New Target For Early Intervention Research Articles

Causal associations between the insulin-like growth factor family and sarcopenia: a bidirectional Mendelian randomization study.

Insulin-like growth factor (IGF) is closely associated with sarcopenia, yet the causal relationship of this association remains unclear. This study aims to explore the potential causal relationship between members of the IGF family and sarcopenia from a genetic perspective through bidirectional Mendelian randomization (MR) analysis using two-sample datasets. Five genetically predicted factors of the IGF family (IGF-1, IGF-1R, IGF-2R, IGFBP-3, IGFBP-7) as one sample, while four relevant features of sarcopenia (low hand grip strength, appendicular lean mass, whole body fat-free mass, and walking pace) as another sample, in conducting a two-sample MR analysis. The forward MR results of the relationship between IGF and sarcopenia showed that elevated levels of IGF-1 reduced the risk of low hand grip strength (OR = 0.936, 95% CI=0.892-0.983, P = 0.008) and increased appendicular lean mass of the extremities and whole body fat-free mass (OR = 1.125, 95% CI=1.070-1.182,P = 0.000; OR =1.076, 95% CI=1.047-1.106, P=0.000), reduced the risk of sarcopenia. Elevated IGF-1R also favored an increase in whole body fat-free mass (OR=1.023, 95% CI=1.008-1.038, P =0.002), and the appendicular lean mass trait was more pronounced with elevated IGFBP-3 and IGFBP-7 (OR=1.034, 95% CI=1.024-1.044, P =0.000; OR=1.020, 95% CI=1.010-1.030, P=0.000). Inverse MR results of the effect of sarcopenia on IGF showed that decreased hand grip strength may elevate IGF-1 levels (OR=1.243, 95% CI=1.026-1.505,P =0.027), whereas improvements in appendicular lean mass, whole body fat-free mass traits, and increased walking pace decreased IGF-1 levels (OR=0.902, 95% CI: 0.877-0.927, P = 0.000; OR=0.903, 95% CI=0.859-0.949,P = 0.000; OR=0.209, 95% CI=0.051-0.862,P = 0.045). Also decreased hand grip strength may elevate IGF-1R levels (OR=1.454, 95% CI=1.108-1.909, P =0.007), and appendicular lean mass stimulated high expression of IGFBP-1 (OR=1.314, 95% CI=1.003-1.722, P =0.047). Heterogeneity and pleiotropy were not detected in all results, and the results were stable and reliable. There is a bi-directional causal association between IGF family members and the risk of sarcopenia, which provides a more adequate basis for early biological monitoring of sarcopenia and may provide new targets for early intervention and treatment of sarcopenia.

Females exhibit higher GluA2 levels and outperform males in active place avoidance despite increased amyloid plaques in TgF344-Alzheimer’s rats

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is most prevalent in females. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, comparing events between sexes in early-stage AD pathology may reveal more effective therapeutic targets of intervention. To address sex differences, we analyzed early-stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1ΔE9) mutations that develops progressive age-dependent AD pathology similar to humans. Tg-AD females significantly outperformed Tg-AD males in the active place avoidance (aPAT) test that assesses hippocampal-dependent spatial learning and memory. However, comparisons between Tg-AD male or female rats and their WT counterparts showed significant deficits for female but not male rats. Nevertheless, Tg-AD females experienced significantly less hippocampal neuronal loss with higher GluA2 subunit levels than Tg-AD males. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques than Tg-AD males. Thus, we propose that GluA2 may provide a neuroprotective function for Tg-AD females in our rat model by mitigating cognitive impairment independently of amyloid plaques. Elucidating this protective mechanism in AD could lead to new targets for early intervention.

Predictive role of endothelial cell activation in cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukaemia.

CD19‐target chimeric antigen receptor (CAR)‐T cell therapy is highly effective for relapsed/refractory (R/R) acute lymphoblastic leukaemia (ALL), but is often complicated by cytokine release syndrome (CRS), which is potentially life‐threatening. Endothelial cells are the core regulator of CRS in many infectious diseases and may also play a key role after CAR‐T cell therapy. We provided a detailed clinical, laboratory description and endothelial cell activation biomarkers in patients with CRS. Endothelial cell activation was associated with occurrence, development and severity of CRS, manifested by decreased serum angiopoietin (Ang)‐1 levels and increased levels of von Willebrand Factor (VWF), Ang‐2, Ang‐2:Ang‐1, sE‐selectin, soluble intercellular adhesion molecule (sICAM‐1) and soluble vascular cell adhesion molecule (sVCAM)‐1. Besides, the endothelial activation was correlated with the hepatic, kidney and hematopoietic dysfunction in CRS patients. After infusion of CAR‐T cells, we detected changes of endothelial activation‐related biomarkers within 36 hours in patients who subsequently developed CRS, especially severe CRS. Using top tree models, we could predict which patients would develop CRS, especially severe CRS, or identify the severity of CRS by certain biomarkers of endothelial activation. These data provide a new idea and will help identify new targets for early intervention and prevention of CRS.

Second-trimester maternal lipid profiles rather than glucose levels predict the occurrence of neonatal macrosomia regardless of glucose tolerance status: A matched cohort study in Beijing.

The mechanism underlying fetal overgrowth during pregnancy remains elusive. We aimed to establish a predictive model to identify the high-risk individuals with macrosomia in the second trimester of pregnancy. A total of 2577 pregnant women with a routine 75-g oral glucose tolerance test during 24-28 gestational weeks were screened in a prospective cohort. Gestational diabetes mellitus (GDM) cases were 1:1 matching with age (±2 years) in normal glucose tolerance (NGT) ones from the same region. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were performed to determine the index and its inflection point for predicting macrosomia occurrence. The data of perinatal outcomes of 565 GDM and 549 NGT who had given birth to single live babies at term were analyzed. Notably, we found serum apolipoprotein B (ApoB) level higher than 4.04 g/L combined with triglycerides (TG)/high-density lipoprotein cholesterol (HDLC) ratio above 1.36 formed the predictive model in both groups. The area under the ROC curve of this predictive model included ApoB and TG/HDL-C reached 0.807 (95% CI: 0.771-0.873) with a sensitivity of 71.9% and a specificity of 78.6%. Mediation analysis revealed that ApoB and TG/HDL-C ratio mediated the harmful effect of FBG on the risk of macrosomia. Maternal ApoB levels and TG/HDL-C ratio could predict macrosomia occurrence in pregnancy, which might be a new target for early intervention to prevent excess fetal growth.

Abstract B06: Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation

Abstract The primary goal of this study is to determine whether sustained expression of the acinar differentiation determinant, PTF1A, is sufficient to prevent and/or reverse KRAS-driven pancreatic cancer initiation. With a 5-year survival of only ~6%, pancreatic ductal adenocarcinoma (PDAC) remains one of the worst prognoses in medicine. In most clinical cases, PDAC is detected after the primary tumor has metastasized, leaving limited treatment options. Our lab is interested in understanding the initiating events that drive early tumorigenesis, which may provide new targets for early intervention. Activating mutations in the “un-druggable” proto-oncogene KRAS are found in over 90% of human PDAC cases, and expression of an oncogenic Kras mutant (KrasG12D) in the acinar epithelium of adult mice recapitulates formation of precancerous pancreatic intraepithelial neoplasia (PanIN) [1]. Because formation of PanINs takes months in these mouse models despite nearly ubiquitous KrasG12D expression, we hypothesized that acinar cell differentiation programs might suppress the transforming ability of this oncogene. Indeed, recent conditional-knockout studies from our lab demonstrate that downregulation of Ptf1a, the master transcriptional regulator of acinar cell differentiation, is rate-limiting for KRAS-driven PanIN formation and subsequent PDAC formation [2]. These findings suggest that acinar cell differentiation may serve as a barrier to tumor development by blocking the earliest phases of oncogenesis. We therefore hypothesized that sustaining Ptf1a expression during pancreatic cancer initiation/progression would inhibit or reverse disease. To test this hypothesis, we generated a Cre- and doxycycline-dependent Ptf1a gain-of function (GOF) mouse model on a KrasG12D background. Eight weeks after we induced recombination, mice expressing both oncogenic KrasG12D and GOF-Ptf1a had a significantly reduced PanIN burden compared to mice expressing KrasG12D alone, suggesting that preservation of acinar cell differentiation does limit pancreatic tumor initiation. Examination of PanINs in KrasG12D + GOF-Ptf1a pancreata revealed that PTF1A expression was completely lost in the few precancerous lesions that did form, suggesting that the cells contributing to these lesions were escapers that did not express transgenic Ptf1a. Taken together, these results suggest that silencing of Ptf1a is a necessary step in PDAC initiation. In ongoing studies, we are using KrasG12D + GOF-Ptf1a mice to test whether reintroduction of Ptf1a into established PanINs can revert these cells to a quiescent phenotype in vivo, and we will present these preliminary data at this meeting. Our results to date suggest that acinar differentiation provides a novel, epigenetic barrier to tumor initiation and highlight the potential importance of cell differentiation in solid tumors [3]. Going forward, we propose that studying cell differentiation in other tumor types may provide insight to disease initiation and potential treatment. 1. De La, O.J., et al., Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A, 2008. 105(48): p. 18907-12. 2. Krah, N.M., et al., The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Elife, 2015. 4. 3. Krah, N.M. and L.C. Murtaugh, Differentiation and inflammation: best enemies in gastrointestinal carcinogenesis. Under review. Citation Format: Nathan M. Krah, Deanne E. Yugawa, Julie A. Straley, Shuba M. Narayanan, Ana C. Azevedo-Pouly, L. Charles Murtaugh. Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B06.

Correlation between unexplained recurrent spontaneous abortion with CD4+CD25+ regulatory T-cell and killer cell immunoglobulin-like receptor levels.

The present study investigated the correlation between unexplained recurrent spontaneous abortion (URSA) with CD4+CD25+ regulatory T-cell (Treg) and killer cell immunoglobulin-like receptor (KIR)-2DL1 levels. A total of 76 URSA patients were enrolled (35 without pregnancy, Group A, and 41 with early abortion, Group B). Additionally, 30 patients who received a regular abortion as planned (Group C) and 30 healthy volunteers (Group D) were selected. Peripheral venous blood and fresh decidual tissue samples were obtained from all the patients, and flow cytometry was performed to detect CD4+CD25+Treg and Foxp3 transcription factor levels. mRNA and protein KIR-2DL1 expression levels were assayed using quantitative PCR and western blot analysis, respectively. No statistically significant differences in peripheral venous blood CD4+CD25+Treg/CD4+ and Foxp3+/CD4+CD25+Treg cell proportions were found among the groups (P>0.05). However, the decidual tissues of Group C presented significantly higher levels of both cell types versus other groups (P<0.05). No statistically significant differences were found in comparisons among Groups A, B, and D (P>0.05). In peripheral venous blood, mRNA and protein KIR-2DL1 expression levels in Group C were significantly higher than those in the other three groups (P<0.05), but again, there were no statistically significant differences among Groups A, B, and D (P>0.05). In decidual tissues, KIR-2DL1 levels were significantly higher in Group C relative to Groups A, B, and D (P<0.05). Decreased CD4+CD25+Treg counts and KIR-2DL1 expression levels were closely associated with the onset of URSA. CD4+CD25+Tregs mainly exert their effects on decidual tissues, while KIR-2DL1 can act on peripheral venous blood and decidual tissues. These may present new targets for early intervention in URSA.

Anti-LG3 Antibodies Aggravate Renal Ischemia-Reperfusion Injury and Long-Term Renal Allograft Dysfunction.

Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes.

Impaired renal function is associated with brain atrophy and poststroke cognitive decline.

To evaluate the interrelationship among impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. The Tel Aviv Brain Acute Stroke Cohort study is a prospective cohort of mild-moderate ischemic stroke/TIA survivors without dementia who underwent a 3T MRI and were cognitively assessed at admission and for 24 months following stroke. Renal function was evaluated at admission by creatinine clearance (CCl) estimation. The volumes of ischemic lesions and preexisting white matter hyperintensities (WMH), brain atrophy, and microstructural changes of the normal-appearing white matter tissue were measured using previously validated methods. Baseline data were available for 431 participants. Participants with a CCl <60 mL/min at baseline performed significantly worse in all cognitive tests over time (p = 0.001) than those with a CCl ≥60 mL/min and had larger WMH volume and cortical atrophy and smaller hippocampal volume (all p < 0.001). After 2 years, 15.5% of the participants were diagnosed with cognitive impairment. Multiple logistic regression analysis, controlling for traditional risk factors, suggested CCl <60 mL/min at baseline as a significant predictor for the development of cognitive impairment 2 years after the index stroke (odds ratio 2.01 [95% confidence interval 1.03-3.92], p = 0.041). Impaired renal function is associated with increased WMH volume and cortical atrophy, known biomarkers of the aging brain, and is a predictor for cognitive decline 2 years after stroke/TIA. Decreased renal function may be associated with cerebral small vessel disease underlying poststroke cognitive decline, suggesting a new target for early intervention.

Abstract 47: Renal Function, MRI Brain Changes and Post-stroke Cognitive Impairment

Background and Purpose: Limited data exist regarding the relationship between chronic kidney disease (CKD) and post-stroke cognitive impairment. We aimed to evaluate the impact of impaired renal function on markers of cerebral small vessel disease, brain pathology and cognitive decline in a longitudinal post-stroke cohort. Methods: The TABASCO study is a prospective cohort of mild-moderate ischemic stroke/TIA patients, who underwent a 3T MRI, and were assessed for their cognitive function at hospital admission, 6, 12 and 24 months following stroke, using the Montreal Cognitive Assessment (MoCA) and a computerized cognitive testing battery. Estimated renal function was evaluated at admission using the Cockcroft Gault creatinine clearance (CCl) equation. The volume and integrity of preexisting white matter hyperintensity (WMH), ischemic lesions and brain atrophy on MRI were measured. Results: Baseline data were available for 462 subjects (mean age 67.4 years, 60.4% males). Participants with a CCl &lt;60 ml/min performed significantly worse in all cognitive tests over time (p&lt;0.001) than those with a CCl ≥60 ml/min. CKD was also associated with enlarged WMH volume (p&lt;0.001), cortical atrophy (p=0.002) and smaller hippocampal volume (p&lt;0.001). After the 2-years follow-up, 16% of the participants developed cognitive impairment. Multiple logistic regression analysis controlling for traditional risk factors, including cardiovascular, showed a significant association of CCl &lt;60 ml/min at baseline with development of cognitive impairment at the end of follow-up [odds ratio: 2.99 (95% confidence interval: 1.08-8.27), p = 0.035]. Conclusions: Decreased renal function is associated with increased WMH volume and cortical atrophy, known biomarkers of the aging brain, and is a predictor of lower performances in cognitive tests and cognitive decline 2 years after stroke/TIA. CKD may contribute to cerebral small vessel disease that underlies post-stroke cognitive decline, suggesting a new target for early intervention.

The proximal prodrome to first episode mania – a new target for early intervention

Affective psychoses and bipolar disorders have been neglected in the development of early intervention strategies. This paper aims to gather current knowledge on the early phase of bipolar disorders in order to define new targets for early intervention. Literature review based on the main computerized databases (MEDLINE, PUBMED and PSYCHLIT) and hand search of relevant literature. Based on current knowledge, it is likely that an approach aiming at the identification of impending first-episode mania is the most realistic and manageable strategy to promote earlier treatment. During the period preceding the onset of the first manic episode, patients go through a prodromal phase marked by the presence of mood fluctuation, sleep disturbance, and other symptoms such as irritability, anger, or functional impairment. Additionally, various risk factors and markers of vulnerability to bipolar disorders have been identified. In the few months preceding first-episode mania, patients go through a prodrome phase (proximal prodrome) that could become an important target for early intervention. However, considering the low specificity of the symptoms observed during this phase, criteria defining high-risk profiles to first-episode mania should also include certain risk factors or markers of vulnerability. While more research is needed in high-risk groups (e.g., bipolar offspring), retrospective studies conducted in first-episode mania cohorts could provide valuable information about this critical phase of the illness.

Natural IgM-mediated innate autoimmunity: a new target for early intervention of ischemia–reperfusion injury

Recent studies showed that innate autoimmunity is an early mechanism for ischemia–reperfusion (I/R) injury. Results from different animal models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving a complement system, which is activated by autoreactive natural IgM. Moreover, ischemia-specific self-targets were identified. In contrast to the unsuccessful attempts in the past to treat I/R injury, targeting natural IgM-mediated innate autoimmunity may open a new avenue for early intervention.