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Importance: In the United States (U.S.), HIV-related health disparities have been reported, particularly among communities of color where the incidence of new HIV cases has been higher. However, it is unclear if disparities exist across different socioeconomic demographics, and whether they are associated with healthcare expenditures.Objectives: To evaluate the association between HIV status and healthcare expenditures, and assess the effect modification of socioeconomic factors on healthcare expenditures among people living with HIV (PLHIV) in the U.S.Methods: Using the Medical Expenditure Panel Survey (MEPS) database from 2011 to 2020, our study employed a serial cross-sectional design to compare total healthcare expenditures of adult household respondents aged ≥ 18 years with and without an HIV diagnosis. We used generalized linear models to estimate the marginal effects of socioeconomic factors on healthcare expenditures adjusting for potential confounders.Results: PLHIV had significantly higher total health care expenditures ($35,363, p

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell–mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared with Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe a tumor cell–extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy.See related Spotlight by van der Burg, p. 724.

Supplementary Figure 1. Gating strategy and representative flow cytometric plots of MC38 tumors from WT and Il11ra-/- hosts. Supplementary Figure 2. IL-11 has no effect on tumor-infiltrating immune cells in MC38 and CT26 tumors from WT and Il11ra-/- hosts. Supplementary Figure 3. IL-11 has no effect on PMA/Iono-induced IFNγ and TNFα production by IL-11RA-deficient CD4+ T cells. Supplementary Figure 4. Single cell profiling of IL11RA and IFNG expression in intra-tumoral CD4+ T cells from colon cancer patients.

Multiplex immunohistochemistry (mIHC) facilitates the simultaneous detection of various immune cell markers on a single tissue section. Here, we describe a protocol for an mIHC staining workflow using specific antibodies against CD4, CD8α, FOXP3, and B220 to identify distinct lymphocyte populations including T and B cells. This staining strategy can be adapted to include other cell markers to evaluate the immune contexture in murine tissues.

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell–mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared with Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe a tumor cell–extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy. See related Spotlight by van der Burg, p. 724.

Objective Diet-related quality of life has not been explored previously in patients with type 2 diabetes using sodium glucose cotransporter 2 (SGLT-2) inhibitors, the latest class of diabetes medications. In this study, we sought to describe the patient experience on SGLT-2 inhibitors and examine whether there have been improvements in dietary perception and satisfaction with these drugs. Methods Adults ≥40 years of age with type 2 diabetes and using SGLT-2 inhibitors for at least 1 month were recruited to take part in one-time 1-on-1 interviews. An interpretive descriptive methodology was used. Data collection and analysis occurred concurrently and a constant comparative analysis was used. Results An overall positive response to SGLT-2 inhibitor use was observed. Interviews revealed 3 themes: Recognizing, Reckoning and Realizing. In Recognizing, all patients reported a significant relationship with food that was typically negative and included feelings of food restriction and deprivation. Positive side effects of the drug in Reckoning included better glycemic control, weight loss and improved energy. Some participants were motivated in Realizing to pursue additional behavioural changes to improve their diabetes management. Conclusions An improved dietary-related quality of life was described by some participants. Although not all individuals were seen to move into the Realizing phase after initiating an SGLT-2 inhibitor, there appeared to be an opportunity to create a behaviour change after positive Reckoning experiences.

BackgroundThe world’s first malaria vaccine RTS,S provides only partial protection against Plasmodium falciparum infections. The explanation for such low efficacy is unclear. This study examined the associations of parasite genetic variations with binding affinity to human immunological proteins including human leukocyte antigen (HLA) and T cell receptors (TCR) involved in RTS,S-induced immune responses.MethodsMultiplicity of infections was determined by amplicon deep sequencing of merozoite surface protein 1 (PfMSP1). Genetic variations in the C-terminal of circumsporozoite protein (PfMSP1) gene were examined across 88 samples of P. falciparum collected from high and low transmission settings of Ghana. Binding interactions of PfMSP1 variants and HLA/TCR were analyzed using NetChop and HADDOCK predictions. Anti-CSP IgG levels were measured by ELISA in a subset of 10 samples.FindingsHigh polyclonality was detected among P. falciparum infections. A total 27 CSP haplotypes were detected among samples. A significant correlation was detected between the CSP and MSP multiplicity of infection (MOI). No clear clustering of haplotypes was observed by geographic regions. The number of genetic differences in PfCSP between 3D7 and non-3D7 variants does not influence binding interactions to HLA/T cells nor anti-CSP IgG levels. Nevertheless, PfCSP peptide length significantly affects its molecular weight and binding affinity to the HLA.InterpretationsThe presence of multiple non-3D7 strains among P. falciparum infections in Ghana impact the effectiveness of RTS,S. Longer PfCSP peptides may elicit a stronger immune response and should be considered in future version RTS,S. The molecular mechanisms of RTS,S cell-mediated immune responses related to longer CSP peptides warrants further investigations.

Multiplex immunohistochemistry (mIHC) enables simultaneous staining of multiple immune markers on a single tissue section. Mounting studies have demonstrated the versatility of mIHC in evaluating immune infiltrates in different diseases and the tumour microenvironment (TME). However, the majority of published studies are limited to the analysis of human patient samples. Performing mIHC on formalin-fixed paraffin-embedded (FFPE) mouse tissues, particularly with sensitive antigens, remain challenging. The aim of our study was to develop a robust and reproducible protocol to uncover the immune landscape in mouse FFPE tissues. Effective antibody stripping while maintaining sensitivity to antigens and tissue adhesion to the glass slide is critical in developing an mIHC panel to allow successive rounds of staining. Thus, we identified a highly efficient stripping method that preserves signal intensity and antigenicity to allow multiple rounds of staining. We subsequently optimised an mIHC workflow with antibodies specific against CD4, CD8α, FOXP3 and B220 to identify distinct T and B cell populations on mouse FFPE tissues. Lastly, the application of this mIHC panel was validated in a mouse model of inflammatory bowel cancer, two allograft mouse models of spontaneous colon adenocarcinoma and a sporadic mouse model of colon cancer. Together, these demonstrate the utility of the aforementioned protocol in establishing the quantity and spatial localisation of immune cells in different pathological tissues.

Understanding the molecular mechanisms that underpin the pleiotropic effects of IL6 in disease are critical to better inform when this cytokine should be therapeutically targeted to provide the most benefit to patients. This is particularly important for cancer and other pathologic conditions strongly linked to chronic inflammation. Shriki and colleagues provide mechanistic evidence that IL6 protects against chronic liver injury and its ensuing tumor development, thereby challenging the prevailing paradigm that IL6 always acts as a tumor-promoting cytokine. These observations contribute to an emerging view of dichotomous and complex activities of IL6 in solid malignancies and will help understand which patients under which circumstances receive the most benefit from therapies that interfere with IL6 signaling. See related article by Shriki et al., p. 4766

Donor-π-spacer-acceptor architectures are a favourable motif in the design of dyes for light harvesting applications. Organic compounds offer cost-effectiveness and synthetic design versatility, while inorganic compounds possess long term redox stability and wide range for absorption. Uniting both types of molecules allows utilization of these properties. Several projects were undertaken with the theme of a hybrid dye system and study of their redox stability. Chapter 1 gives a brief overview of the inorganic and organic compounds that paved the research in DSSC dyes. Chapter 2 details a review on copper(I) dyes in the literature and preliminary synthesis towards a D-π-A templated copper(I) dye. Chapter 3 looks into the robust potential of novel BODIPY dyes that utilize ferrocene as an electron rich donor. Chapter 4 represents a series of BODIPY-redox active donor dyads, the study of their redox stability provide insight on the decomposition pathway of these conjugates.

A wide deployment of malaria control tools have significantly reduced malaria morbidity and mortality across Africa. However, in the last five to seven years, there has been a resurgence of malaria in several African countries, raising the questions of whether and why current control mechanisms are failing. Since the first Plasmodium falciparum reference genome was published in 2002, few thousands more representing a broad range of geographical isolates have been sequenced. These advances in parasite genomics have improved our understanding of mutational changes, molecular structure, and genetic mechanisms associated with diagnostic testing, antimalarial resistance, and preventive measures such as vaccine development. In this chapter, we summarize the current progress on: (1) genomic characteristics of P. falciparum; (2) novel biomarkers and revolutionary techniques for diagnosing malaria infections; and (3) current vaccine targets and challenges for developing efficacious and long-lasting malaria vaccines.

OBJECTIVE The aim of the study was to evaluate remission of type 2 diabetes following a short-term intervention with insulin glargine, sitagliptin/metformin, and lifestyle approaches. RESEARCH DESIGN AND METHODS In this open multicenter trial, 102 patients with type 2 diabetes were randomized to 1) a 12-week intervention with sitagliptin/metformin, insulin glargine, and lifestyle therapy or 2) control group. Participants with HbA1c 10 mmol/L over 1 week, and reinitiation of diabetes medications with or without abnormal fasting plasma glucose (FPG) or 2-h plasma glucose on an oral glucose tolerance test (OGTT). Time-to-relapse analysis was conducted to compare the treatment groups with (primary analysis) and without (supplementary analysis) FPG/OGTT relapse criteria. RESULTS With the FPG/OGTT relapse criteria included, the hazard ratio (HR) of relapse was 0.72 (95% CI 0.47–1.10) in the intervention group compared with the control group (primary analysis), and the number of participants remaining in remission was not significantly different between treatment groups at 24, 36, 48, and 64 weeks. In the supplementary analyses without these criteria, HR of relapse was 0.60 (95% CI 0.39–0.95), and the number of participants remaining in remission was significantly higher (26 vs. 10%) in the intervention group at 36 weeks. CONCLUSIONS Although our primary outcome was not statistically significant, the tested approach deserves further study with further optimization of its components.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL- 6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130ΔSTAT allele (GP130ΔSTAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL- 6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

Interleukin-36 gamma (IL-36G) is a member of the IL-36 subfamily of cytokines and acts as a potent driver of inflammation. IL-36G has been extensively characterized in the pathogenesis of psoriasis and has been recently described to play roles in wound healing particularly in the gastrointestinal tract. However, the effects of IL-36G during cancer development including gastric cancer remain unexplored. Here, we show that IL-36G induced ERK1/2 activation in AGS, MKN1 and MKN45 human gastric cancer cell lines. Moreover, IL-36G induced colony formation, migration and invasion of these gastric cancer cell lines that was inhibited by the natural antagonist, IL-36 receptor antagonist (RA). Interrogation of TCGA stomach adenocarcinoma patient datasets revealed highly elevated IL-36G gene expression in human gastric cancer compared to normal tissue independent of tumor stage, and high IL-36G expression corresponded with poorer patient survival. Collectively, our results indicate for the first time that IL-36G supports a neoplastic phenotype in human gastric cancer cells.

Assessment of myocardial strain using cardiac magnetic resonance (CMR) tissue tracking provides prognostic information incremental to left ventricular ejection fraction and allows for detailed analysis of regional myocardial deformation. This study sought to evaluate the effect of percutaneous

AIMS: This study aimed to evaluate associations between coronary collaterals and myocardial viability as assessed by quantitative cardiac magnetic resonance (CMR) imaging in patients with a chronic coronary total occlusion (CTO). METHODS AND RESULTS: A total of 218 patients with a CTO who underwent CMR between 2013 and 2018 were included. A concomitant collateral connection (CC) score 2 and Rentrop grade 3 defined well-developed collaterals in 146 (67%) patients, whereas lower CC scores or Rentrop grades characterised poorly developed collaterals. Dysfunctional myocardium (50%) was observed in only 5% of CTO segments. In the CTO territory, SWT was greater (3.72±1.51 vs 3.05±1.60 mm, p

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4

A simple modular approach is presented which has been directed towards the synthesis of potentially monoanionic NN′N′′, NN′C, and NN′P pincer-type ligands. These pincers incorporate an amide functionality derived from the skeletal structure of readily available 2-(2-aminophenyl)-4,5-dioxooxazoles. All of the pincers are synthesized in moderate yields (up to 74%) and are characterised by nuclear magnetic spectroscopy (NMR), elemental analyses, and infrared (IR) spectroscopy. X-ray crystallography is also performed on the chiral and achiral alkyl halide precursors and on an oxide derivative of a pincer with a NN′P-atom donor set. A palladium derivative of one of the NN′N′′-pincers is shown to be an active catalyst for the addition of an allyl group to various benzaldehydes using n-Bu3Sn(allyl) as allyl source.

Current guidelines advocate viability assessment before revascularization of chronic coronary total occlusions (CTO). The present study evaluated associations between coronary collaterals and myocardial viability assessed by cardiac magnetic resonance (CMR) imaging in patients with a CTO. Patients

The tightly orchestrated temporal and spatial control of signal transducer and activator of transcription 3 (STAT3) activity in epithelial, immune and stromal cells is critical for wound healing and tissue repair. Excessive STAT3 activation within cancer cells and cells of the tumour microenvironment can be viewed as a neoplastic mimic of an inflammation-driven repair response that collectively promotes tumour progression. In addition to the canonical transcriptional pathways by which STAT3 promotes stem cell-like characteristics, survival, proliferation, metastatic potential and immune evasion, cytoplasmic STAT3 activity fuels tumour growth by metabolic and other non-transcriptional mechanisms. Here, we review the tumour-modulating activities of STAT3 in light of its role as a signalling node integrating inflammatory responses during wound healing. Accordingly, many of the cytokines that contribute to the para-inflammatory state of most solid malignancies converge on and underpin dysregulated STAT3 activity. Targeting of these cytokines, their cognate receptors and associated signalling cascades in clinical trials is beginning to demonstrate therapeutic efficacy, given that interference with STAT3 activity is likely to simultaneously curb the growth of cancer cells and augment antitumour immunity. This Review discusses how excessive signal transducer and activator of transcription 3 (STAT3) activation within cancer cells and cells of the tumour microenvironment can be viewed as a neoplastic mimic of an inflammation-driven repair response that promotes tumour progression.

Gestational diabetes mellitus is associated with an increased risk of type 2 diabetes mellitus and hypertension. Additionally, gestational dysglycemia has been associated with an increased risk of type 2 diabetes mellitus but not yet associated with hypertension subsequent to pregnancy in long-term follow-up. Therefore, we set out to examine this relationship as well as the role of race/ethnicity in modifying this relationship. We analyzed a prospective observational cohort followed between 1998 and 2007. There were 17 655 women with self-reported race/ethnicity and full-term, live births. A 1-hour 50 g oral glucose-load test and a 3-hour 100 g oral glucose-tolerance test enabled third trimester stratification of women into 1 of 4 glucose-tolerance groups: (1) normal (n=15 056); (2) abnormal glucose-load test (n=1558); (3) abnormal glucose-load and -tolerance tests (n=520); and (4) gestational diabetes mellitus (n=521). Women were then followed for a mean±standard deviation of 4.1±2.9 years after delivery for the development of hypertension. Although gestational diabetes mellitus was associated with an increased risk of hypertension after pregnancy (odds ratio [95% confidence interval]: 1.58 [1.02, 2.45]; P =0.04), dysglycemia defined by an abnormal glucose-load test predicted hypertension only among black women (4.52 [1.24, 16.52]; P =0.02). The risk of hypertension after pregnancy among dysglycemia groups not meeting criteria for gestational diabetes mellitus varied based on the race/ethnicity of the population. Further research on the implications of the intersection of race/ethnicity and gestational dysglycemia on subsequent hypertension is warranted.

Introduction The relationship between gestational diabetes mellitus (GDM) and postpregnancy mental health disorders has been inconsistently reported. Additionally, race/ethnicity data are limited. We sought to elucidate the intersection of these relationships. Methods We analyzed 18,109 women aged 18–40 with self-reported race/ethnicity. Women with (n = 659) and without (n = 14,461) GDM were followed for a median of 4.4 (interquartile range 1.4–6.8) and 4.0 (1.5–6.4) years, respectively, for incident mental health disorders. Multivariable repeated measures analyses were conducted to examine associations between GDM and postpregnancy mental health disorders, race/ethnicity, and the interaction of these factors. Results Women with compared to women without GDM were older (mean ± standard deviation, 32 ± 5 vs. 30 ± 5 years; P < .001) and had higher body mass index (29.0 ± 7.2 vs. 25.3 ± 5.2 kg/m2; P < .001). GDM was associated with increased risk for depression and anxiety after adjusting for age and pregnancy complications; however, loss of significance in the fully adjusted model for depression (odds ratio [95% CI]: 1.29 [0.98, 1.70]; P = .064) and anxiety (1.14 [0.83, 1.57], P = .421) suggested that clinical and socioeconomic factors influence this relationship. Hispanic compared to white women had a greater risk for depression (1.40 [1.15, 1.72]; P = .001), even after multivariable adjustment. The interaction between GDM and race was evident in complication-adjusted but not fully adjusted models. Conclusions The incidence of mental health disorders subsequent to GDM was attenuated after adjustment for clinical and socioeconomic factors. Moreover, race/ethnicity influenced this relationship. Further investigation is warranted to clarify potential underlying mechanisms.

Introduction During a pregnancy complicated by diabetes, the human placenta undergoes a number of functional and structural pathologic changes, such as increased placental weight and increased incidence of placental lesions including villous maturational defects and fibrinoid necrosis. The pathologic findings reported have differed among studies, potentially reflecting differences in type of diabetes, study methodology, or glycemic control of study participants. Alternatively, these discrepancies may represent different biologic adaptations to distinct metabolic diseases. Methods We conducted a comprehensive review of English language citations in Pubmed and Embase using the keywords “diabetes”, “placenta”, AND “pathology”. Abstracts were reviewed for relevance then full-text articles were reviewed in order to extract a comprehensive summary of current pathological findings associated with pregestational and gestational diabetes mellitus, as well as an understanding of the impact of glycemic control on placental pathology. Results Placental abnormalities most consistently associated with maternal diabetes are an increased incidence of villous immaturity, increased measures of angiogenesis, and increased placental weight. Conclusions The literature suggests that, despite similarities in placental abnormalities, differences in placental pathology may reflect differences in pathophysiology among different types of diabetes. Consequently, standardization of terminology used to define placental lesions is warranted. Moreover, further research is needed to investigate the impact of pathophysiology, glycemic control and clinical factors, such as infant sex, weight and race, on placental structure and function.

Porphyromonas gingivalis is a keystone pathogen in chronic periodontitis. Its expression of gingipain proteases (Kgp and RgpA/B) is central to the stimulation of chronic inflammation. In this study, we investigated the inflammatory response of oral epithelial cells to P. gingivalis. The cells responded by upregulating the expression of the orphan chemokine CXCL14. The stimulation of CXCL14 expression was largely triggered by the gingipain proteases and was dependent on the host protease-activated receptor PAR-3. Significantly, CXCL14 expression was transcriptionally repressed in response to epidermal growth factor (EGF)-induced activation of the MEK-ERK1/2 pathway. P. gingivalis overcomes the repression of CXCL14 via the gingipain protease-mediated degradation of EGF. Therefore, P. gingivalis not only directly stimulates CXCL14 expression via PAR-3 but also promotes its expression by antagonising EGF signalling. In addition to chemotactic activity, some chemokines also have antimicrobial activities. CXCL14 was demonstrated to have bactericidal activity, against commensal oral streptococci associated with health. Notably though, P. gingivalis was not susceptible to killing by CXCL14, potentially because the gingipain proteases can degrade CXCL14. This suggests that the stimulation of dysregulated CXCL14 expression by P. gingivalis may help promote dysbiosis and the development of chronic periodontitis.

Intercellular communication between tumor cells, immune cells and the stroma characterises the tumor microenvironment, which is instrumental for establishing the ecological niche that fosters tumor growth and metastasis. While tumor cell intrinsic STAT3 signaling provides a crucial axis to support cell proliferation and survival, it also regulates many activities of the non-transformed cells that collectively make up the tumor microenvironment. Accordingly, excessive activation of STAT3 is a hallmark of many malignancies, and often occurs in response to cytokines of the IL-6 and IL-10 families. However, tumor extrinsic STAT3 signaling also regulates the effector function of tumor-associated immune and stromal cells, which support the growth of tumors by suppressing the host's anti-tumor immune response. Given that STAT3 mediates tumorigenic effects in many cell types, the molecular players of STAT3 signaling and its upstream JAK kinases provide viable therapeutic targets for the treatment of cancer. Here we provide an update on novel insights into the role of STAT3 in immune suppression and describe current therapeutic strategies that target the JAK/STAT3 signaling axis for the treatment of malignancies.

Introduction: Gestational diabetes mellitus (GDM) is associated with increased maternal cardiovascular disease (CVD) risk manifest as hypertension subsequent to pregnancy. The impacts of dysglycemia and race/ethnicity on hypertension risk have been examined; however, the study of putative risk factors has been limited. Hypothesis: We hypothesize that GDM and gestational dysglycemia are sufficiently predictive of hypertension subsequent to pregnancy and that a risk score based on degree of dysglycemia can be used to identify at-risk patients. Methods: We examined a cohort of 23,223 women who presented for prenatal care to the Massachusetts General Hospital Obstetrical Department between September 1998 and January 2007. We selected women, ages 18 to 40 years, free of CVD or pre-GDM, with complete glycemic and demographic data who delivered a singleton, live birth. Each woman’s initial pregnancy was selected in order to not violate the independence assumption. The population was stratified by incident hypertension subsequent to pregnancy. Logistic regression models (with and without stepwise selection) were used to identify significant maternal risk factors based on their predictive performance. Finally, the risk prediction score was developed from β-coefficients in multivariable Weibull models. Results: The study sample comprised of 11,161 women, 547 (4.9%) of whom developed hypertension during 4.2 years (median) follow-up. Significant predictors of hypertension included age, body mass index, systolic and diastolic blood pressures, parity, dysglycemia, and race/ethnicity. These factors were used to develop a risk score for subsequent hypertension risk. The final risk score achieved a c-statistic of 0.76, indicating moderate discriminative ability (Figure 1). Conclusions: We developed a risk score that may be used to identify patients with an elevated risk of hypertension subsequent to a pregnancy complicated by dysglycemia. Further external validation is warranted to determine clinical effectiveness.

Colony stimulating factor-1 (CSF-1) mediates its pleiotropic effects on macrophages through the CSF-1 receptor (CSF-1R), a receptor tyrosine kinase. Current models of CSF-1 signalling imply that the CSF-1R activates signalling pathways exclusively at the plasma membrane and the subsequent internalisation of the CSF-1R simply facilitates its lysosomal degradation in order to prevent on-going signalling. Here, we sought to establish if the CSF-1R may in fact continue to signal following its internalisation. Erk1/2, Akt and Stat3 activation were abrogated when the internalisation of the CSF-1R was impaired, with the effects on Stat3 distinct from those for Erk1/2 and Akt. Pharmacologic inhibition of the CSF-1R following its internalisation resulted in less sustained Erk1/2 and Akt activity, whereas Stat3 activity was unaffected. Significantly, the suppressive effects of the CSF-1R inhibitor on the up-regulation of gene expression by CSF-1 (e.g. cyclin D1 and Bcl-xL gene expression) were comparable irrespective of whether the inhibitor was added prior to CSF-1 stimulation or following the internalisation of the CSF-1R. Similarly, pharmacologic inhibition of Erk1/2 (or Akt) activity either prior to CSF-1 stimulation or subsequent to CSF-1R internalisation had comparable effects on the regulation of gene expression by CSF-1. Together, our data argue that key signalling responses to CSF-1 depend on the ability of the CSF-1R to signal from endosomes following its internalisation, thus adding an important spatiotemporal aspect to CSF-1R signalling.