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Background: Many studies examining weight trajectories have used adiposity measures shown to be problematic for trajectory analysis in children with obesity, and remission of obesity remains poorly understood., Objectives: To describe weight trajectories for school-aged children, the rate of obesity remission and factors associated., Methods: Children between 6 and 11 years of age with ≥3 valid height and weight measurements from an Oregon hospital-system over a minimum six-month period were included. Percent distance from the median body mass index (BMI) was used for modeling. Latent class analysis and linear mixed models were used to classify children based on their weight trajectory., Results: We included 11,247 subjects with a median of 2.1 years of follow-up, with 1,614 (14.4%) classified as overweight and 1,794 (16.0%) classified as obese. Of subjects with obesity, 1% experienced remission during follow-up, whereas 23% of those with overweight moved to within a healthy weight range. Latent class analysis identified three classes within each weight-based stratum over time. The majority of children with overweight or obesity had a flat trajectory over time. Lower socioeconomic status was associated with a worsening trajectory. Latent class models using alternate measures (BMI, BMI z-scores, tri-ponderal mass index (TMI)) differed substantially from each other., Conclusions: Obesity remission was uncommon using the adiposity metric of distance from the median though transition from overweight to healthy weight was more common. Children with low socioeconomic status have worse trajectories overall. The choice of adiposity metric may have a substantial effect on the outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Foster et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Disclosure of HIV positive status to children and adolescents is a complex process. However, disclosure has been found to be associated with improved outcomes. The objective of the current study was to identify the predictors that facilitate disclosure of HIV status to children and adolescents and to study the reasons for non-disclosure., Methods: Interviews of caregivers and reviews of records were done to collect data on caregiver and child information and details regarding the disclosure status of children. Bivariate analysis was done to test the association between HIV status disclosure and different caregiver and child factors. To identify the independent predictors of disclosure, we did multivariable logistic regression., Results: A total of 177 children attending an HIV clinic were included. The mean age of the participants was 10.1 years (SD = 2.8), and about half (50.8%) were female. Most caregivers, 137 (77.8%) stated that disclosure of HIV status to children is important and should be done. However, disclosure had only been made to 59 (33.3%) of the participants. Child age more than 10 years [AOR = 6.7; 95%CI: 1.73-26.01], duration of HIV diagnosis of 5 years or more [AOR = 4.4; 95%CI: 1.26-15.06] and taking a zidovudin (AZT) based regimen [AOR = 3.5; 95%CI: 1.31-9.53] predicted HIV positive status disclosure. Additionally, length of treatment of caregivers of more than 14 years [AOR = 3.9; 95%CI: 1.07-14.61], disclosure of caregiver's HIV status to children and/or others [AOR = 4.7; 95%CI: 1.19-18.74], and the child's inquiry about their condition [AOR = 4.5; 95%CI: 1.16-17.43] increased the odds of disclosure., Conclusion: The rate of disclosure among HIV infected children in southern Ethiopia is low. Primarily time-based factors were associated with the probability of HIV positive status disclosure and a specific regimen which has not been found previously. Further qualitative research may elucidate more on these factors; educational strategies may address some of these determinants.

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol) has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW), were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg), or QW (50 µg/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW) and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW). However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086), and reduced tumor proliferation (p = 0.0467). By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823). Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age)(p = 0.0003). Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.

Stem cell enrichment provides a tool to examine prostate stem cells obtained from benign and malignant tissue. Functional assays can enrich stem cells based on common stem cell phenotypes, such as high ATP binding cassette (ABC) transporter mediated efflux of Hoechst substrates (side population assay). This functional assay is based upon mechanisms that protect cells from environmental insult thus contributing to the survival and protection of the stem cell population. We have isolated and analyzed cells digested from twelve clinical prostate specimens based on the side population assay. Prostate stem cell properties of the isolated cells were tested by serial recombination with rat urogenital mesenchyme. Recombinants with side population cells demonstrate an increase in the frequency of human ductal growth and the number of glands per recombinant when compared to recombinants with non-side population cells. Isolated cells were capable of prostatic growth for up to three generations in the recombination assay with as little as 125 sorted prostate cells. The ability to reproducibly use cells isolated by fluorescence activated cell sorting from human prostate tissue is an essential step to a better understanding of human prostate stem cell biology. ABC transporter G2 (ABCG2) was expressed in recombinants from side population cells indicating the side population cells have self-renewal properties. Epithelial cell differentiation of recombinants was determined by immunohistochemical analysis for expression of the basal, luminal, and neuroendocrine markers, p63, androgen receptor, prostate specific antigen, and chromogranin A, respectively. Thus, the ABCG2 expressing side population demonstrates multipotency and self-renewal properties indicating stem cells are within this population.

Chronic inflammation leads to the formation of a pro-tumorigenic microenvironment that can promote tumor development, growth and differentiation through augmentation of tumor angiogenesis. Prostate cancer (CaP) risk and prognosis are adversely correlated with a number of inflammatory and angiogenic mediators, including Toll-like receptors (TLRs), NF-κB and vascular endothelial growth factor (VEGF). Peroxiredoxin 1 (Prx1) was recently identified as an endogenous ligand for TLR4 that is secreted from CaP cells and promotes inflammation. Inhibition of Prx1 by CaP cells resulted in reduced expression of VEGF, diminished tumor vasculature and retarded tumor growth. The mechanism by which Prx1 regulates VEGF expression in normoxic conditions was investigated in the current study. Our results show that incubation of mouse vascular endothelial cells with recombinant Prx1 caused increases in VEGF expression that was dependent upon TLR4 and required hypoxia inducible factor-1 (HIF-1) interaction with the VEGF promoter. The induction of VEGF was also dependent upon NF-κB; however, NF-κB interaction with the VEGF promoter was not required for Prx1 induction of VEGF suggesting that NF-κB was acting indirectly to induce VEGF expression. The results presented here show that Prx1 stimulation increased NF-κB interaction with the HIF-1α promoter, leading to enhanced promoter activity and increases in HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. Prx1 induced HIF-1 also promoted NF-κB activity, suggesting the presence of a positive feedback loop that has the potential to perpetuate Prx1 induction of angiogenesis. Strikingly, inhibition of Prx1 expression in CaP was accompanied with reduced expression of HIF-1α. The combined findings of the current study and our previous study suggest that Prx1 interaction with TLR4 promotes CaP growth potentially through chronic activation of tumor angiogenesis.

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor which regulates the expression of many cytoprotective genes. In the present study, we found that the expression of Nrf2 was suppressed in prostate tumor of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice. Similarly, the expression of Nrf2 and the induction of NQO1 were also substantially suppressed in tumorigenic TRAMP C1 cells but not in non-tumorigenic TRAMP C3 cells. Examination of the promoter region of the mouse Nrf2 gene identified a CpG island, which was methylated at specific CpG sites in prostate TRAMP tumor and in TRAMP C1 cells but not in normal prostate or TRAMP C3 cells, as shown by bisulfite genomic sequencing. Reporter assays indicated that methylation of these CpG sites dramatically inhibited the transcriptional activity of the Nrf2 promoter. Chromatin immunopreceipitation (ChIP) assays revealed increased binding of the methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in the TRAMP C1 cells as compared to TRAMP C3 cells. In contrast, the binding of RNA Pol II and acetylated histone H3 to the Nrf2 promoter was decreased. Furthermore, treatment of TRAMP C1 cells with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-aza) and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) restored the expression of Nrf2 as well as the induction of NQO1 in TRAMP C1 cells. Taken together, these results indicate that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with MBD2 and histone modifications in the prostate tumor of TRAMP mice. Our present findings reveal a novel mechanism by which Nrf2 expression is suppressed in TRAMP prostate tumor, shed new light on the role of Nrf2 in carcinogenesis and provide potential new directions for the detection and prevention of prostate cancer.