RFX4 is an intrinsic factor for neuronal differentiation through induction of proneural genes POU3F2 and NEUROD1.

Proneural genes play a crucial role in neuronal differentiation. However, our understanding of the regulatory mechanisms governing proneural genes during neuronal differentiation remains limited. RFX4, identified as a candidate regulator of proneural genes, has been reported to be associated with the development of neuropsychiatric disorders. To uncover the regulatory relationship, we utilized a combination of multi-omics data, including ATAC-seq, ChIP-seq, Hi-C, and RNA-seq, to identify RFX4 as an upstream regulator of proneural genes. We further validated the role of RFX4 using an in vitro model of neuronal differentiation with RFX4 knock-in and a CRISPR-Cas9 knock-out system. As a result, we found that RFX4 directly interacts with the promoters of POU3F2 and NEUROD1. Transcriptomic analysis revealed a set of genes associated with neuronal development, which are highly implicated in the development of neuropsychiatric disorders, including schizophrenia. Notably, ectopic expression of RFX4 can drive human embryonic stem cells toward a neuronal fate. Our results strongly indicate that RFX4 serves as a direct upstream regulator of proneural genes, a role that is essential for normal neuronal development. Impairments in RFX4 function could potentially be related to the development of various neuropsychiatric disorders. However, understanding the precise mechanisms by which the RFX4 gene influences the onset of neuropsychiatric disorders requires further investigation through human genetic studies.

The iron chelator deferriferrichrysin induces paraptosis via extracellular signal-related kinase activation in cancer cells.

Cancer cells generally exhibit increased iron uptake, which contributes to their abnormal growth and metastatic ability. Iron chelators have thus recently attracted attention as potential anticancer agents. Here, we show that deferriferrichrysin (Dfcy), a natural product from Aspergillus oryzae acts as an iron chelator to induce paraptosis (a programmed cell death pathway characterized by ER dilation) in MCF-7 human breast cancer cells and H1299 human lung cancer cells. We first examined the anticancer efficacy of Dfcy in cancer cells and found that Dfcy induced ER dilation and reduced the number of viable cells. Extracellular signal-related kinase (ERK) was activated by Dfcy treatment, and the MEK inhibitor U0126, a small molecule commonly used to inhibit ERK activity, prevented the increase in ER dilation in Dfcy-treated cells. Concomitantly, the decrease in the number of viable cells upon treatment with Dfcy was attenuated by U0126. Taken together, these results demonstrate that the iron chelator Dfcy exhibits anticancer effects via induction of ERK-dependent paraptosis.

Breast cancer screening among Medicare Advantage enrollees with dementia.

BACKGROUND: The decision to screen for breast cancer among older adults with dementia is complex and must often be individualized, as these individuals have an elevated risk of harm from over-screening. Medicare beneficiaries with dementia are increasingly enrolling in Medicare Advantage plans, which typically promote receipt of preventive cancer screening among their enrollees. This study examined the utilization of breast cancer screening among Medicare enrollees with dementia, in Medicare Advantage and in fee-for-service Medicare. METHODS: We conducted a pooled cross-sectional study of women with Alzheimer's disease and related dementias or cognitive impairment who were eligible for mammogram screening. We used Medicare Current Beneficiary Survey data to identify utilization of biennial mammogram screening between 2012 and 2019. Poisson regression models were used to estimate prevalence ratios of mammogram utilization and to calculate adjusted mammogram rates for Medicare Advantage and fee-for-service Medicare enrollees with dementia, and further stratified by rurality and by dual eligibility for Medicare and Medicaid. RESULTS: Mammogram utilization was 16% higher (Prevalence Ratio [PR] 1.16; 95% CI: 1.05, 1.29) among Medicare Advantage enrollees with dementia, compared to their counterparts in fee-for-service Medicare. Rural enrollees experienced no significant difference (PR 0.99; 95% CI: 0.72, 1.37) in mammogram use between Medicare Advantage and fee-for-service Medicare enrollees. Among urban enrollees, Medicare Advantage enrollment was associated with a 21% higher mammogram rate (PR 1.21; 95% CI: 1.09, 1.35). Dual-eligible Medicare Advantage enrollees had a 34% higher mammogram rate (PR 1.34; 95% CI: 1.10, 1.63) than dual-eligible fee-for-service Medicare enrollees. Among non-dual-eligible enrollees, adjusted mammogram rates were not significantly different (PR 1.11; 95% CI: 0.99, 1.24) between Medicare Advantage and fee-for-service Medicare enrollees. CONCLUSIONS: Medicare beneficiaries age 65-74 with Alzheimer's disease and related dementias or cognitive impairment had a higher mammogram use rate when they were enrolled in Medicare Advantage plans compared to fee-for-service Medicare, especially when they were dual-eligible or lived in urban areas. However, some Medicare Advantage enrollees with Alzheimer's disease and related dementias or cognitive impairment may have experienced over-screening for breast cancer.

Risk of sleep apnea associated with higher blood pressure among Chinese and Korean Americans.

OBJECTIVE: This study examines associations between sleep apnea risk and hypertension in a sample of immigrant Chinese and Korean Americans. DESIGN: The dataset included Chinese and Korean patients ages 50-75 recruited from primary care physicians' offices from April 2018 to June 2020 in the Baltimore-Washington DC Metropolitan Area (n = 394). Hypertension risk was determined using a combination of blood pressure measurements, self-reported diagnosis of hypertension by a medical professional, and/or self-reported use of antihypertensive medications. Linear regression models examined the associations between sleep apnea risk and blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). Poisson regression models examined associations sleep apnea risk and hypertension. Models controlled for body mass index (BMI), demographic, and socioeconomic risk factors. We further examined models for potential effect modification by age, gender, Asian subgroup, and obesity, as well as effect modification of daytime sleepiness on the association between snoring and hypertension risk. RESULTS: High risk of sleep apnea appeared to be associated positively with SBP (ß = 6.77, 95% CI: 0.00-13.53), but not with DBP. The association was positive for hypertension, but it was not statistically significant (PR = 1.11, 95% CI: 0.87-1.41). We did not find effect modification of the associations between sleep apnea and hypertension risk, but we did find that daytime sleepiness moderated the effect of snoring on SBP. Snoring was associated with higher SBP, primarily in the presence of daytime sleepiness, such that predicted SBP was 133.27 mmHg (95% CI: 126.52, 140.02) for someone with both snoring and daytime sleepiness, compared to 123.37 mmHg (95% CI: 120.40, 126.34) for someone neither snoring nor daytime sleepiness. CONCLUSION: Chinese and Korean immigrants living in the U.S. who are at high risk of sleep apnea have higher SBP on average, even after accounting for sociodemographic characteristics and BMI. CLINICAL TRAIL REGISTRATION: : NCT03481296, date of registration: 3/29/2018.

The Cross-Sectional Association of Sleep Disturbance and Sleep Apnea With Complex Multimorbidity Among Chinese and Korean Americans.

A new concept called complex multimorbidity provides a more reliable measure of disease burden than multimorbidity based on a simple count of diseases, by categorizing diseases according to the body system they affect. This study examined associations between sleep measures and complex multimorbidity among Chinese and Korean Americans in the Baltimore-Washington DC Metropolitan Area, using cross-sectional data (n = 400) from the Screening to Prevent Colorectal Cancer study (2018-2020). Sleep disturbance was measured using the 8-item Patient Reported Outcomes Measurement Information System Sleep Disturbance scale and sleep apnea risk was assessed using the Berlin questionnaire. Complex multimorbidity was defined as the coexistence of 3 or more of body system disorders assessed by self-report of physician-diagnosed diseases. Poisson regression models with adjustments indicated that individuals with sleep disturbance had 2.15 times the prevalence of having complex multimorbidity (95% confidence interval (CI): 1.07, 4.29). Individuals with a high risk of sleep apnea had 1.19 times the prevalence of having complex multimorbidity (95% CI: 0.47, 3.01). These findings suggest a need for interventions to increase awareness of the importance of sleep among health-care providers and the public and to educate them about causes, signs, and treatment of sleep disturbance and sleep apnea.

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Predicted Health Literacy Disparities Between Immigrant and US-Born Racial/Ethnic Minorities: a Nationwide Study.

BACKGROUND: Racial/ethnic minorities in the USA exhibit reduced health literacy (HL) proficiency, leading to increased health disparities. It is unclear how the effect of birth status (immigrant/US-born) affects HL proficiency among racial/ethnic minorities. OBJECTIVE: To identify the direct, indirect, and total effects of birth status on HL proficiency among a nationally representative population of racial/ethnic minority adults in the USA. DESIGN: A cross-sectional study of 2019 data from the Medial Expenditure Panel Survey. PARTICIPANTS: Participants aged 18 or older reporting as racial/ethnic minorities (Black, Asian, or Hispanic) with non-missing data. MAIN MEASURES: We predicted HL proficiency for each participant using a previously published model. Path analysis was used to estimate the direct, indirect, and total effects of birth status on HL proficiency, accounting for several other covariates. Prevalence ratios were estimated using adjusted Poisson regression to evaluate differences in the "Below Basic" HL category. KEY RESULTS: An estimated weighted 81,092,505 participants were included (57.5% US-born, 42.5% immigrant). More racial/ethnic minority immigrant participants fell into the lowest category of HL proficiency, "Below Basic" (14.3% vs 5.5%, p < 0.05). Results of the path analysis indicated a significant, negative direct effect of birth status on HL proficiency (standardized coefficient = - 0.24, SE = 0.01, 95%CI: - 0.26, - 0.23) in addition to an indirect effect mediated through insurance status, health-system resource use, and English proficiency. The total effect of birth status on HL proficiency was found to be - 0.29. The immigrant participant group had 81% higher prevalence of falling into the "Below Basic" HL category compared to US-born participants (prevalence ratio = 1.81, 95%CI: 1.52, 2.16). CONCLUSIONS: Immigrant status has a strong, negative, direct effect on HL proficiency among racial/ethnic minorities in the USA. This may be a result of barriers that prevent equitable access to resources that improve proper HL proficiency. US policymakers may consider several methods to reduce this disparity at the health-system-, provider-, and patient-levels.

Frequency of Consuming Breakfast Meals and After-Dinner Snacks Is not Associated with Postmenopausal Breast Cancer Risk: Women's Health Initiative Observational Study.

BACKGROUND: There has been little investigation into how the timing of meals and eating occasions associates with postmenopausal breast cancer risk. OBJECTIVE: We examined the association between the frequency of consuming breakfast meals and after-dinner snacks with the risk for postmenopausal breast cancer. METHODS: A prospective analysis of 74,825 postmenopausal women aged 49 to 81 y from the Women's Health Initiative Observational Study cohort. Breakfast and after-dinner snack intake were assessed at year 1 examination. Risk for invasive and in situ breast cancer diagnosed before 28 February 2020 was modeled with multivariable Cox proportional hazards regression models according to breakfast and after-dinner snack consumption frequencies. The models were adjusted for age, self-identified race/ethnicity, education, income, physical activity, smoking, alcohol intake, diet quality score (Healthy Eating Index 2015), energy intake, diabetic status, hormone therapy, and BMI. RESULTS: During the follow-up period, 5313 participants were diagnosed with invasive breast cancer and 1197 participants with in situ breast cancer. Compared with participants who did not eat breakfast, those with daily breakfast consumption was not associated with invasive breast cancer (HR: 1.04; 95% CI: 0.9, 1.19) nor in situ (HR: 1.25; 95% CI: 0.91, 1.74) breast cancer. There were monotonic higher point estimates of in situ breast cancer for each higher category of breakfast intake from 0 to 7 times per week (P-trend = 0.04, Wald test). Compared with consumption of daily after-dinner snacks, avoidance of after-dinner snacks was not associated with invasive breast cancer (HR: 0.97; 95% CI: 0.87, 1.08) nor in situ (HR: 1.12; 95% CI: 0.89, 1.42) breast cancer. CONCLUSIONS: There was no association between intake frequency of breakfast meals or after-dinner snack habits and with risk of breast cancer in postmenopausal women.

Rural-urban disparities in preventive breast and cervical cancer screening among women with early-onset dementia.

BACKGROUND: The early onset of Alzheimer's disease and related dementias (ADRD) before age 65 can introduce life and health care complications. Preserving an early-onset ADRD patient's daily functioning longer and delaying declines in health from non-ADRD conditions become important preventive goals. This study examined the differences in utilization of preventive cancer screenings between patients with and without early-onset ADRD, and compared utilization of the screenings in rural versus urban areas among women with early-onset ADRD in the United States. METHODS: We conducted a cross-sectional study of women aged 40 to 64 years eligible for mammogram and cervical cancer screenings using commercial insurance claims from 2012 to 2018. We measured the use of biennial mammogram among women 50 to 64 years old, and the use of triennial Pap smear test among women 40 to 64 years old. We used inverse probability weighted logistic regressions to estimate the odds of receiving preventive cancer screenings by the presence of early-onset ADRD or cognitive impairments (CI). We used multivariable logistic regressions to estimate the odds of receiving preventive cancer screenings by rural or urban residence among women with early-onset ADRD/CI. RESULTS: Among 6,349,308 women in the breast cancer screening sample (mean [SD] age, 56.52 [4.03] years), 36,131 had early-onset ADRD/CI (mean [SD] age, 57.99 [3.98] years). Among 6,583,088 women in the cervical cancer screening sample (mean [SD] age, 52.37 [6.81] years), 30,919 had early-onset ADRD/CI (mean [SD] age, 55.79 [6.22] years). Having early-onset ADRD/CI was associated with lower utilization of mammogram (OR: 0.92, 95% CI: 0.90-0.95). No significant difference was observed in Pap smear screening (OR: 0.99, 95% CI: 0.96-1.02) between patients with and without early-onset ADRD/CI. Among patients with early-onset ADRD/CI, those in rural areas were less likely than those in urban areas to have mammograms (OR: 0.91, 95% CI: 0.85-0.97) and Pap smears (OR: 0.65, 95% CI: 0.61-0.71). CONCLUSIONS: The observed pattern of rural-urban differences in cancer screening in our study emphasizes the need for efforts to promote evidence-based, individualized decision-making processes in the early-onset ADRD population.

The Mediating Role of Sleep Disturbance on the Association Between Stress and Self-Rated Health Among Chinese and Korean Immigrant Americans.

INTRODUCTION: Disturbed sleep may be a factor that links stress with poor health, especially among groups experiencing high levels of stress caused by racial and ethnic minority and nativity status. The objective of this study was to describe the potential mediating role of sleep disturbance in the associations between various types of stress and self-rated health among Chinese and Korean Americans. METHODS: Our cross-sectional study consisted of 400 Chinese and Korean immigrants aged 50 to 75 years recruited from August 2018 through June 2020 from physicians' clinics in the Baltimore-Washington, DC, metropolitan area. We used the Patient Reported Outcomes Measurement Information System (PROMIS) short-form questionnaire to measure sleep disturbance. Linear regression analyses examined associations between 3 types of stress (acculturative stress, perceived stress, and distress) and self-rated health, accounting for demographic, socioeconomic, and health insurance factors. The Karlson-Holm-Breen method was used to estimate the total and direct effects of stresses on self-rated health and the indirect effects of stresses on health through sleep disturbance. RESULTS: Greater acculturative stress (ß = 0.08; 95% CI, 0.01-0.14), perceived stress (ß = 0.05; 95% CI, 0.03-0.08), and distress (ß = 0.09; 95% CI, 0.05-0.13) were all associated with poorer self-rated health. Sleep disturbance was a partial mediator, with sleep disturbance accounting for 21.7%, 14.9%, and 18.7% of the associations between acculturative stress, perceived stress, and distress and self-rated health, respectively. CONCLUSION: Because sleep disturbance partially mediates the associations between stress and poor self-rated health, future interventions and research may consider mitigating sleep disturbances and stress among racial and ethnic minority populations to address health disparities.

Keratinized tissue augmentation using collagen-based soft tissue substitute with/without epidermal growth factor on buccally positioned implants: a pilot preclinical study.

OBJECTIVES: To investigate the effect of epithelial growth factor (EGF) with collagen matrix (CM) on the gain of KT for buccally positioned implants in dogs. MATERIALS AND METHODS: In five dogs, four implants were placed buccally with the whole part of KT excision on the buccal side (two implants per each hemi-mandible). After one month, KT augmentation was performed: 1) free gingival grafts (FGG), 2) collagen matrix (CM) only, 3) CM soaked with 1 µg/g of EGF, and 4) CM soaked with 10 µg/g of EGF (n = 5 in each group). The experimental animals were sacrificed three months post-KT augmentation. Clinical, histologic, and histomorphometric analyses were performed. RESULTS: The clinical KT zone was the highest in group FGG (5.16 ± 1.63 mm). Histologically, all groups presented buccal bony dehiscence. Regarding newly formed KT, no specific difference was found among the groups, but robust rete pegs formation in some specimens in group FGG. Histomorphometric KT height (4.66 ± 1.81 mm) and length (5.56 ± 2.25 mm) were the highest in group FGG, whereas similar increases were noted in the rest. The buccal soft tissue thickness at the coronal part of the implant did not exceed 2 mm in all groups. CONCLUSION: All groups presented increased KT zone, but FGG treatment was more favored. The addition of EGF to CM appeared not to enhance KT formation. CLINICAL RELEVANCE: FGG treatment was more favorable to re-establish the KT zone than other treatment modalities.

A Data-Driven Approach to Identify the Predictors of Perceived Health Status Among Chinese and Korean Americans.

Asian Americans are the country's fastest-growing racial group, and several studies have focused on the health outcomes of Asian Americans, including perceived health status. Perceived health status provides a summarized view of the health of populations for diverse domains, such as the psychological, social, and behavioral aspects. Given its multifaceted nature, perceived health status should be carefully approached when examining any variables' influence because it results from interactions among many variables. A data-driven approach using machine learning provides an effective way to discover new insights when there are complex interactions among multiple variables. To date, there are not many studies available that use machine learning to examine the effects of diverse variables on the perceived health status of Chinese and Korean Americans. This study aims to develop and evaluate three prediction models using logistic regression, random forest, and support vector machines to find the predictors of perceived health status among Chinese and Korean Americans from survey data. The prediction models identified specific predictors of perceived health status. These predictors can be utilized when planning for effective interventions for the better health outcomes of Chinese and Korean Americans.

Lung cancer screening decisional needs among African American smokers of lower socioeconomic status.

OBJECTIVES: Adherence to most evidence-based cancer screenings is lower among African Americans due to system- and individual-level factors that contribute to persistent disparities. Given the recommendation for low-dose computed tomography (LDCT) screening among individuals at high risk for lung cancer, we sought to describe aspects of decision-making for LDCT among African Americans and to examine associations between select components of decision-making and screening-related intentions. DESIGN: African Americans (N = 119) with a long-term smoking history, aged 55-80 years, and without lung cancer were recruited to participate in a cross-sectional survey. We measured knowledge, awareness, decisional conflict, preferences, and values related to lung cancer screening. RESULTS: The majority of the study population was of lower socioeconomic status (67.2% had an annual income of ≤$20,000) and long-term current (79%) smokers. Participants had a median 20 pack-years smoking history. Most participants (65.8%) had not heard of LDCT and the total lung cancer screening knowledge score was M = 7.1/15.0 (SD = 1.8). Participants with higher scores on the importance of the pros and cons of screening expressed greater likelihood of talking with a doctor, family, and friends about screening (p's < .10). CONCLUSIONS: Findings have implications for addressing the decisional needs of lower socioeconomic African American current and former smokers to promote informed decision-making for LDCT.

Correlates of Undiagnosed Hypertension Among Chinese and Korean American Immigrants.

Asian Americans are more likely to be unaware that they have hypertension compared to non-Hispanic white Americans, despite having higher risk of hypertension at lower body-mass indices. Furthermore, immigrants are more likely than their United States (U.S.)-born counterparts to have undiagnosed hypertension, placing them at greater risk of subsequent morbidity and mortality. This study examines the social determinants of undiagnosed hypertension among Asian American immigrants. Using a study of foreign-born Chinese and Korean Americans between the ages of 50-75 years-old recruited from physicians' clinics in the Baltimore-Washington DC Metropolitan Area (n = 355), we used blood pressure readings measured by trained staff members, self-reported diagnosis by a medical professional, and self-reported hypertension medication use to determine hypertension status-whether patients were non-hypertensive, had diagnosed hypertension, or had undiagnosed hypertension. Using multinomial logistic regression, we examined how demographic, socioeconomic, and immigration-related factors were associated with hypertension status. Results indicated that older age, male gender, Korean subgroup, and marital status were associated with having diagnosed hypertension compared to being non-hypertensive. Lack of health insurance was the strongest predictor of having undiagnosed hypertension compared to being non-hypertensive. Acculturation variables had no strong associations with hypertension status. We then explored correlates of health insurance status for Chinese and Korean American immigrants. Those without health insurance were more likely to have lower income and to be not currently employed. Our findings point to the importance of increasing health insurance access for Asian American immigrant groups to ensure that hypertension is not left undiagnosed and untreated.

The Influence of Asian Subgroup and Acculturation on Colorectal Cancer Screening Knowledge and Attitudes Among Chinese and Korean Americans.

Understanding how knowledge and attitudes about colorectal cancer (CRC) screening differs among Asian immigrants is important for informing targeted health interventions aimed at preventing and treating CRC in this diverse population. This study examines how Asian subgroup and acculturation are associated with CRC knowledge and attitudes among Chinese and Korean immigrants in the United States (U.S.). Data come from the baseline survey of a randomized controlled trial to increase CRC screening among Chinese and Korean American immigrants living in the Baltimore-Washington DC Metropolitan Area (n = 400). We use linear regression to examine how Asian subgroup, time in the U.S., English-speaking proficiency, and ethnic identity are associated with CRC knowledge and screening attitudes, accounting for demographic variables, socioeconomic status, and health insurance status. Results show that greater socioeconomic status was associated with higher CRC knowledge, and socioeconomic status explained more of the variance in CRC knowledge than acculturation factors. Additionally, attitudes varied by Asian subgroup, with Chinese reporting lower CRC screening salience, worry, response efficacy, and social influence compared to Koreans. Findings suggest that in-language interventions aimed at increasing CRC knowledge and capitalizing on attitudes about screening can help to bridge disparities in CRC screening by socioeconomic status and country of origin. We discuss implications for future interventions to increase CRC screening uptake among Chinese and Korean immigrants in the U.S.

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. PATIENTS AND METHODS: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. RESULTS: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). CONCLUSION: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

Exploring the metabolomic diversity of plant species across spatial (leaf and stem) components and phylogenic groups.

BACKGROUND: Plants have been used as an important source of indispensable bioactive compounds in various cosmetics, foods, and medicines. However, the subsequent functional annotation of these compounds seems arduous because of the largely uncharacterized, vast metabolic repertoire of plant species with known biological phenotypes. Hence, a rapid multi-parallel screening and characterization approach is needed for plant functional metabolites. RESULTS: Fifty-one species representing three plant families, namely Asteraceae, Fabaceae, and Rosaceae, were subjected to metabolite profiling using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) and ultrahigh-performance liquid chromatography quadrupole orbitrap ion trap tandem mass spectrometry (UHPLC-Q-orbitrap-MS/MS) as well as multivariate analyses. Partial least squares discriminant analysis (PLS-DA) of the metabolite profiling datasets indicated a distinct clustered pattern for 51 species depending on plant parts (leaves and stems) and relative phylogeny. Examination of their relative metabolite contents showed that the extracts from Fabaceae plants were abundant in amino acids, fatty acids, and genistein compounds. However, the extracts from Rosaceae had higher levels of catechin and ellagic acid derivatives, whereas those from Asteraceae were higher in kaempferol derivatives and organic acids. Regardless of the different families, aromatic amino acids, branch chain amino acids, chlorogenic acid, flavonoids, and phenylpropanoids related to the shikimate pathway were abundant in leaves. Alternatively, certain amino acids (proline, lysine, and arginine) as well as fatty acids levels were higher in stem extracts. Further, we investigated the associated phenotypes, i.e., antioxidant activities, affected by the observed spatial (leaves and stem) and intra-family metabolomic disparity in the plant extracts. Pearson's correlation analysis indicated that ellagic acid, mannitol, catechin, epicatechin, and quercetin derivatives were positively correlated with antioxidant phenotypes, whereas eriodictyol was positively correlated with tyrosinase inhibition activity. CONCLUSIONS: This work suggests that metabolite profiling, including multi-parallel approaches and integrated bioassays, may help the expeditious characterization of plant-derived metabolites while simultaneously unraveling their chemodiversity.

Intragenic CpG islands play important roles in bivalent chromatin assembly of developmental genes.

CpG, 5'-C-phosphate-G-3', islands (CGIs) have long been known for their association with enhancers, silencers, and promoters, and for their epigenetic signatures. They are maintained in embryonic stem cells (ESCs) in a poised but inactive state via the formation of bivalent chromatin containing both active and repressive marks. CGIs also occur within coding sequences, where their functional role has remained obscure. Intragenic CGIs (iCGIs) are largely absent from housekeeping genes, but they are found in all genes associated with organ development and cell lineage control. In this paper, we investigated the epigenetic status of iCGIs and found that they too reside in bivalent chromatin in ESCs. Cell type-specific DNA methylation of iCGIs in differentiated cells was linked to the loss of both the H3K4me3 and H3K27me3 marks, and disruption of physical interaction with promoter regions, resulting in transcriptional activation of key regulators of differentiation such as PAXs, HOXs, and WNTs. The differential epigenetic modification of iCGIs appears to be mediated by cell type-specific transcription factors distinct from those bound by promoter, and these transcription factors may be involved in the hypermethylation of iCGIs upon cell differentiation. iCGIs thus play a key role in the cell type-specific regulation of transcription.

Novel hybrid models between bivariate statistics, artificial neural networks and boosting algorithms for flood susceptibility assessment.

Across the world, the flood magnitude is expected to increase as well as the damage caused by their occurrence. In this case, the prediction of areas which are highly susceptible to these phenomena becomes very important for the authorities. The present study is focused on the evaluation of flood potential within Trotuș river basin in Romania using six ensemble models created by the combination of Analytical Hierarchy Process (AHP), Certainty Factor (CF) and Weights of Evidence (WOE) on one hand, and Gradient Boosting Trees (GBT) and Multilayer Perceptron (MLP) on the other hand. A number of 12 flood predictors, 172 flood locations and 172 non-flood locations were used. A percentage of 70% of flood and non-flood locations were used as input in models. From the input data, 70% were used as training sample and 30% as validating sample. The highest accuracy was obtained by the MLP-CF model in terms of both training (0.899) and testing (0.889) samples. A percentage between 21.88% and 36.33% of study area is covered with high and very high flood potential. The results validation, performed through the ROC Curve method, highlights that the MLP-CF model provided the most accurate results.