new group of 9-month-olds was tested with intonation-only versions of the 3 affective intent types. Under these conditions, they were found to prefer directive to comforting, but not directive to approving types. The results of this study have implications for what infants pay attention to in their social and linguistic environment over the course of the first year.