Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Activation of interleukin 33-NFκB axis in granulosa cells during atresia and its role in disposal of atretic follicles†.

It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1ß (IL1ß) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6.

Diminutive compound odontoma in a child: a case report with emphasis on early detection.

The odontoma is regarded as a hamartomatous process of the jaws. Most are discovered as an incidental radiographic finding, averaging 15 mm in size. This report describes a case of a diminutive odontoma that was surgically removed before the onset of eruptive and pathologic consequences. A compilation of documented complications and syndromes associated with odontomas is also presented.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Risk of myocarditis and pericarditis after the COVID-19 mRNA vaccination in the USA: a cohort study in claims databases.

BACKGROUND: Several passive surveillance systems reported increased risks of myocarditis or pericarditis, or both, after COVID-19 mRNA vaccination, especially in young men. We used active surveillance from large health-care databases to quantify and enable the direct comparison of the risk of myocarditis or pericarditis, or both, after mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccinations. METHODS: We conducted a retrospective cohort study, examining the primary outcome of myocarditis or pericarditis, or both, identified using the International Classification of Diseases diagnosis codes, occurring 1-7 days post-vaccination, evaluated in COVID-19 mRNA vaccinees aged 18-64 years using health plan claims databases in the USA. Observed (O) incidence rates were compared with expected (E) incidence rates estimated from historical cohorts by each database. We used multivariate Poisson regression to estimate the adjusted incidence rates, specific to each brand of vaccine, and incidence rate ratios (IRRs) comparing mRNA-1273 and BNT162b2. We used meta-analyses to pool the adjusted incidence rates and IRRs across databases. FINDINGS: A total of 411 myocarditis or pericarditis, or both, events were observed among 15 148 369 people aged 18-64 years who received 16 912 716 doses of BNT162b2 and 10 631 554 doses of mRNA-1273. Among men aged 18-25 years, the pooled incidence rate was highest after the second dose, at 1·71 (95% CI 1·31 to 2·23) per 100 000 person-days for BNT162b2 and 2·17 (1·55 to 3·04) per 100 000 person-days for mRNA-1273. The pooled IRR in the head-to-head comparison of the two mRNA vaccines was 1·43 (95% CI 0·88 to 2·34), with an excess risk of 27·80 per million doses (-21·88 to 77·48) in mRNA-1273 recipients compared with BNT162b2. INTERPRETATION: An increased risk of myocarditis or pericarditis was observed after COVID-19 mRNA vaccination and was highest in men aged 18-25 years after a second dose of the vaccine. However, the incidence was rare. These results do not indicate a statistically significant risk difference between mRNA-1273 and BNT162b2, but it should not be ruled out that a difference might exist. Our study results, along with the benefit-risk profile, continue to support vaccination using either of the two mRNA vaccines. FUNDING: US Food and Drug Administration.

Cross-Sectional Observational Study of Typical in utero Fetal Movements Using Machine Learning.

Early variations of fetal movements are the hallmark of a healthy developing central nervous system. However, there are no automatic methods to quantify the complex 3D motion of the developing fetus in utero. The aim of this prospective study was to use machine learning (ML) on in utero MRI to perform quantitative kinematic analysis of fetal limb movement, assessing the impact of maternal, placental, and fetal factors. In this cross-sectional, observational study, we used 76 sets of fetal (24-40 gestational weeks [GW]) blood oxygenation level-dependent (BOLD) MRI scans of 52 women (18-45 years old) during typical pregnancies. Pregnant women were scanned for 5-10 min while breathing room air (21% O2) and for 5-10 min while breathing 100% FiO2 in supine and/or lateral position. BOLD acquisition time was 20 min in total with effective temporal resolution approximately 3 s. To quantify upper and lower limb kinematics, we used a 3D convolutional neural network previously trained to track fetal key points (wrists, elbows, shoulders, ankles, knees, hips) on similar BOLD time series. Tracking was visually assessed, errors were manually corrected, and the absolute movement time (AMT) for each joint was calculated. To identify variables that had a significant association with AMT, we constructed a mixed-model ANOVA with interaction terms. Fetuses showed significantly longer duration of limb movements during maternal hyperoxia. We also found a significant centrifugal increase of AMT across limbs and significantly longer AMT of upper extremities <31 GW and longer AMT of lower extremities >35 GW. In conclusion, using ML we successfully quantified complex 3D fetal limb motion in utero and across gestation, showing maternal factors (hyperoxia) and fetal factors (gestational age, joint) that impact movement. Quantification of fetal motion on MRI is a potential new biomarker of fetal health and neuromuscular development.

Immune globulin usage trends in commercially insured and Medicare populations, 2009-2019.

BACKGROUND: Longitudinal patterns of immune globulins (IG) use have not been described in large populations. Understanding IG usage is important given potential supply limitations impacting individuals for whom IG is the sole life-saving/health-preserving therapy. The study describes US IG utilization patterns from 2009 to 2019. STUDY DESIGN AND METHODS: Using IBM MarketScan commercial and Medicare claims data, we examined four metrics overall and by condition-specific categories during 2009-2019: (1) IG administrations per 100,000 person-years, (2) IG recipients per 100,000 enrollees, (3) average annual administrations per recipient, and (4) average annual dose per recipient. RESULTS: In the commercial and Medicare populations respectively: IG administrations per 100,000 person-years increased by 120% (213-470) and 144% (692-1693); IG recipients per 100,000 enrollees grew by 71% (24-42) and 102% (89-179); average annual administrations per recipient rose by 28% (8-10) and 19% (8-9); and average annual dose (grams) per recipient increased by 29% (384-497) and 34% (317-426). IG administrations associated with immunodeficiency (per 100,000 person-years) increased by 154% (from 127 to 321) and 176% (from 365 to 1007). Autoimmune and neurologic conditions were associated with higher annual average administrations and dose than other conditions. DISCUSSION: IG use increased, coinciding with a growth in the IG recipient population in the United States. Several conditions contributed to the trend, with the largest increase observed among immunodeficient individuals. Future investigations should assess changes in the demand for IVIG by disease state or indication and consider treatment effectiveness.

Spindle cell lipoma of the buccal mucosa: Uncommon finding in an older adult.

OBJECTIVE: This article reports a case of a longstanding, slowly enlarging intraoral spindle cell lipoma (SCL) that had become increasingly painful during mastication. BACKGROUND: The SCL represents an uncommon variant of the conventional lipoma. There is limited information regarding this lesion in the gerodontologic literature. MATERIALS AND METHODS: A 68-year-old patient underwent an excisional biopsy of a 9-mm slightly yellow papule along the buccal mucosa. RESULTS: The surgical specimen was composed of mature adipocytes with abundant spindle cell populations and was diagnosed as a SCL. CONCLUSIONS: Timely removal of the SCL may reduce the incidence of clinical and surgical complications, particularly in older adults. The management of a SCL is complete excision, and recurrence is rare. Lesions must be carefully distinguished microscopically from its malignant counterpart, the spindle cell liposarcoma.

Characterization of test positivity among patients with coronavirus disease 2019 (COVID-19) in three electronic health records databases, February-November 2020.

BACKGROUND: Monitoring COVID-19 testing volumes and test positivity is an integral part of the response to the pandemic. We described the characteristics of individuals who were tested and tested positive for SARS-CoV-2 during the pre-vaccine phase of the pandemic in the United States (U.S.). METHODS: This descriptive study analyzed three U.S. electronic health record (EHR) databases (Explorys, Academic Health System, and OneFlorida) between February and November 2020, identifying patients who received an interpretable nucleic acid amplification test (NAAT) result. Test-level data were used to characterize the settings in which tests were administered. Patient-level data were used to calculate test positivity rates and characterize the demographics, comorbidities, and hospitalization rates of COVID-19-positive patients. RESULTS: Over 40% of tests were conducted in outpatient care settings, with a median time between test order and result of 0-1 day for most settings. Patients tested were mostly female (55.6-57.7%), 18-44 years of age (33.9-41.2%), and Caucasian (44.0-66.7%). The overall test positivity rate was 13.0% in Explorys, 8.0% in Academic Health System, and 8.9% in OneFlorida. The proportion of patients hospitalized within 14 days of a positive COVID-19 NAAT result was 24.2-33.1% across databases, with patients over 75 years demonstrating the highest hospitalization rates (46.7-69.7% of positive tests). CONCLUSIONS: This analysis of COVID-19 testing volume and positivity patterns across three large EHR databases provides insight into the characteristics of COVID-19-tested, COVID-19-test-positive, and hospitalized COVID-19-test-positive patients during the early phase of the pandemic in the U.S.

Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model.

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.

The MAPK Signaling Pathway Presents Novel Molecular Targets for Therapeutic Intervention after Traumatic Spinal Cord Injury: A Comparative Cross-Species Transcriptional Analysis.

Despite the debilitating consequences following traumatic spinal cord injury (SCI), there is a lack of safe and effective therapeutics in the clinic. The species-specific responses to SCI present major challenges and opportunities for the clinical translation of biomolecular and pharmacological interventions. Recent transcriptional analyses in preclinical SCI studies have provided a snapshot of the local SCI-induced molecular responses in different animal models. However, the variation in the pathogenesis of traumatic SCI across species is yet to be explored. This study aims to identify and characterize the common and inconsistent SCI-induced differentially expressed genes across species to identify potential therapeutic targets of translational relevance. A comprehensive search of open-source transcriptome datasets identified four cross-compatible microarray experiments in rats, mice, and salamanders. We observed consistent expressional changes in extracellular matrix components across the species. Conversely, salamanders showed downregulation of intracellular MAPK signaling compared to rodents. Additionally, sequence conservation and interactome analyses highlighted the well-preserved sequences of Fn1 and Jun with extensive protein-protein interaction networks. Lastly, in vivo immunohistochemical staining for fibronectin was used to validate the observed expressional pattern. These transcriptional changes in extracellular and MAPK pathways present potential therapeutic targets for traumatic SCI with promising translational relevance.

Overall and abdominal obesity and prostate cancer risk in a West African population: An analysis of the Ghana Prostate Study.

Obesity has been associated with an increased risk of advanced prostate cancer. However, most studies have been conducted among North American and European populations. Prostate cancer mortality appears elevated in West Africa, yet risk factors for prostate cancer in this region are unknown. We thus examined the relationship between obesity and prostate cancer using a case-control study conducted in Accra, Ghana in 2004 to 2012. Cases and controls were drawn from a population-based sample of 1037 men screened for prostate cancer, yielding 73 cases and 964 controls. An additional 493 incident cases were recruited from the Korle-Bu Teaching Hospital. Anthropometric measurements were taken at enrollment. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and prostate cancer, adjusting for potential confounders. The mean BMI was 25.1 kg/m2 for cases and 24.3 kg/m2 for controls. After adjustment, men with BMI ≥ 30 kg/m2 had an increased risk of prostate cancer relative to men with BMI < 25 kg/m2 (OR 1.86, 95% CI 1.11-3.13). Elevated WC (OR 1.76, 95% CI 1.24-2.51) and WHR (OR 1.46, 95% CI 0.99-2.16) were also associated with prostate cancer. Associations were not modified by smoking status and were evident for low- and high-grade disease. These findings indicate that overall and abdominal obesity are positively associated with prostate cancer among men in Ghana, implicating obesity as a potentially modifiable risk factor for prostate cancer in this region.

Trends and Patterns of Testosterone Therapy among U.S. Male Medicare Beneficiaries, 1999 to 2014.

PURPOSE: We explored the Medicare database (1999 to 2014) to provide a comprehensive assessment of testosterone therapy patterns in the older U.S. male population. MATERIALS AND METHODS: We estimated annual age-standardized incidence (new users) and prevalence (existing users) of testosterone therapy according to demographic characteristics, comorbidities and potential indications. RESULTS: There were 392,698 incident testosterone therapy users during 88 million person-years. Testosterone therapy users were predominantly younger, white nonHispanic, and located in South and West U.S. Census regions. On average testosterone therapy use increased dramatically during 2007 to 2014 (average annual percent change 15.5%), despite a decrease in 2014. In 2014 the most common recorded potential indications for any testosterone therapy were hypogonadism (48%), fatigue (18%), erectile dysfunction (15%), depression (4%) and psychosexual dysfunction (1%). Laboratory tests to measure circulating testosterone concentrations for testosterone therapy were infrequent with 35% having had at least 1 testosterone test in the 120 days preceding testosterone therapy, 4% the recommended 2 pre-testosterone therapy tests, and 16% at least 1 pre-testosterone therapy test and at least 1 post-testosterone therapy test. CONCLUSIONS: Testosterone therapy remains common in the older U.S. male population, despite a recent decrease. Although testosterone therapy prescriptions are predominantly for hypogonadism, a substantial proportion appear to be for less specific conditions. Testosterone tests among men prescribed testosterone therapy appear to be infrequent.

Usual adult occupation and risk of prostate cancer in West African men: the Ghana Prostate Study.

OBJECTIVES: Established prostate cancer (PCa) risk factors include age, family history of PCa and African ancestry. Studies, mostly among highly screened, predominantly European ancestral populations, suggest that employment in certain occupations (eg, farming, military) may also have an increased risk for PCa. Here, we evaluated the association between usual adult occupation and PCa risk in Ghanaian men, a population with historically low rates of PCa screening. METHODS: The Ghana Prostate Study is a case-control study of PCa that was conducted from 2004 to 2012 in 749 cases and 964 controls. In-person interviews were conducted to collect information from participants, including longest held job. Industrial hygienists classified job titles into occupational categories. Unconditional logistic regression was used to calculate ORs and 95% CIs for the association between longest held job and PCa risk (overall, aggressive (Gleason≥7)), controlling for potential confounders. RESULTS: Risk was increased among men in management (overall PCa OR=2.2, 95% CI 1.4 to 3.2; aggressive PCa OR=2.2, 95% CI 1.3 to 3.5) and military occupations (overall PCa OR=3.4, 95% CI 1.7 to 7.0; aggressive PCa OR=3.5, 95% CI 1.5 to 8.3). Risks were also elevated for management and military-specific jobs based on 3-digit level Standard Occupational Classification definitions. Sensitivity analyses accounting for access to medical care did not show significant differences. CONCLUSIONS: Our study provides some evidence for increased risk of PCa among men in management and military occupations, which is consistent with the published literature. Additional research is needed to clarify the drivers of the associations between these occupations and PCa.

Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences.

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers.

BACKGROUND: Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. METHODS: We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (<7 vs ≥7) and race (European American vs. African American). RESULTS: We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. CONCLUSIONS: This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak-to-null associations between balding status and intraprostatic sex hormones reaffirm differences in organ-specific sex hormone metabolism, implying that other sex steroid hormone-related factors (eg, androgen receptor) play important roles in organ-specific androgenic actions, and that other overlapping pathways may be involved in associations between the two complex conditions.

IL-33 is required for disposal of unnecessary cells during ovarian atresia through regulation of autophagy and macrophage migration.

Physiological processes such as ovarian follicle atresia generate large amounts of unnecessary cells or tissue detritus, which needs to be disposed of rapidly. IL-33 is a member of the IL-1 cytokine gene family. Constitutive expression of IL-33 in a wide range of tissues has hinted at its role beyond immune defense. We have previously reported a close correlation between IL-33 expression patterns and ovarian atresia. In this study, we demonstrated that IL-33 is required for disposal of degenerative tissue during ovarian atresia using Il33(-/-) mice. Deletion of the Il33 gene impaired normal disposal of atretic follicles, resulting in massive accumulations of tissue wastes abundant with aging-related catabolic wastes such as lipofuscin. Accumulation of tissue wastes in Il33(-/-) mice, in turn, accelerated ovarian aging and functional decline. Thus, their reproductive life span was shortened to two thirds of that for Il33(+/-) littermates. IL-33 orchestrated disposal mechanism through regulation of autophagy in degenerating tissues and macrophage migration into the tissues. Our study provides direct evidence supporting an expanded role of IL-33 in tissue integrity and aging through regulating disposal of unnecessary tissues or cells.

Oxidative stress mediated by nitrogen at elevated pressure inhibits non-small cell lung cancer growth.

Purpose/Aim: High pressures of gases such as nitrogen enhance production of singlet oxygen. Therefore, we hypothesized that growth of non-small cell lung cancer (NSCLC) A549 cells and a human-derived NSCLC explant could be inhibited by an oxidative stress mechanism using high-pressure nitrogen. MATERIALS AND METHODS: Growth of human NSCLC explants and A549 cells in Matrigel were assessed after implantation into nude mice who were exposed to elevated pressures. RESULTS: Subcutaneous implant growth of NSCLC in nude mice was inhibited by a daily 78-minute protocol using nitrogen/oxygen breathing mixture such that at the maximum pressure of 2.78 atmospheres over ambient, mice breathed oxygen at normal atmospheric pressure. In vivo growth inhibition of A549 cells by high-pressure nitrogen could be abrogated in subcutaneous Matrigel implants when supplemented with 10-mM N-acetylcysteine as an antioxidant. Ex vivo A549 cell exposures exhibited elevated singlet oxygen production, and reactive oxygen species were produced for up to 4 hours after short-term high-pressure nitrogen exposure. CONCLUSIONS: This pilot study demonstrates that elevated normoxic nitrogen pressure can exacerbate oxidative stress in NSCLC to inhibit growth.

Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group.

Prostate cancer is a significant public health burden and a major cause of morbidity and mortality among men worldwide. Analyzing geographic patterns and temporal trends may help identify high-risk populations, suggest the degree of PSA testing, and provide clues to etiology. We used incidence data available from the International Agency for Research on Cancer (IARC) and certain cancer registries for 43 populations across five continents during a median period of 24 years. Trends in overall prostate cancer rates showed five distinct patterns ranging from generally monotonic increases to peaking of rates followed by declines, which coincide somewhat with changes in the prevalence of PSA testing. Trends in age-specific rates generally mirrored those in the overall rates, with several notable exceptions. For populations where overall rates increased rapidly and then peaked, exemplified in North America and Oceania, the highest incidence tended to be most pronounced and occurred during earlier calendar years among older men compared with younger ones. For populations with almost continual increases in overall rates, exemplified in Eastern Europe and Asia, peaks were evident among men aged ≥ 75 years in many instances. Rates for ages 45-54 years did not clearly stabilize or decline in the majority of studied populations. Global geographic variation remained substantial for both overall and age-specific incidence rates regardless of levels of PSA testing, with the lowest rates consistently in Asia. Explanations for the persistent geographic differences and the continuing increases of especially early-onset prostate cancer remain unclear.