Ethnic disparities in early-onset colorectal cancer incidence, screening rates and risk factors prevalence in Guam.

Objective: Colorectal cancer (CRC) is one of the four most common cancers and the third leading cause of cancer-related deaths in Guam. This study investigated CRC incidence, screening, and risk factors of early onset CRC across Guam's ethnic groups using data from the Guam Cancer Registry (1998-2020) and the Guam Behavioral Risk Factor Surveillance System (2018-2019). Methods: Incidence rate ratios (IRRs) were calculated to compare incidence rates across different age groups stratified by sex, ethnicity, and stage. Incidence rate differences (IRDs) were used to test for significant differences across sex and ethnicity. The Pearson chi-square test was used to assess differences in CRC screening rates by age, sex, education, income, healthcare coverage, and ethnicity, and to examine ethnic group disparities in the prevalence of CRC risk factors. Results: The steepest increase in CRC incidence was observed between the 35-39 and 40-44 age groups (IRR = 2.01; 95 % CI: 1.14-3.53) and between the 40-44 and 45-49 age groups (IRR = 1.99; 95 % CI: 1.34-2.97). CHamorus exhibited rate increases at younger ages compared to Filipinos. CRC screening prevalence and associated risk factors showed considerable variation among ethnicities. Conclusions: Elevated early-onset CRC rates were observed for both CHamorus and the broader Guam population under 50. The findings support the new recommendation to begin screening at age 45 and efforts to increase screening in Guam.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Reproductive Factors and Thyroid Cancer Risk: The Multiethnic Cohort Study.

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice.

Time to Diagnosis and Treatment Initiation During the COVID-19 Pandemic Among Rural Patients With Cancer.

Time to diagnosis (TTD) and treatment initiation (TTI) are important measures of access to and quality of cancer care. This study addressed the knowledge gap on the impact of the COVID-19 pandemic on TTD and TTI for rural cancer patients. Sixty-three cancer patients residing in rural areas of the state of Hawaii were surveyed in 2020 to 2021. Overall, 67.5% of participants reported TTD within one month of reporting symptoms to a health care provider. Mean TTI for the overall sample was 55.3 days, and among breast cancer patients, 57.9 days. Compared with pre-pandemic state registry data, mean TTI for the overall sample and breast cancer patients were significantly longer than the state registry null value of 40 days (P = .02 and P =.05, respectively). During the COVID-19 pandemic, cancer patients in rural Hawaii experienced substantial delays in TTI compared with pre-pandemic years.

Thyroid Cancer Survival in the Multiethnic Cohort Study.

OBJECTIVE: The US 5-year survival rate after thyroid cancer (TC) diagnosis is over 95%. Our aim was to investigate survival differences by sex and race and ethnicity in a multiethnic US population. DESIGN: In the Multiethnic Cohort (MEC) study, a total of 605 incident TC cases were identified by linkage to HI and CA statewide cancer registries. Cox models were performed to compare the risk of all-cause mortality among TC cases by sex and race and ethnicity, with adjustment for age, first course of treatment, baseline body mass index, smoking status, alcohol intake, and neighborhood socioeconomic status. Survival among cases was also compared to matched MEC controls with no thyroid cancer. RESULTS: After a mean follow-up of 10.1 years, 250 deaths occurred among TC cases, including 63 deaths attributed to thyroid cancer. The median survival was 14.7 years, and the 5-year age-adjusted overall survival was 84.4% for female cases and 68.7% for male cases (p < 0.0001, HR 2.28 (95% CI: 1.72, 3.01)). Age-adjusted survival was lower among African American, Native Hawaiian, and Filipino cases, compared to Japanese American cases, with Whites and Latinos being intermediate. Men and Filipinos were found to have excess mortality due to thyroid cancer compared to controls (adjusted HR 1.39, 95% CI: 1.11, 1.74; HR 1.62, 95% CI: 1.04, 2.53, respectively). CONCLUSIONS: Sex and racial and ethnic disparities in survival among TC cases were similar to those found in the general population. However, cases with TC had an excess risk of death among males and for Filipinos.

Evolutionary and Structural Analysis of PP16 in Viridiplantae.

Members of the phloem protein 16 (PP16) gene family are induced by elicitors in rice and the corresponding proteins from cucurbits, which display RNA binding and intercellular transport activities, are accumulated in phloem sap. These proteins facilitate the movement of protein complexes through the phloem translocation flow and may be involved in the response to water deficit, among other functions. However, there is scant information regarding their function in other plants, including the identification of paralog genes in non-vascular plants and chlorophytes. In the present work, an evolutionary and structural analysis of the PP16 family in green plants (Viridiplantae) was carried out. Data mining in different databases indicated that PP16 likely originated from a larger gene present in an ancestral lineage that gave rise to chlorophytes and multicellular plants. This gene encodes a protein related to synaptotagmin, which is involved in vesicular transport in animal systems, although other members of this family play a role in lipid turnover in endomembranes and organelles. These proteins contain a membrane-binding C2 domain shared with PP16 proteins in vascular plants. In silico analysis of the predicted structure of the PP16 protein family identified several ß-sheets, one α-helix, and intrinsically disordered regions. PP16 may have been originally involved in vesicular trafficking and/or membrane maintenance but specialized in long-distance signaling during the emergence of the plant vascular system.

Multiethnic Trends in Early Onset Colorectal Cancer.

Current characteristics of early onset colorectal cancer (EOCRC) in the United States have been mainly studied in Whites, African Americans, and Hispanics, but little is known in regard to EOCRC in Asians and Native Hawaiians in the US. EOCRC was examined in Hawaii's multiethnic population. Data from the Hawaii Tumor Registry was used to analyze colorectal cancer (CRC) cases diagnosed in Hawaii from 2000-2019 by subsite, age, gender, ethnicity, and stage. Ethnicity analyses were limited to 3524 CRC cases, diagnosed between 2015-2019. Average annual 5-year age-adjusted incidence and mortality rates, average annual percent change over time, and 5-year survival were evaluated. Group comparisons utilized Chi-square and binomial proportion tests. Overall CRC incidence and mortality declined and were more pronounced for colon than rectal/rectosigmoid junction cancers. Colon cancer incidence rates significantly increased 1.46-fold for cases diagnosed under 45 years of age and rectal/rectosigmoid cancers significantly increased 1.54-fold for cases 45-54 years of age. CRC incidence increased sharply for females aged 45-54 years from 2000-2009 to 2010-2019, and increases in colon and rectal/rectosigmoid cancer among individuals aged 45-54 were higher for females. Among both sexes, the increase in rectal/rectosigmoid cancer incidence for individuals under 55 years was highest for stage I cancers. Overall, the mean (SD) age of CRC diagnosis was 5-10 years earlier for Native Hawaiians (60.6 [13.3] years) compared with Japanese, Chinese, Filipinos, Whites, and Other Asians (p < 0.001). Native Hawaiians constituted a greater proportion of CRC diagnosed under age 55 years and, conversely, a smaller proportion of cases 55 years and older compared with Japanese, Chinese, Filipinos, Whites, and Other Asians. Native Hawaiians had a significantly higher CRC-related mortality rate (14.5 per 100,000 [95% CI: 12.4, 16.8]) compared with Japanese (10.7 per 100,000 [95% CI: 9.3, 12.3]) and a significantly lower CRC survival rate (62.2% [95% CI: 59.1, 65.2]) compared with Japanese (71.9% [95% CI: 69.9, 73.8]), Filipinos (71.9% [95% CI: 69.2, 74.4]), Chinese (70.2% [95% CI: 65.5, 74.4]), Whites (69.3% [95% CI: 67.1, 71.4]), and Other Asians (71.7% [95% CI: 66.2, 76.5]). In our diverse US population, Native Hawaiians contribute disproportionately to EOCRC and present 5-10 years earlier than Whites, Japanese, Chinese, and Filipinos. EOCRCs are increasing faster in females than males in Hawaii, which differs from trends in the general US population. Emerging ethnic disparities in EOCRC in the US speak to the need for studies on targeted interventions and ethnic-specific risk factors for EOCRC.

Factors Associated With Delays in Presentation and Treatment of Gonorrhea, Massachusetts 2015-2019.

BACKGROUND: Rates of gonorrhea are increasing across the United States. Understanding and addressing contributing factors associated with longer time to diagnosis and treatment may shorten the duration of infectiousness, which in turn may limit transmission. METHODS: We used Massachusetts data from the US Centers for Disease Control and Prevention Sexually Transmitted Disease Surveillance Network collected between July 2015 and September 2019, along with routinely reported surveillance data, to assess time from gonorrhea symptom onset to presentation to care, and time from presentation to care to receipt of treatment. Factors associated with longer time to presentation (TTP) and time to treatment (TTT) were assessed using Cox proportional hazard models with a constant time variable. RESULTS: Among symptomatic patients (n = 672), 31% did not receive medical care within 7 days of symptom onset. Longer TTP was associated with younger age, female gender, reporting cost as a barrier to care, and provider report of proctitis. Among patients with symptoms and/or known contact to gonorrhea (n = 827), 42% did not receive presumptive treatment. Longer TTT was associated with female gender, non-Hispanic other race/ethnicity, and clinics with less gonorrhea treatment experience. Among asymptomatic patients without known exposure to STI (n = 235), 26% did not receive treatment within 7 days. Longer TTT was associated with sexually transmitted disease clinic/family planning/reproductive health clinics and a test turnaround time of ≥3 days. CONCLUSIONS: Delays in presentation to care and receipt of treatment for gonorrhea are common. Factors associated with longer TTP and TTT highlight multiple opportunities for reducing the infectious period of patients with gonorrhea.

Oral Human Papillomavirus Infection among Smokeless Tobacco-using Tribal Women in Mysuru, India.

Smokeless tobacco (SLT) is consumed by more than 300 million people worldwide. Studies show high use among Indian indigenous women who are also at high risk for oral cancers. Both human papillomavirus infection (HPV) and SLT have been associated with oral cancer, this study examined the presence of high-risk HPV in oral samples collected from tribal smokeless tobacco users in Mysuru, India. Between June and August 2019, 100 tribal females (50 SLT-users and 50 non-users) from rural Mysuru District, Karnataka, were enrolled in a cross-sectional study. Following informed consent, demographic data and oral samples were collected and processed using a digene HC2 High-Risk HPV DNA test (Qiagen, USA). On average participants were 45.5 (SD: ±6.6) years. Chronic SLT users were mostly married (73%), Hindu (100%), illiterate (62%), and employed (90%). One woman was positive for high-risk HPV infection. Oral HPV infection was low in this sample and this is consistent with the literature from other low and middle-income countries. SLT use is high in this group so interventions to reduce tobacco use are warranted.

No Association of Trichomonas vaginalis Seropositivity with Advanced Prostate Cancer Risk in the Multiethnic Cohort: A Nested Case-Control Study.

The potential involvement of a sexually transmitted agent has been suggested to contribute to the high number of prostate cancers in the United States and worldwide. We investigated the relationship of Trichomonas vaginalis seropositivity with prostate cancer risk in a nested case-control study within the Multiethnic Cohort in Hawaii and California using blood samples collected prior to cancer diagnoses. Incident cases of advanced prostate cancer (intermediate- to high-grade based on Gleason score ≥ 7 and/or disease spread outside the prostate) were matched to controls by age, ethnicity, and the date of blood collection. T. vaginalis serostatus was measured using an ELISA detecting IgG antibodies against a recombinant T. vaginalis α-actinin protein. Seropositivity to T. vaginalis was observed in 35 of 470 (7.4%) cases and 26 of 470 (5.5%) controls (unadjusted OR = 1.47, 95% CI 0.82-2.64; adjusted OR = 1.31, 95% CI 0.67-2.53). The association was similarly not significant when cases were confined to extraprostatic tumors having regional or distant spread (n = 121) regardless of grade (unadjusted OR = 1.37, 95% CI 0.63-3.01; adjusted OR = 1.20, 95% CI 0.46-3.11). The association of T. vaginalis with prostate cancer risk did not vary by aspirin use. Our findings do not support a role for T. vaginalis in the etiology of advanced prostate cancer.

Advancing Social and Environmental Research in Cancer Registries Using Geomasking for Address-Level Data.

Understanding the social and environmental causes of cancer in the United States, particularly in marginalized communities, is a major research priority. Population-based cancer registries are essential for advancing this research, given their nearly complete capture of incident cases within their catchment areas. Most registries limit the release of address-level geocodes linked to cancer outcomes to comply with state health departmental regulations. These policies ensure patient privacy, uphold data confidentiality, and enhance trust in research. However, these restrictions also limit the conduct of high-quality epidemiologic studies on social and environmental factors that may contribute to cancer burden. Geomasking refers to computational algorithms that distort locational data to attain a balance between effectively "masking" the original address location while faithfully maintaining the spatial structure in the data. We propose that the systematic deployment of scalable geomasking algorithms could accelerate research on social and environmental contributions across the cancer continuum by reducing measurement error bias while also protecting privacy. We encourage multidisciplinary teams of registry officials, geospatial analysts, cancer researchers, and others engaged in this form of research to evaluate and apply geomasking procedures based on feasibility of implementation, accuracy, and privacy protection to accelerate population-based research on social and environmental causes of cancer.

Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival.

Host immunity involves various immune cells working in concert to achieve balanced immune response. Host immunity interacts with tumorigenic process impacting disease outcome. Clusters of different immune cells may reveal unique host immunity in relation to breast cancer progression. CIBERSORT algorithm was used to estimate relative abundances of 22 immune cell types in 3 datasets, METABRIC, TCGA, and our study. The cell type data in METABRIC were analyzed for cluster using unsupervised hierarchical clustering (UHC). The UHC results were employed to train machine learning models. Kaplan-Meier and Cox regression survival analyses were performed to assess cell clusters in association with relapse-free and overall survival. Differentially expressed genes by clusters were interrogated with IPA for molecular signatures. UHC analysis identified two distinct immune cell clusters, clusters A (83.2%) and B (16.8%). Memory B cells, plasma cells, CD8 positive T cells, resting memory CD4 T cells, activated NK cells, monocytes, M1 macrophages, and resting mast cells were more abundant in clusters A than B, whereas regulatory T cells and M0 and M2 macrophages were more in clusters B than A. Patients in cluster A had favorable survival. Similar survival associations were also observed in other independent studies. IPA analysis showed that pathogen-induced cytokine storm signaling pathway, phagosome formation, and T cell receptor signaling were related to the cell type clusters. Our finding suggests that different immune cell clusters may indicate distinct immune responses to tumor growth, suggesting their potential for disease management.

Complete chloroplast genomes of six neotropical palm species, structural comparison, and evolutionary dynamic patterns.

The Arecaceae family has a worldwide distribution, especially in tropical and subtropical regions. We sequenced the chloroplast genomes of Acrocomia intumescens and A. totai, widely used in the food and energy industries; Bactris gasipaes, important for palm heart; Copernicia alba and C. prunifera, worldwide known for wax utilization; and Syagrus romanzoffiana, of great ornamental potential. Copernicia spp. showed the largest chloroplast genomes (C. prunifera: 157,323 bp and C. alba: 157,192 bp), while S. romanzoffiana and B. gasipaes var. gasipaes presented the smallest (155,078 bp and 155,604 bp). Structurally, great synteny was detected among palms. Conservation was also observed in the distribution of single sequence repeats (SSR). Copernicia spp. presented less dispersed repeats, without occurrence in the small single copy (SSC). All RNA editing sites were C (cytidine) to U (uridine) conversions. Overall, closely phylogenetically related species shared more sites. Almost all nodes of the phylogenetic analysis showed a posterior probability (PP) of 1.0, reaffirming the close relationship between Acrocomia species. These results elucidate the conservation among palm chloroplast genomes, but point to subtle structural changes, providing support for the evolutionary dynamics of the Arecaceae family.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The Characterization of Melanaphis sacchari Microbiota and Antibiotic Treatment Effect on Insects.

Insects are under constant selective pressure, which has resulted in adaptations to novel niches such as crops. This is the case of the pest Melanaphis sacchari, the sugarcane aphid, native to Africa and currently spreading worldwide. The aphid undergoes successful parthenogenesis, causing important damage to a variety of crops and leading to important economic losses for farmers. A natural M. sacchari population grown in sorghum was studied to identify its microbiome through the sequencing of its 16S rDNA metagenome. A high proportion of Proteobacteria, followed by Firmicutes, Bacteroidetes, and Actinobacteria, was observed. We also detected Wolbachia, which correlates with the asexual reproduction of its host. M. sacchari was challenged in a bioassay with the antibiotics oxytetracycline and streptomycin, resulting in a dose-dependent decay of its survival rate. The possibility of controlling this pest by altering its microbiota is proposed.

The effects of female age on blood-feeding, insemination, sperm storage, and fertility in the dengue vector mosquito Aedes aegypti (Diptera: Culicidae).

Mating induces behavioral and physiological changes in female insects-collectively referred to as the female post-mating response (PMR)-that facilitate the production of progeny. PMRs are elicited by transfer of male-derived seminal components during mating, but are altered by other factors, including adult age. Increased female age is often accompanied by declines in fertility. However, mating shortly after emergence also impacts fertility in the insect model Drosophila melanogaster. Here, we determined the age post-emergence when females of the vector mosquito Aedes aegypti can be inseminated and blood-feed. We next examined fecundity, fertility, and the storage of sperm in the female reproductive tract in "young" (30-41 hours-old) and "old" (2- and 3-week-old) females, finding that blood-feeding began at 14 hours, and mating at ∼24 hours post-emergence. Although young females consumed smaller blood quantities and stored fewer sperm, they were similarly fertile to 4-day-old controls. Old females, however, suffered significant declines in fecundity by 2 weeks of age. Our results show that female Ae. aegypti start to become sexually receptive 1 day after their emergence, but can ingest blood much sooner, suggesting that mating is not a prerequisite to blood-feeding, and that females can ingest an arbovirus infected blood-meal shortly after emergence.

Corrigendum: Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species.

[This corrects the article DOI: 10.3389/fnmol.2023.1210962.].

Txnip expression promotes JNK-mediated neuronal death in response to reactive oxygen species.

TXNIP is a protein sensitive to oxidant conditions whose expression is related to the progression of death in cancer, diabetes, ischemia, and neurodegenerative diseases, among others. Because of this, many studies propose TXNIP as a therapeutic target in several diseases. Exposure of cerebellar granule neurons to staurosporine or low potassium leads to apoptotic death. Both conditions generate an early production of reactive oxygen species (ROS) that induces the activation of the ASK1 pathway and the apoptotic machinery. In these models, it has been shown an increase in TXNIP protein mediated by ROS. Here, we evaluated the molecular mechanisms involved in the regulation of the Txnip expression during neuronal death, as well as the role of the protein in the progression of cell death induced by these two apoptotic conditions. In cultured cerebellar granule neurons, we observed that low potassium and staurosporine induced an early increase in ROS that correlated with an increase in Txnip mRNA. When we evaluated the promoter of the gene, we found that the JASPAR-reported FOXO1/3 transcription factor motifs are close to the transcription start site (TSS). We then verified through the Chromatin immunoprecipitation technique (ChIP) that FOXO3 interacts with the Txnip promoter after 1 h of low potassium treatment. We also detected FOXO3 nuclear translocation by low potassium and staurosporine treatments. Finally, by using shRNA in the neuroblastoma MSN cell line, we found that Txnip downregulation decreased neuronal death induced by staurosporine stimulus. Together, these results suggest that ROS promotes the expression of Txnip through the activation of the FOXO3 transcription factor mediated by Akt inhibition. We also demonstrated that TXNIP is necessary for neuronal death progression.

Use of the Decipher genomic classifier among men with prostate cancer in the United States.

BACKGROUND: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer. METHODS: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy. RESULTS: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84). CONCLUSIONS: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens.

Impact on the Volume of Pathology Reports Before and During the COVID-19 Pandemic in SEER Cancer Registries.

INTRODUCTION: Health care procedures including cancer screening and diagnosis were interrupted due to the COVID-19 pandemic. The extent of this impact on cancer care in the United States is not fully understood. We investigated pathology report volume as a reflection of trends in oncology services pre-pandemic and during the pandemic. METHODS: Electronic pathology reports were obtained from 11 U.S. central cancer registries from NCI's SEER Program. The reports were sorted by cancer site and document type using a validated algorithm. Joinpoint regression was used to model temporal trends from January 2018 to February 2020, project expected counts from March 2020 to February 2021 and calculate observed-to-expected ratios. Results were stratified by sex, age, cancer site, and report type. RESULTS: During the first 3 months of the pandemic, pathology report volume decreased by 25.5% and 17.4% for biopsy and surgery reports, respectively. The 12-month O/E ratio (March 2020-February 2021) was lowest for women (O/E 0.90) and patients 65 years and older (O/E 0.91) and lower for cancers with screening (melanoma skin, O/E 0.86; breast, O/E 0.88; lung O/E 0.89, prostate, O/E 0.90; colorectal, O/E 0.91) when compared with all other cancers combined. CONCLUSIONS: These findings indicate a decrease in cancer diagnosis, likely due to the COVID-19 pandemic. This decrease in the number of pathology reports may result in a stage shift causing a subsequent longer-term impact on survival patterns. IMPACT: Investigation on the longer-term impact of the pandemic on pathology services is vital to understand if cancer care delivery levels continue to be affected.