Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer Disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS: We aimed to study CSF PDGFRß protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. RESULTS: Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRß and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRß levels were not associated with either the CSF Aß42 or the amyloid-PET. CONCLUSIONS: We demonstrated a moderate positive correlation between PDGFRß and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094939.

Pain Is Associated With Depressive Symptoms, Inflammation, and Poorer Physical Function in Older Adults With HIV.

OBJECTIVE: People living with HIV (PLWH) frequently experience pain, which often co-occurs with psychological symptoms and may impact functional outcomes. We investigated cross-sectional associations between pain, depressive symptoms, and inflammation, and then explored whether pain was related to poorer physical function among older PLWH. METHODS: We examined data from PLWH aged 54 to 78 years ( n = 162) recruited from a single outpatient program for a larger study on HIV and aging. Participants reported depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) and then attended a biomedical visit in which they reported past-month pain (Medical Outcomes Study-HIV pain subscale), completed physical function assessments, and provided blood samples (assayed for interleukin 6, interferon-γ, tumor necrosis factor α, and C-reactive protein). Links between pain, depressive symptoms, inflammation, and physical function were tested using linear regression models. RESULTS: PLWH with greater depressive symptoms experienced more pain than did those with fewer depressive symptoms ( B = 1.31, SE = 0.28, p < .001), adjusting for age, sex, race, body mass index, smoking, disease burden, time since HIV diagnosis, and medication use. Higher composite cytokine levels were associated with worse pain ( B = 5.70, SE = 2.54, p = .027 in adjusted model). Poorer physical function indicators, including slower gait speed, weaker grip strength, recent falls, and prefrail or frail status, were observed among those with worse pain. Exploratory mediation analyses suggested that pain may partially explain links between depressive symptoms and several physical function outcomes. CONCLUSIONS: Pain is a potential pathway linking depressive symptoms and inflammation to age-related health vulnerabilities among older PLWH; longitudinal investigation of this pattern is warranted. PLWH presenting with pain may benefit from multidisciplinary resources, including behavioral health and geriatric medicine approaches.

Plasma Cell-Free Mitochondrial DNA as a Marker of Geriatric Syndromes in Older Adults With HIV.

BACKGROUND: Older people with HIV experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps due to residual inflammation despite suppressive antiretroviral therapy. Cell-free mitochondrial DNA (cfmtDNA) released during necrosis-mediated cell death potentially acts as both mediator and marker of inflammatory dysregulation. Thus, we evaluated plasma cfmtDNA as a potential biomarker of geriatric syndromes. METHODS: Participants underwent the Montreal Cognitive Assessment (MoCA), frailty testing, and measurement of plasma cfmtDNA by qPCR and inflammatory markers including C-reactive protein, interleukin-6 (IL-6), interferon gamma, and tumor necrosis factor alpha in this cross-sectional study. RESULTS: Across 155 participants, the median age was 60 years (Q1, Q3: 56, 64), one-third were female, and 92% had HIV-1 viral load <200 copies/mL. The median MoCA score was 24 (21, 27). The plasma cfmtDNA level was higher in those with cognitive impairment (MoCA <23) ( P = 0.02 by the t test) and remained significantly associated with cognitive impairment in a multivariable logistic regression model controlling for age, sex, race, CD4 T-cell nadir, HIV-1 viremia, and depression. Two-thirds of participants met the criteria for a prefrail or frail state; higher plasma cfmtDNA was associated with slow walk and exhaustion but not overall frailty state. Cognitive dysfunction was not associated with C-reactive protein, IL-6, interferon gamma, or tumor necrosis factor alpha, and frailty state was only associated with IL-6. CONCLUSIONS: Plasma cfmtDNA may have a role as a novel biomarker of cognitive dysfunction and key components of frailty. Longitudinal investigation of cfmtDNA is warranted to assess its utility as a biomarker of geriatric syndromes in older people with HIV.

Molecular and cellular functions of long non-coding RNAs in prostate and breast cancer.

Long noncoding RNAs (lncRNAs) are defined as noncoding RNA transcripts with a length greater than 200 nucleotides. Research over the last decade has made great strides in our understanding of lncRNAs, especially in the biology of their role in cancer. In this article, we will briefly discuss the biogenesis and characteristics of lncRNAs, then review their molecular and cellular functions in cancer by using prostate and breast cancer as examples. LncRNAs are abundant, diverse, and evolutionarily, less conserved than protein-coding genes. They are often expressed in a tumor and cell-specific manner. As a key epigenetic factor, lncRNAs can use a wide variety of molecular mechanisms to regulate gene expression at each step of the genetic information flow pathway. LncRNAs display widespread effects on cell behavior, tumor growth, and metastasis. They act intracellularly and extracellularly in an autocrine, paracrine and endocrine fashion. Increased understanding of lncRNA's role in cancer has facilitated the development of novel biomarkers for cancer diagnosis, led to greater understanding of cancer prognosis, enabled better prediction of therapeutic responses, and promoted identification of potential targets for cancer therapy.

Links Between Inflammation, Mood, and Physical Function Among Older Adults With HIV.

OBJECTIVES: People living with human immunodeficiency virus (PLWH) treated with antiretrovirals have life spans similar to their HIV-negative peers. Yet, they experience elevated inflammation-related multimorbidity. Drawing on biopsychosocial determinants of health may inform interventions, but these links are understudied in older PLWH. We investigated cross-sectional relationships between psychosocial factors (mood, loneliness, and stigma), inflammatory markers, and age-related health outcomes among 143 PLWH aged 54-78 years. METHOD: Participants provided blood samples for serum cytokine and C-reactive protein (CRP) analyses, completed surveys assessing psychosocial factors and health, and completed frailty assessments. Regression models tested relationships between key psychosocial-, inflammation, and age-related health variables, adjusting for relevant sociodemographic and clinical factors. RESULTS: Participants with more depressive symptoms had higher composite cytokine levels than those with fewer depressive symptoms (ß = 0.22, t(126) = 2.71, p = .008). Those with higher cytokine levels were more likely to be prefrail or frail (adjusted odds ratio = 1.72, 95% confidence interval = 1.01-2.93) and reported worse physical function (ß = -0.23, t(129) = -2.64, p = .009) and more cognitive complaints (ß = -0.20, t(129) = -2.16, p = .03) than those with lower cytokine levels. CRP was not significantly related to these outcomes; 6-month fall history was not significantly related to inflammatory markers. DISCUSSION: Novel approaches are needed to manage comorbidities and maximize quality of life among older PLWH. Illustrating key expected biopsychosocial links, our findings highlight several factors (e.g., depressive symptoms, poorer physical function) that may share bidirectional relationships with chronic inflammation, a key factor driving morbidity. These links may be leveraged to modify factors that drive excessive health risk among older PLWH.

Childhood sexual abuse history amplifies the link between disease burden and inflammation among older adults with HIV.

As they age, people living with HIV (PLWH) experience greater rates of inflammation-related health conditions compared to their HIV-negative peers. Because early life adversity can exaggerate proinflammatory effects of later physiological challenges, inflammation may be higher among PLWH with these combined risks, which could inform intervention approaches to mitigate multimorbidity. In this cross-sectional analysis, we investigated individual and combined effects of childhood sexual abuse (CSA) history and physiological burden (Veterans Aging Cohort Study Index scores) on serum cytokine and C-reactive protein (CRP) levels among PLWH. Participants (n â€‹= â€‹131; age 54 and older) were patients at an outpatient HIV clinic who completed a psychosocial survey and biomedical research visit as part of a larger study. 93% were virally suppressed, and 40% reported experiencing sexual abuse in childhood. Composite cytokine levels (summarizing IL-6, TNF-α, IFN-γ), CRP, and disease burden did not differ significantly between those who had a history of CSA and those who did not. Participants with greater disease burden had higher composite cytokine levels (r â€‹= â€‹0.29, p â€‹= â€‹0.001). The disease burden by CSA interaction effect was a significant predictor of composite cytokine levels (but not CRP), and remained significant after controlling for age, sex, race, BMI, anti-inflammatory medication use, selective serotonin reuptake inhibitor use, depressive symptoms, and smoking status (F(1, 114) â€‹= â€‹5.68, p â€‹= â€‹0.02). In follow-up simple slopes analysis, greater disease burden was associated with higher cytokine levels among those with CSA history (b â€‹= â€‹0.03, SE â€‹= â€‹0.008, p<0.001), but not among those without CSA history. Further, in the context of greater disease burden, individuals with a CSA history tended to have higher cytokine levels than those without a CSA history (b â€‹= â€‹0.38, SE â€‹= â€‹0.21, p â€‹= â€‹0.07). These data suggest that the physiological sequelae of childhood trauma may persist into older age among those with HIV. Specifically, links between physiological burden and inflammation were stronger among survivors of CSA in this study. The combined presence of CSA history and higher disease burden may signal a greater need for and potential benefit from interventions to reduce inflammation, an area for future work.

Urine Cell-Free Mitochondrial DNA as a Marker of Weight Loss and Body Composition in Older Adults With HIV.

BACKGROUND: Older adults with HIV (OAH) experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps because of chronic inflammation. Cell-free mitochondrial DNA (cfmtDNA) released from cells undergoing necrosis-mediated cell death potentially acts as both a mediator and marker of inflammatory dysregulation. We hypothesized that urinary cfmtDNA would be associated with frailty, body composition, and fall history in OAH. METHODS: OAH completed frailty testing, a psychosocial survey, body composition assessment, and measurement of urine cfmtDNA and urine albumin:creatinine in this cross-sectional study. Urine cfmtDNA was measured by quantative polymerase chain reaction and normalized to urinary creatinine. RESULTS: Across 150 participants, the mean age was 61 years (SD 6 years), half identified as Black, one-third were women, and 93% had HIV-1 viral load <200 copies/mL. Two-thirds met criteria for a prefrail or frail state. Those with unintentional weight loss had higher urine cfmtDNA concentrations (P = 0.03). Higher urine cfmtDNA was inversely associated with the skeletal muscle index (ß = -0.19, P < 0.01) and fat mass index (ß = -0.08, P = 0.02) in separate multiple linear regression models adjusted for age, sex, and presence of moderate-severe albuminuria. CONCLUSIONS: In this cross-sectional study of OAH, higher levels of urine cfmtDNA were more common in subjects with less robust physical condition, including unintentional weight loss and less height-scaled body mass of fat and muscle. These findings suggest urine cfmtDNA may reflect pathophysiologic aging processes in OAH, predisposing them to geriatric syndromes. Longitudinal investigation of urine cfmtDNA as a biomarker of geriatric syndromes is warranted.

Tumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease.

BACKGROUND: Mineral and bone disorder (MBD) and growth impairment are common complications of pediatric chronic kidney disease (CKD). Chronic inflammation detrimentally affects bone health and statural growth in non-CKD settings, but the impact of inflammation on CKD-MBD and growth in pediatric CKD remains poorly understood. This study assessed associations between inflammatory cytokines with biomarkers of CKD-MBD and statural growth in pediatric CKD. METHODS: This is a cross-sectional study of children with predialysis CKD stages II-V. Cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α, interferon-γ), bone alkaline phosphatase (BAP), and procollagen type 1 N-terminal propeptide (P1NP) were measured at the same time as standard CKD-MBD biomarkers. Associations between cytokines, CKD-MBD biomarkers, and height z-score were assessed using linear regression analysis. RESULTS: Among 63 children, 52.4% had stage 3 CKD, 76.2% non-glomerular CKD etiology, and 21% short stature. TNF-α was the only cytokine associated with parathyroid hormone (PTH) independent of glomerular filtration rate. After stratification by low, medium, and high TNF-α tertiles, significant differences in PTH, serum phosphorus, alkaline phosphatase, BAP, P1NP, and height z-score were found. In a multivariate analysis, TNF-α positively associated with phosphorus, PTH, and alkaline phosphatase and inversely associated with height z-score, independent of kidney function, age, sex, and active vitamin D analogue use. CONCLUSIONS: TNF-α is positively associated with biomarkers of CKD-MBD and inversely associated with height z-score, indicating that inflammation likely contributes to the development of CKD-MBD and growth impairment in pediatric CKD. Prospective studies to definitively assess causative effects of inflammation on bone health and growth in children with CKD are warranted.

Carbonyl iron and iron dextran therapies cause adverse effects on bone health in juveniles with chronic kidney disease.

Anemia is a frequent complication of chronic kidney disease (CKD), related in part to the disruption of iron metabolism. Iron therapy is very common in children with CKD and excess iron has been shown to induce bone loss in non-CKD settings, but the impact of iron on bone health in CKD remains poorly understood. Here, we evaluated the effect of oral and parenteral iron therapy on bone transcriptome, bone histology and morphometry in two mouse models of juvenile CKD (adenine-induced and 5/6-nephrectomy). Both modalities of iron therapy effectively improved anemia in the mice with CKD, and lowered bone Fgf23 expression. At the same time, iron therapy suppressed genes implicated in bone formation and resulted in the loss of cortical and trabecular bone in the mice with CKD. Bone resorption was activated in untreated CKD, but iron therapy had no additional effect on this. Furthermore, we assessed the relationship between biomarkers of bone turnover and iron status in a cohort of children with CKD. Children treated with iron had lower levels of circulating biomarkers of bone formation (bone-specific alkaline phosphatase and the amino-terminal propeptide of type 1 procollagen), as well as fewer circulating osteoblast precursors, compared to children not treated with iron. These differences were independent of age, sex, and glomerular filtration rate. Thus, iron therapy adversely affected bone health in juvenile mice with CKD and was associated with low levels of bone formation biomarkers in children with CKD.

Intestinal Dysbiosis and Markers of Systemic Inflammation in Viscerally and Generally Obese Persons Living With HIV.

BACKGROUND: The intestinal microbiota contributes to the pathogenesis of obesity and metabolic disorders. People living with HIV (PLWH) have a higher risk for the development of visceral adiposity with accompanying worsened cardiovascular risk. SETTING: Convenience sample from an HIV clinic and research unit. METHODS: To understand the relationship between adiposity and intestinal dysbiosis, we compared the gut microbiota and inflammatory markers in a cross-sectional study of viscerally obese, generally obese, and lean PLWH. Fecal intestinal microbiota was characterized by 16S ribosomal DNA sequencing. Abdominal CTs quantified subcutaneous adipose tissue and visceral adipose tissue (SAT; VAT). Serum high sensitivity C-reactive protein, adiponectin, leptin, IL-6, MCP-1, and sCD14 were assayed. RESULTS: We studied 15, 9, and 11 participants with visceral obesity, general obesity, and lean body type, respectively. The generally obese group were all women and 2/3 African American, whereas the visceral obesity and lean groups were predominantly white and men who have sex with men. Markers of systemic inflammation and sCD14 were higher in general obesity compared with lean. sCD14 was positively correlated with VAT, but not SAT. Bacterial diversity was significantly reduced in participants with visceral and general obesity and composition of intestinal microbiota was significantly different from lean body types. Bacterial alpha diversity was negatively correlated with VAT area, waist/hip ratio, and sCD14, but not with SAT area. CONCLUSIONS: In this exploratory study, obesity in general was associated with dysbiotic intestinal microbiota. The relationships of VAT to bacterial diversity and sCD14 suggest that dysbiosis in viscerally obese PLWH could be associated with heightened inflammatory state.

Statins induce cell apoptosis through a modulation of AKT/FOXO1 pathway in prostate cancer cells.

BACKGROUND: In recent years, statins have been frequently investigated in neoplasms. However, the potential roles of statins on prostate cancer cells and the underlying mechanisms have not been fully elucidated. In current study, we explored the effect and molecular mechanism of statins on cell proliferation and apoptosis in prostate cancer cells. METHODS: Prostate cancer cell were treated with gradient doses of simvastatin and fluvastatin for 24-72 h. Cell proliferation was analyzed by using MTS assay and colony formation. Cell apoptosis was measured by Hoechst staining, flow cytometry and caspase-3 activity. Western blotting was used to evaluate the proteins levels. RESULTS: Both simvastatin and fluvastatin produced a dose- and time-dependent inhibition of cell viability and colony formation while a promotion of cell apoptosis as evident with increases in caspase-3 activity, cleaved-caspase-3, cleaved-caspase-8 and cleaved-PARP levels in PC3 cells. Similar statin effects were observed in DU145 prostate cancer cells. Furthermore, statins produced a time- and dose-dependent reduction of phosphorylated-AKT and phosphorylated-FOXO1 levels in PC3 cells, and pretreatment of cells with an AKT phosphorylation inhibitor, MK2206, potentiated statins' effect. CONCLUSION: Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells, which may have a potential benefit in prostate cancer prevention and therapy.

Long non-coding RNAs in prostate cancer: Functional roles and clinical implications.

Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

LncRNA Profile Study Reveals a Three-LncRNA Signature Associated With the Pathological Complete Response Following Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The purpose of this study is to develop an effective but concise long non-coding RNA (lncRNA) expression signature that can predict response to neoadjuvant chemotherapy for breast cancer (BC) patients. METHODS: lncRNA expression profiling in 1102 BC patients from Gene Expression Omnibus datasets was analyzed using lncRNA-mining approach. The association between lncRNA signature and pathological complete response (pCR) was analyzed using logistic regression model in the training set (GSE25066, n = 488). Validation was performed in independent testing datasets, GSE20194, GSE20271, GSE22093, and GSE23988 (n = 614). Bonferroni method was employed for multiple testing corrections. Cell proliferation assay and Western blot assay were performed to evaluate the cell viability and protein expression level, respectively. RESULTS: Three lncRNAs (AK291479, U79293, and BC032585) have been identified to be significantly associated with pCR in the training dataset (Bonferroni p-value < 0.05). Expression signature with these lncRNAs was predictive of pCR in the training (AUC = 0.74) and testing (AUC = 0.72) datasets. Weighted gene co-expression network analysis and gene functional annotation suggest that the three lncRNAs were involved in cell cycle process. To confirm the functional significance of the identified lncRNAs, BC032585 was selectively silenced using RNA interference. Knockdown of BC032585 lncRNA significantly promoted cell resistance to multiple anticancer-drugs through upregulating MDR1 expression in breast cancer cells. CONCLUSION: These results suggest that lncRNAs such as BC032585 might be involved in chemotherapeutic response in breast cancer patients, and the three-lncRNA signature identified in the present study may serve as a useful biomarker for the selection of responsive breast cancer patients in neoadjuvant chemotherapy.

Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD.

INTRODUCTION: Anemia is a common complication of chronic kidney disease (CKD) in children; however, the role of inflammation in its pathogenesis remains incompletely understood. METHODS: To elucidate the role of interleukin (IL)-6 in renal anemia, we induced CKD by adenine diet in juvenile wild-type (WT) and IL-6 deficient (Il6KO) mice, and examined serum IL-6 and relevant parameters in children with CKD. RESULTS: WT-CKD mice developed anemia despite increases in serum erythropoietin and displayed low serum iron and elevated serum IL-6. IL-6 deficiency resulted in a significant improvement of red blood cell count and hemoglobin in CKD mice. This effect was associated with improvement of hypoferremia by Il6 deletion, likely mediated by hepcidin. However, correction of hypoferremia by oral iron supplementation in WT-CKD mice did not fully replicate the protective effects of Il6 deletion, suggesting an additional iron-independent role for IL-6 in CKD-anemia. Indeed, Il6 deletion mitigated the severity of renal fibrosis and alleviated relative erythropoietin insufficiency in CKD mice. Cytokine profiling in a pediatric CKD cohort demonstrated that of 10 cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ), only IL-6 was significantly (inversely) associated with hemoglobin when adjusted for glomerular filtration rate (GFR). The association between IL-6 and hemoglobin in children with CKD remained significant after adjustment for CKD stage, iron therapy, and hepcidin. DISCUSSION: IL-6 contributes to development of anemia in juvenile CKD, through mechanisms that include induction of hypoferremia, aggravation of renal fibrosis, and alteration of the erythropoietin axis. IL-6 appears to be a promising therapeutic target in the management of CKD-anemia.

Epilepsy, depression, and growth hormone.

Depression affects a large proportion of patients with epilepsy, and is likely due in part to biological mechanism. Hormonal dysregulation due to the disruptive effects of seizures and interictal epileptiform discharges on the hypothalamic-pituitary-adrenal axis likely contributes to high rates of depression in epilepsy. This paper reviews the largely unexplored role of neuroendocrine factors in epilepsy-related depression, focusing on Growth Hormone (GH). While GH deficiency is traditionally considered a childhood disorder manifested by impaired skeletal growth, GH deficiency in adulthood is now recognized as a serious disorder characterized by impairments in multiple domains including mood and quality of life. Could high rates of depression in patients with epilepsy relate to subtle GH deficiency? Because GH replacement therapy has been shown to improve mood and quality of life in patients with GH deficiency, this emerging area may hold promise for patients suffering from epilepsy-related depression.

Polymorphisms in IGF2/H19 gene locus are associated with platinum-based chemotherapeutic response in Chinese patients with epithelial ovarian cancer.

AIM: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC). METHODS: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. 21 polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay. RESULTS: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10-0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III-IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02-1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07-0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05-0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04-0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05-0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00-2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01-2.88). CONCLUSION: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.

MALAT1: a potential biomarker in cancer.

PURPOSE: The research of long non-coding RNAs (lncRNAs) has become a new passion with the discovery of abundant new lncRNAs and extensive investigation of their roles in various diseases, especially in cancers. Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) emerges as a hotspot, which has been reported to be involved in dysregulation of cell signaling and closely correlated with cancer development, progression, and response to therapy. This review is a brief update of the current knowledge related to the role of MALAT1 in cancer-associated molecular pathways and pathophysiology and possible determinants for MALAT1 to function as a biomarker, aiming to stimulate the basic investigation of lncRNA MALAT1 as well as its translation to clinical applications. METHODS: We have selected vast literature from electronic databases including studies associated with its clinical significance and the pivotal functions in cancer processes such as cell proliferation, apoptosis, metastasis, immunity, angiogenesis, and drug resistance. RESULTS: Studies have shown that aberrant expression of MALAT1 is related to cancer pathophysiology with the potential to be translated clinically and MALAT1 can regulate cancer processes by interacting with molecules, such as proteins, RNAs and DNAs, and further altering different signal pathways. CONCLUSION: MALAT1 lncRNA promises to be a potential biomarker for cancer diagnosis as well as prognosis. Additionally, it might be a therapeutic target for human cancers.

Emerging role of long non-coding RNAs in cisplatin resistance.

Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

Pirfenidone inhibits cryoablation induced local macrophage infiltration along with its associated TGFb1 expression and serum cytokine level in a mouse model.

PURPOSE: To investigate the effects of pirfenidone (PFD) on post-cryoablation inflammation in a mouse model. MATERIALS AND METHODS: In this IACUC-approved study, eighty Balb/c mice were randomly divided into four groups (20/group): sham + vehicle, sham + PFD, cryoablation + vehicle, and cryoablation + PFD. For cryoablation groups, a 20% freeze rate cryoablation (20 s to less than -100 °C) was used to ablate normal muscle in the right flank. For sham groups, the cryoprobe was advanced into the flank and maintained for 20 s without ablation. PFD or vehicle solution was intraperitoneally injected (5 mg/kg) at days 0, 1, 2, 3, and then every other day until day 13 after cryoablation. Mice were euthanized at days 1, 3, 7, and 14. Blood samples were used for serum IL-6, IL-10, and TGFß1 analysis using electrochemiluminescence and ELISA assays, respectively. Immunohistochemistry-stained ablated tissues were used to analyze macrophage infiltration and local TGFß1 expression in the border region surrounding the cryoablation-induced coagulation zone. RESULTS: Cryoablation induced macrophage infiltration and increased TGFß1 expression in the border of the necrotic zone, and high levels of serum IL-6, peaking at days 7 (70.5 ±â€¯8.46/HPF), 14 (228 ±â€¯18.36/HPF), and 7 (298.67 ±â€¯92.63), respectively. Animals receiving PFD showed reduced macrophage infiltration (35.5 ±â€¯16.93/HPF at day 7, p < 0.01) and cytokine levels (60.2 ±â€¯7.6/HPF at day 14, p < 0.01). PFD also significantly reduced serum IL-6 levels (p < 0.001 vs. all non-PFD groups). CONCLUSIONS: PFD mitigates cryoablation induced muscle tissue macrophage infiltration, increased IL-6 levels, and local TGFß1 expression in a small animal model.

Blood pressure and mortality in a prospective cohort of HIV-infected adults in Port-au-Prince, Haiti.

OBJECTIVE: The objective of this study was to determine how baseline blood pressure and incident hypertension related to antiretroviral therapy (ART) initiation, HIV-related inflammation and mortality in HIV-infected adults in a low-income country. METHODS: We conducted long-term follow-up of HIV-infected adults who had participated in a trial of early vs. delayed initiation of ART in Port-au-Prince, Haiti. Between 2005 and 2008, 816 HIV-infected adults were randomized to early (N = 408) vs. delayed ART (when CD4 cell count <200 cells/µl or AIDS-defining condition; N = 408). Blood pressure was measured every 3 months. Hypertension was diagnosed according to the Joint National Committee (JNC-7) guidelines. Biomarkers of inflammation and coagulation were measured from banked enrolment plasma samples. Survival analyses were performed using Stata 14. RESULTS: The median age at enrolment was 39 years. The median follow-up time was 7.3 years. The hypertension incidence rate was 3.41 per 100 person-years, and was similar in early and delayed ART groups. In multivariable models, independent predictors of incident hypertension were older age, higher BMI and plasma interleukin (IL)-6 levels (adjusted hazard ratio, aHR = 1.23, P < 0.001). Systolic pressure more than 140 mmHg at enrolment was associated with increased mortality (aHR = 2.47, P = 0.03) as was systolic pressure less than 90 mmHg (aHR = 2.25, P = 0.04). Prevalent and incident hypertension were also significantly associated with mortality. CONCLUSION: In a large prospective study of HIV-infected adults, we found a high incidence of hypertension associated with HIV-related inflammation. Baseline hypertension conferred a more than two-fold increased risk of death. Among HIV-infected adults in low-income countries, hypertension should be considered a serious threat to long-term survival.