RNA-Binding Protein LIN28a Regulates New Myocyte Formation in the Heart Through Long Noncoding RNA-H19.

BACKGROUND: Developmental cardiac tissue holds remarkable capacity to regenerate after injury and consists of regenerative mononuclear diploid cardiomyocytes. On maturation, mononuclear diploid cardiomyocytes become binucleated or polyploid and exit the cell cycle. Cardiomyocyte metabolism undergoes a profound shift that coincides with cessation of regeneration in the postnatal heart. However, whether reprogramming metabolism promotes persistence of regenerative mononuclear diploid cardiomyocytes enhancing cardiac function and repair after injury is unknown. Here, we identify a novel role for RNA-binding protein LIN28a, a master regulator of cellular metabolism in cardiac repair after injury. METHODS: LIN28a overexpression was tested using mouse transgenesis on postnatal cardiomyocyte numbers, cell cycle, and response to apical resection injury. With the use of neonatal and adult cell culture systems and adult and Mosaic Analysis with Double Markers myocardial injury models in mice, the effect of LIN28a overexpression on cardiomyocyte cell cycle and metabolism was tested. Last, isolated adult cardiomyocytes from LIN28a and wild-type mice 4 days after myocardial injury were used for RNA-immunoprecipitation sequencing. RESULTS: LIN28a was found to be active primarily during cardiac development and rapidly decreases after birth. LIN28a reintroduction at postnatal day (P) 1, P3, P5, and P7 decreased maturation-associated polyploidization, nucleation, and cell size, enhancing cardiomyocyte cell cycle activity in LIN28a transgenic pups compared with wild-type littermates. Moreover, LIN28a overexpression extended cardiomyocyte cell cycle activity beyond P7 concurrent with increased cardiac function 30 days after apical resection. In the adult heart, LIN28a overexpression attenuated cardiomyocyte apoptosis, enhanced cell cycle activity, cardiac function, and survival in mice 12 weeks after myocardial infarction compared with wild-type littermate controls. Instead, LIN28a small molecule inhibitor attenuated the proreparative effects of LIN28a on the heart. Neonatal rat ventricular myocytes overexpressing LIN28a mechanistically showed increased glycolysis, ATP production, and levels of metabolic enzymes compared with control. LIN28a immunoprecipitation followed by RNA-immunoprecipitation sequencing in cardiomyocytes isolated from LIN28a-overexpressing hearts after injury identified long noncoding RNA-H19 as its most significantly altered target. Ablation of long noncoding RNA-H19 blunted LIN28a-induced enhancement on cardiomyocyte metabolism and cell cycle activity. CONCLUSIONS: Collectively, LIN28a reprograms cardiomyocyte metabolism and promotes persistence of mononuclear diploid cardiomyocytes in the injured heart, enhancing proreparative processes, thereby linking cardiomyocyte metabolism to regulation of ploidy/nucleation and repair in the heart.

Access and barriers to genomic classifiers for breast cancer and prostate cancer in India.

The incidence of cancer in general, including breast and prostate cancer specifically, is increasing in India. Breast and prostate cancers have genomic classifiers developed to guide therapy decisions. However, these genomic classifiers are often inaccessible in India due to high cost. These classifiers may also be less suitable to the Indian population, as data primarily from patients in wealthy Western countries were used in developing these genomic classifiers. In addition to the limitations in using these existing genomic classifiers, developing and validating new genomic classifiers for breast and prostate cancer in India is challenging due to the heterogeneity in the Indian population. However, there are steps that can be taken to address the various barriers that currently exist for accurate, accessible genomic classifiers for cancer in India.

Colon Cancer Disparities in Stage at Presentation and Time to Surgery for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study with Disaggregated Ethnic Groups.

BACKGROUND: Vast differences in barriers to care exist among Asian American, Native Hawaiian, and Pacific Islander (AANHPI) groups and may manifest as disparities in stage at presentation and access to treatment. Thus, we characterized AANHPI patients with stage 0-IV colon cancer and examined differences in (1) stage at presentation and (2) time to surgery relative to white patients. PATIENTS AND METHODS: We assessed all patients in the National Cancer Database (NCDB) with stage 0-IV colon cancer from 2004 to 2016 who identified as white, Chinese, Japanese, Filipino, Native Hawaiian, Korean, Vietnamese, Laotian, Hmong, Kampuchean, Thai, Asian Indian or Pakistani, and Pacific Islander. Multivariable ordinal logistic regression defined adjusted odds ratios (AORs), with 95% confidence intervals (CI), of (1) patients presenting with advanced stage colon cancer and (2) patients with stage 0-III colon cancer receiving surgery at ≥ 60 days versus 30-59 days versus < 30 days postdiagnosis, adjusting for sociodemographic/clinical factors. RESULTS: Among 694,876 patients, Japanese [AOR 1.08 (95% CI 1.01-1.15), p < 0.05], Filipino [AOR 1.17 (95% CI 1.09-1.25), p < 0.001], Korean [AOR 1.09 (95% CI 1.01-1.18), p < 0.05], Laotian [AOR 1.51 (95% CI 1.17-1.95), p < 0.01], Kampuchean [AOR 1.33 (95% CI 1.04-1.70), p < 0.01], Thai [AOR 1.60 (95% CI 1.22-2.10), p = 0.001], and Pacific Islander [AOR 1.41 (95% CI 1.20-1.67), p < 0.001] patients were more likely to present with more advanced colon cancer compared with white patients. Chinese [AOR 1.27 (95% CI 1.17-1.38), p < 0.001], Japanese [AOR 1.23 (95% CI 1.10-1.37], p < 0.001], Filipino [AOR 1.36 (95% CI 1.22-1.52), p < 0.001], Korean [AOR 1.16 (95% CI 1.02-1.32), p < 0.05], and Vietnamese [AOR 1.55 (95% CI 1.36-1.77), p < 0.001] patients were more likely to experience greater time to surgery than white patients. Disparities persisted when comparing among AANHPI subgroups. CONCLUSIONS: Our findings reveal key disparities in stage at presentation and time to surgery by race/ethnicity among AANHPI subgroups. Heterogeneity upon disaggregation underscores the importance of examining and addressing access barriers and clinical disparities.

A burden shared: the financial, psychological, and health-related consequences borne by family members and caregivers of people with cancer in India.

In India, approximately 1.4 million new cases of cancer are recorded annually, with 26.7 million people living with cancer in 2021. Providing care for family members with cancer impacts caregivers' health and financial resources. Effects on caregivers' health and financial resources, understood as family and caregiver "financial toxicity" of cancer, are important to explore in the Indian context, where family members often serve as caregivers, in light of cultural attitudes towards family. This is reinforced by other structural issues such as grave disparities in socioeconomic status, barriers in access to care, and limited access to supportive care services for many patients. Effects on family caregivers' financial resources are particularly prevalent in India given the increased dependency on out-of-pocket financing for healthcare, disparate access to insurance coverage, and limitations in public expenditure on healthcare. In this paper, we explore family and caregiver financial toxicity of cancer in the Indian context, highlighting the multiple psychosocial aspects through which these factors may play out. We suggest steps forward, including future directions in (1) health services research, (2) community-level interventions, and (3) policy changes. We underscore that multidisciplinary and multi-sectoral efforts are needed to study and address family and caregiver financial toxicity in India.

Altered Retrograde Signaling Patterns in Breast Cancer Cells Cybrids with H and J Mitochondrial DNA Haplogroups.

The aim of this study was to determine the role of retrograde signaling (mitochondria to nucleus) in MCF7 breast cancer cells. Therefore, in the present study, MCF7-H and MCF7-J cybrids were produced using the mitochondria from the same H and J individuals that were already used in our non-diseased retinal pigment epithelium (ARPE19) cybrids. MCF7 cybrids were treated with cisplatin and analyzed for cell viability, mitochondrial membrane potential, ROS, and expression levels of genes associated with the cGAS-STING and cancer-related pathways. Results showed that unlike the ARPE19-H and ARPE19-J cybrids, the untreated MCF7-H and MCF7-J cybrids had similar levels of ATP, lactate, and OCR: ECAR ratios. After cisplatin treatment, MCF7-H and MCF7-J cybrids showed similar (a) decreases in cell viability and ROS levels; (b) upregulation of ABCC1, BRCA1 and CDKN1A/P21; and (c) downregulation of EGFR. Cisplatin-treated ARPE19-H and ARPE19-J cybrids showed increased expression of six cGAS-STING pathway genes, while two were increased for MCF7-J cybrids. In summary, the ARPE19-H and ARPE19-J cybrids behave differentially from each other with or without cisplatin. In contrast, the MCF7-H and MCF7-J cybrids had identical metabolic/bioenergetic profiles and cisplatin responses. Our findings suggest that cancer cell nuclei might have a diminished ability to respond to the modulating signaling of the mtDNA that occurs via the cGAS-STING pathway.

Sepsis and the Obesity Paradox: Size Matters in More Than One Way.

OBJECTIVES: Multiple studies have demonstrated an obesity paradox such that obese ICU patients have lower mortality and better outcomes. We conducted this study to determine if the mortality benefit conferred by obesity is affected by baseline serum lactate and mean arterial pressure. DESIGN: Retrospective analysis of prospectively collected clinical data. SETTING: Five community-based and one academic medical center in the Omaha, NE. PATIENTS: 7,967 adults hospitalized with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized by body mass index as underweight, normal weight, overweight, or obese. Multivariable logistic regression models were used to estimate the odds of in-hospital death by body mass index category; two-way interactions between body mass index and each covariate were also evaluated. Subgroup and sensitivity analyses were conducted using an ICU cohort and Acute Physiology and Chronic Health Evaluation III scores, respectively. The overall unadjusted mortality rate was 12.1% and was consistently lower in higher body mass index categories (all comparisons, p < 0.007). The adjusted mortality benefit observed in patients with higher body mass index was smaller in patients with higher lactate levels with no mortality benefit in higher body mass index categories observed at lactate greater than 5 mmol/L. By contrast, the association between lower MAP and higher mortality was constant across body mass index categories. Similar results were observed in the ICU cohort. Finally, the obesity paradox was not observed after including Acute Physiology and Chronic Health Evaluation III scores as a covariate. CONCLUSIONS: Our retrospective analysis suggests that although patient size (i.e., body mass index) is a predictor of in-hospital death among all-comers with sepsis-providing further evidence to the obesity paradox-it adds that illness severity is critically important whether quantified as higher lactate or by Acute Physiology and Chronic Health Evaluation III score. Our results highlight that the obesity paradox is more than a simple association between body mass index and mortality and reinforces the importance of illness severity.

Trends in Location of Death for Individuals With Ovarian Cancer in the United States.

Using the publicly available Centers for Disease Control and Prevention's WONDER (Wide-ranging Online Data for Epidemiologic Research) database from 2003 to 2019, we evaluated associations between decedent characteristics and location of death for patients with ovarian malignancy. We found that Black, Native American, Asian American, and Hispanic patients were more likely to die in hospitals than White patients, despite an overall reduction in hospital deaths and an overall increase in hospice facility deaths. Additionally, patients with lesser educational attainment were more likely to die in nursing facilities and less likely to die in hospice facilities. Although there may be some contribution from cultural preferences, these findings may represent disparities in access to palliative care affecting people with cancer from racial and ethnic minoritized groups.

Associations Between Annual Medicare Part D Low-Income Subsidy Loss and Prescription Drug Spending and Use.

Importance: The Medicare Part D Low Income Subsidy (LIS) program provides millions of beneficiaries with drug plan premium and cost-sharing assistance. The extent to which LIS recipients experience subsidy losses with annual redetermination cycles and the resulting associations with prescription drug affordability and use are unknown. Objective: To examine how frequently annual LIS benefits are lost among Medicare Part D beneficiaries and how this is associated with prescription drug use and out-of-pocket costs. Design, Setting, and Participants: In this cohort study of Medicare Part D beneficiaries from 2007 to 2018, annual changes in LIS recipients among those automatically deemed eligible (eg, due to dual eligibility for Medicare and Medicaid) and nondeemed beneficiaries who must apply for LIS benefits were analyzed using Medicare enrollment and Part D event data. Subsidy losses were classified in 4 groups: temporary losses (<1 year); extended losses (≥1 year); subsidy reductions (change to partial LIS); and disenrollment from Medicare Part D after subsidy loss. Temporary losses could more likely represent subsidy losses among eligible beneficiaries. Multinomial logit models were used to examine associations between beneficiary characteristics and subsidy loss; linear regression models were used to compare changes in prescription drug cost and use in the months after subsidy losses vs before. Analyses were conducted between November 2022 and November 2023. Exposure: Subsidy loss at the beginning of each year among subsidy recipients in December of the prior year. Main Outcomes and Measures: The main outcomes were out-of-pocket costs and prescription drug fills overall and for 4 classes: antidiabetes, antilipid, antidepressant, and antipsychotic drugs. Results: In 2008, 731 070 full LIS beneficiaries (17%) were not deemed automatically eligible (39% were aged <65 years; 59% were female). Nearly all beneficiaries deemed automatically eligible (≥99%) retained the subsidy annually from 2007 to 2018, compared with 78% to 84% of nondeemed beneficiaries. Among nondeemed beneficiaries, disabled individuals younger than 65 years and racial and ethnic minority groups were more likely to have temporary subsidy losses vs none. Temporary losses were associated with an average 700% increase in out-of-pocket drug costs (+$52.72/mo [95% CI, 52.52-52.92]) and 15% reductions in prescription fills (-0.58 fills/mo [95% CI, -0.59 to -0.57]) overall. Similar changes were found for antidiabetes, antilipid, antidepressant, and antipsychotic prescription drug classes. Beneficiaries who retained their subsidy had few changes. Conclusions and Relevance: The conclusions of this cohort study suggest that efforts to help eligible beneficiaries retain Medicare Part D subsidies could improve drug affordability, treatment adherence, and reduce disparities in medication access.

From bench to bedside: the past, present and future of IL-21 immunotherapy.

As immunotherapy gains momentum as a promising approach for treating several types of cancer, IL-21 has emerged as the latest discovery within the γ chain cytokine family, known for its decisive effects on innate and adaptive immunity and immunopathology. Through the modulation of immune cells, IL-21 has demonstrated significant anti-tumor effects in preclinical studies. The potential of IL-21 in cancer treatment has been explored in phase I and II clinical trials, where it has been utilized both as monotherapy and in combination with other drug agents. Further investigation, alongside larger studies, is necessary before final evaluation and application of IL-21 as immunotherapy. This review aims to summarize these pre-clinical and clinical studies and to discuss the possible future directions of IL-21 immunotherapy development. Such a study may be helpful to accelerate the process of clinical application for IL21 immunotherapy.

Trends in Utilization and Medicare Spending on Short-Course Radiation Therapy for Breast and Prostate Cancer: An Episode-Based Analysis From 2015 to 2019.

PURPOSE: Evidence supports the value of shorter, similarly efficacious, and potentially more cost-effective hypofractionated radiation therapy (RT) regimens in many clinical scenarios for breast cancer (BC) and prostate cancer (PC). However, practice patterns vary considerably. We used the most recent Centers for Medicare and Medicaid Services data to assess trends in RT cost and practice patterns among episodes of BC and PC. METHODS AND MATERIALS: We performed a retrospective cohort analysis of all external beam RT episodes for BC and PC from 2015 to 2019 to assess predictors of short-course RT (SCRT) use and calculated spending differences. Multivariable logistic regression defined adjusted odds ratios of receipt of SCRT over longer-course RT (LCRT) by treatment modality, age, year of diagnosis, type of practice, and the interaction between year and treatment setting. Medicare spending was evaluated using multivariable linear regression controlling for duration of RT regimen (SCRT vs LCRT) in addition to the above covariables. RESULTS: Of 143,729 BC episodes and 114,214 PC episodes, 63,623 (44.27%) and 25,955 (22.72%) were SCRT regimens, respectively. Median total spending for SCRT regimens among BC episodes was $9418 (interquartile range [IQR], $7966-$10,983) versus $13,602 (IQR, $11,814-$15,499) for LCRT. Among PC episodes, median total spending was $6924 (IQR, $4,509-$12,905) for stereotactic body RT, $18,768 (IQR, $15,421-$20,740) for moderate hypofractionation, and $27,319 (IQR, $25,446-$29,421) for LCRT. On logistic regression, receipt of SCRT was associated with older age among both BC and PC episodes as well as treatment at hospital-affiliated over freestanding sites (P < .001 for all). CONCLUSIONS: In this evaluation of BC and PC RT episodes from 2015 to 2019, we found that shorter-course RT resulted in lower costs than longer-course RT. SCRT was also more common in hospital-affiliated sites. Future research focusing on potential payment incentives encouraging SCRT when clinically appropriate in the 2 most common cancers treated with RT will be valuable as the field continues to prospectively evaluate cost-effective hypofractionation in other disease sites.

Inter- and intra-observer variability of radial-endobronchial ultrasound image interpretation for peripheral pulmonary lesions.

Background: Radial probe endobronchial ultrasound (R-EBUS) is often utilized in guided bronchoscopy for the diagnosis of peripheral pulmonary lesions. R-EBUS probe positioning has been shown to correlate with diagnostic yield, but overall diagnostic yield with this technology has been inconsistent across the published literature. Currently there is no standardization for R-EBUS image interpretation, which may result in variability in grading concentricity of lesions and subsequently procedure performance. This was a survey-based study evaluating variability among practicing pulmonologists in R-EBUS image interpretation. Methods: R-EBUS images from peripheral bronchoscopy cases were sent to 10 practicing Interventional Pulmonologists at two different time points (baseline and 3 months). Participants were asked to grade the images as concentric, eccentric, or no image. Cohen's Kappa-coefficient was calculated for inter- and intra-observer variability. Results: A total of 100 R-EBUS images were included in the survey. There was 100% participation with complete survey responses from all 10 participants. Overall kappa-statistic for inter-observer variability for Survey 1 and 2 was 0.496 and 0.477 respectively. Overall kappa-statistic for intra-observer variability between the two surveys was 0.803. Conclusions: There is significant variability between pulmonologists when characterizing R-EBUS images. However, there is strong intra-rater agreement from each participant between surveys. A standardized approach and grading system for radial EBUS patterns may improve inter-observer variability in order to optimize our clinical use and research efforts in the field.

Disparities in Stage at Presentation Among Hispanic and Latinx Patients With Non-Small-Cell Lung Cancer in the United States.

PURPOSE: Hispanic and Latinx people in the United States are the fastest-growing ethnic group. However, previous studies in non-small-cell lung cancer (NSCLC) often analyze these diverse communities in aggregate. We aimed to identify differences in NSCLC stage at diagnosis in the US population, focusing on disaggregated Hispanic/Latinx individuals. METHODS: Data from the National Cancer Database from 2004 to 2018 identified patients with primary NSCLC. Individuals were disaggregated by racial and ethnic subgroup and Hispanic country of origin. Ordinal logistic regression adjusting for age, facility type, income, educational attainment, comorbidity index, insurance, and year of diagnosis was used to create adjusted odds ratios (aORs), with higher odds representing diagnosis at later-stage NSCLC. RESULTS: Of 1,565,159 patients with NSCLC, 46,616 were Hispanic/Latinx (3.0%). When analyzed in the setting of race and ethnicity, Hispanic patients were more likely to be diagnosed with metastatic disease compared with non-Hispanic White (NHW) patients: 47.0% for Hispanic Black, 46.0% Hispanic White, and 44.3% of Hispanic other patients versus 39.1% of non-Hispanic White patients (P < .001 for all). By country of origin, 51.4% of Mexican, 41.7% of Puerto Rican, 44.6% of Cuban, 50.8% of South or Central American, 48.4% of Dominican, and 45.6% of other Hispanic patients were diagnosed with metastatic disease, compared with 39.1% of NHWs. Conversely, 20.2% of Mexican, 26.9% of Puerto Rican, 24.2% of Cuban, 22.5% of South or Central American, 23.7% of Dominican, and 24.5% of other Hispanic patients were diagnosed with stage I disease, compared with 30.0% of NHWs. All Hispanic groups were more likely to present with later-stage NSCLC than NHW patients (greatest odds for Mexican patients, aOR, 1.44; P < .001). CONCLUSION: Hispanic/Latinx patients with non-small-cell lung cancer were more likely to be diagnosed with advanced disease compared with NHWs. Disparities persisted upon disaggregation by both race and country of origin, with over half of Mexican patients with metastatic disease at diagnosis. Disparities among Hispanic/Latinx groups by race and by country of origin highlight the shortcomings of treating these groups as a monolith and underscore the need for disaggregated research and targeted interventions.