PFAS-Contaminated Pesticides Applied near Public Supply Wells Disproportionately Impact Communities of Color in California.

Contaminated drinking water from widespread environmental pollutants such as perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a rising threat to public health. PFAS monitoring in groundwater is limited and fails to consider pesticides found to contain PFAS as a potential contamination source. Given previous findings on the disproportionate exposure of communities of Color to both pesticides and PFAS, we investigated disparities in PFAS-contaminated pesticide applications in California based on community-level sociodemographic characteristics. We utilized statewide pesticide application data from the California Department of Pesticide Regulation and recently reported concentrations of PFAS chemicals detected in eight pesticide products to calculate the areal density of PFAS applied within 1 km of individual community water systems' (CWSs) supply wells. Spatial regression analyses suggest that statewide, CWSs that serve a greater proportion of Latinx and non-Latinx People of Color residents experience a greater areal density of PFAS applied and greater likelihood of PFAS application near their public supply wells. These results highlight agroecosystems as potentially important sources of PFAS in drinking water and identify areas that may be at risk of PFAS contamination and warrant additional PFAS monitoring and remediation.

FOXM1 Participates in Trophoblast Migration and Early Trophoblast Invasion: Potential Role in Blastocyst Implantation.

Successful implantation requires coordinated migration and invasion of trophoblast cells into a receptive endometrium. Reduced forkhead box M1 (FOXM1) expression limits trophoblast migration and angiogenesis in choriocarcinoma cell lines, and in a rat model, placental FOXM1 protein expression was significantly upregulated in the early stages of pregnancy compared to term pregnancy. However, the precise role of FOXM1 in implantation events remains unknown. By analyzing mice blastocysts at embryonic day (E3.5), we have demonstrated that FOXM1 is expressed as early as the blastocyst stage, and it is expressed in the trophectoderm of the blastocyst. Since controlled oxygen tension is determinant for achieving normal implantation and placentation and a chronic hypoxic environment leads to shallow trophoblast invasion, we evaluated if FOXM1 expression changes in response to different oxygen tensions in the HTR-8/SVneo first trimester human trophoblast cell line and observed that FOXM1 expression was significantly higher when trophoblast cells were cultured at 3% O2, which coincides with oxygen concentrations in the uteroplacental interface at the time of implantation. Conversely, FOXM1 expression diminished in response to 1% O2 that resembles a hypoxic environment in utero. Migration and angiogenesis were assessed following FOXM1 knockdown and overexpression at 3% O2 and 1% O2, respectively, in HTR-8/SVneo cells. FOXM1 overexpression increased transmigration ability and tubule formation. Using a 3D trophoblast invasion model with trophospheres from HTR-8/SVneo cells cultured on a layer of MATRIGEL and of mesenchymal stem cells isolated from menstrual fluid, we observed that trophospheres obtained from 3D trophoblast invasion displayed higher FOXM1 expression compared with pre-invasion trophospheres. Moreover, we have also observed that FOXM1-overexpressing trophospheres increased trophoblast invasion compared with controls. HTR-8/SVneo-FOXM1-depleted cells led to a downregulation of PLK4, VEGF, and MMP2 mRNA expression. Our current findings suggest that FOXM1 participates in embryo implantation by contributing to trophoblast migration and early trophoblast invasion, by inducing transcription activation of genes involved in these processes. Maternal-fetal communication is crucial for trophoblast invasion, and maternal stromal cells may induce higher levels of FOXM1 in trophoblast cells.

Environmental management of asthma in clinical practice: Results from the 2012 National Ambulatory Medical Care Survey.

Background: The National Asthma Education and Prevention Program guidelines emphasize environmental control as an integral part of asthma management; however, limited national-level data exist on how clinicians implement environmental control recommendations. Objective: We analyzed data on clinicians' self-reported use of recommended environmental control practices in a nationally representative sample (n = 1645) of primary care physicians, asthma specialists, and advanced practice providers from the National Asthma Survey of Physicians, a supplemental questionnaire to the 2012 National Ambulatory Medical Care Survey. Methods: We examined clinician and practice characteristics as well as clinicians' decisions and strategies regarding environmental trigger assessment and environmental control across provider groups. Regression modeling was used to identify clinician and practice characteristics associated with implementation of guideline recommendations. Results: A higher percentage of specialists assessed asthma triggers at home, school, and/or work than primary care or advanced practice providers (almost always: 53.6% vs 29.4% and 23.7%, respectively, P < .001). Almost all clinicians (>93%) recommended avoidance of secondhand tobacco smoke, whereas recommendations regarding cooking appliances (eg, proper ventilation) were infrequent. Although assessment and recommendation practices differed between clinician groups, modeling results showed that clinicians who reported almost always assessing asthma control were 5- to 6-fold more likely to assess environmental asthma triggers. Use of asthma action plans was also strongly associated with implementation of environmental control recommendations. Conclusions: Environmental assessment and recommendations to patients varied among asthma care providers. High adherence to other key guideline components, such as assessing asthma control, was associated with environmental assessment and recommendation practices on environmental control.

Towards Understanding the Development of Breast Cancer: The Role of RhoJ in the Obesity Microenvironment.

Obesity is a growing pandemic with an increasing risk of inducing different cancer types, including breast cancer. Adipose tissue is proposed to be a major player in the initiation and progression of breast cancer in obese people. However, the mechanistic link between adipogenicity and tumorigenicity in breast tissues is poorly understood. We used in vitro and in vivo approaches to investigate the mechanistic relationship between obesity and the onset and progression of breast cancer. In obesity, adipose tissue expansion and remodeling are associated with increased inflammatory mediator's release and anti-inflammatory mediators' reduction.. In order to mimic the obesity micro-environment, we cultured cells in an enriched pro-inflammatory cytokine medium to which we added a low concentration of beneficial adipokines. Epithelial cells exposed to the obesity micro-environment were phenotypically transformed into mesenchymal-like cells, characterized by an increase in different mesenchymal markers and the acquisition of the major hallmarks of cancerous cells; these include sustained DNA damage, the activation of the ATR-Chk2 pathway, an increase in proliferation rate, cell invasion, and resistance to conventional chemotherapy. Transcriptomic analysis revealed that several genes, including RhoJ, CCL7, and MMP9, acted as potential major players in the observed phenomenon. The transcriptomics findings were confirmed in vitro using qRT-PCR and in vivo using high-fat-diet-fed mice. Our data suggests RhoJ as a potential novel molecular driver of tumor development in breast tissues and a mediator of cell resistance to conventional chemotherapy through PAK1 activation. These data propose that RhoJ is a potential target for therapeutic interventions in obese breast cancer patients.

Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives.

Cancer is a global health challenge with high morbidity and mortality rates. However, conventional cancer treatment methods often have severe side effects and limited success rates. In the last decade, extensive research has been conducted to develop safe, and efficient alternative treatments that do not have the limitations of existing anticancer medicines. Plant-derived compounds have shown promise in cancer treatment for their anti-carcinogenic and anti-proliferative properties. Rosmarinic acid (RA) and carnosic acid (CA) are potent polyphenolic compounds found in rosemary (Rosmarinus officinalis) extract. They have been extensively studied for their biological properties, which include anti-diabetic, anti-inflammatory, antioxidant, and anticancer activities. In addition, RA and CA have demonstrated effective anti-proliferative properties against various cancers, making them promising targets for extensive research to develop candidate or leading compounds for cancer treatment. This review discusses and summarizes the anti-tumor effect of RA and CA against various cancers and highlights the involved biochemical and mechanistic pathways.

Race, Racism, and Drinking Water Contamination Risk From Oil and Gas Wells in Los Angeles County, 2020.

Objectives. To evaluate the potential for drinking water contamination in Los Angeles (LA) County, California, based on the proximity of supply wells to oil and gas wells, and characterize risk with respect to race/ethnicity and measures of structural racism. Methods. We identified at-risk community water systems (CWSs) as those with supply wells within 1 kilometer of an oil or gas well. We characterized sociodemographics of the populations served by each CWS by using the 2013-2017 American Community Survey. We estimated the degree of redlining in each CWS service area by using 1930s Home Owners' Loan Corporation security maps, and characterized segregation by using the Index of Concentration at the Extremes. Multivariable regression models estimated associations between these variables and CWS contamination risk. Results. A quarter of LA County CWSs serving more than 7 million residents have supply wells within 1 kilometer of an oil or gas well. Higher percentages of Hispanic, Black, and Asian/Pacific Islander residents and a greater degree of redlining and residential segregation were associated with higher contamination risk. Conclusions. Redlining and segregation predict drinking water contamination risks from oil development in LA County, with people of color at greater risk. (Am J Public Health. 2023;113(11):1191-1200. https://doi.org/10.2105/AJPH.2023.307374).

Potential anticancer properties of calotropis procera: An investigation on breast and colon cancer cells.

Calotropis procera is a perennial flowering plant of the Apocynaceae family, traditionally used in medicine to treat various ailments. Recent investigations have revealed its potential therapeutic activities such as anti-inflammatory, gastroprotective, analgesic, anti-obesity, and anti-diabetic properties. RP-HPLC qualitatively and quantitatively evaluated the phenolic acids and flavonoids in the ethanolic extract at two different wavelengths, 280 and 330 nm. In addition, total phenolic and flavonoid contents were measured via spectrophotometric determination in addition to the antioxidant activity. The antiproliferative effects of C. procera were investigated on two cancer cell lines: human colon (HCT-116) and breast (MCF-7) cancer. Several methods were utilised to analyse the effectiveness of the plant extract on the cytotoxicity, apoptosis, cell cycle progression, genes involved in the cell cycle, and protein expression profiles of HCT-116 and MCF-7 cells. These included the MTT assay, Annexin V-FITC/PI, analysis of the cell cycle, and Western blot. Results indicated that ferulic and caffeic acids were the major compounds at λmax 280 nm (1.374% and 0.561%, respectively), while the major compounds at λmax 325 nm were kaempferol and luteolin (1.036% and 0.512%, respectively). The ethanolic extract had significantly higher antioxidant activity (80 ± 2.3%) compared to ascorbic acid (90 ± 3.1%). C. procera extract exhibited dose-dependent cell growth inhibition, with an estimated IC50 of 50 µg/mL for MCF-7 and 55 µg/mL for HCT-116 cells at 24 h. Annexin V-FITC/PI confirmed the induction of apoptosis. Remarkably, cell cycle arrest occurred at the sub-G1 phase in MCF-7 cells, while in HCT-116 cells, it was observed at the G2-M phase. The sub-G1 arrest was associated with dysregulation of Akt, p-AKT, mTOR, and p-mTOR proteins, as confirmed by the Western blot analysis, while downregulation of CDK1, cyclin B1, and survivin caused G2-M arrest.

Assessment of long-term cognitive dysfunction in older patients who undergo heart surgery.

INTRODUCTION: Older patients are more likely to have cognitive dysfunction, and a great proportion of patients undergone surgical procedures are older adults. Postoperative cognitive dysfunction (POCD) has been shown as a consistent complication after major surgical procedures such as heart surgery. AIM: To determine the presence of long-term POCD in ≥65-year-old patients undergoing coronary artery bypass grafting and aortic valve replacement, and to establish related risk factors. METHODS: We prospectively and sequentially included 44 patients with coronary disease and aortic stenosis scheduled for heart surgery. Follow-up of all patients was standardized and a neurocognitive evaluation were performed preoperatively and at 1, 6 and 12 months after surgery. RESULTS: Patients experienced a significantly postoperative cognitive dysfunction (33.5%, 63.4% and 38.9% at 1, 6 and 12 months, respectively) from baseline (20.5%). Patient-associated aspects such as age (p<0.01), history of smoking (p<0.01), arterial hypertension (p=0.022), diabetes mellitus (p=0.024), heart failure (p=0.036) and preoperative cognitive dysfunction (p<0.01), and surgery-associated aspects such as EuroSCORE (p<0.01) and operation time (p<0.01) were identified as related risk factors. CONCLUSIONS: Older patients who underwent heart surgery had long-term POCD. Both patient- and surgery-related risk factors were established as related risk factors. These findings suggest that the prevalence of cognitive dysfunction after cardiac surgery in older patients could be related to a possible progression to dementia. In addition, many of the risk factors identified may be modifiable but in practice, these patients are not attended to for their possible cognitive impairment.

Cardiotoxicities of Non-Chemotherapeutic Metastatic Breast Cancer Treatments.

PURPOSE OF REVIEW: Although mortality rates have declined significantly in recent years, breast cancer remains the second most common cause of cancer death in women, with rates significantly higher among women with metastatic disease. New therapeutic agents have improved the prognosis of patients with metastatic breast cancer but raise concerns around the risk of cardiovascular disease. This review aims to discuss the oncologic treatment of the different subtypes of breast cancer along with the cardiac complications associated with each therapy. RECENT FINDINGS: This article emphasizes human epidermal growth factor receptor targeted therapies with a focus on incidence of cardiotoxicity, reversibility, long-term outcomes, and management in high-risk patients. This review will address the use of cardiac biomarkers to monitor for toxicity, as well as the utility of cardiac imaging, including global longitudinal strain as a prognostic factor. We will also include recent findings on tyrosine kinase inhibitors, cyclin dependent kinase 4/6, and immune checkpoint inhibitors. Cardiotoxicity may lead to premature discontinuation of novel cancer therapies; optimizing cardiovascular risk factors and close monitoring for cardiotoxicity allow patients to maximize their oncologic and cardiovascular outcomes.

PROTACs: Walking through hematological malignancies.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small molecule inhibitors, PROTACs have proven highly effective in targeting undruggable proteins and those bearing mutations. Because of these considerations, PROTACs have increasingly become an emerging technology for the development of novel targeted anticancer therapeutics. Interestingly, many PROTACs have demonstrated a great potency and specificity in degrading several oncogenic drivers. Many of these, following extensive preclinical evaluation, have reached advanced stages of clinical testing in various cancers including hematologic malignancies. In this review, we provide a comprehensive summary of the recent advances in the development of PROTACs as therapeutic strategies in diverse hematological malignancies. A particular attention has been given to clinically relevant PROTACs and those targeting oncogenic mutants that drive resistance to therapies. We also discus limitations, and various considerations to optimize the design for effective PROTACs.

Three-Dimensional (3D) in vitro cell culture protocols to enhance glioblastoma research.

Three-dimensional (3D) cell culture models can help bridge the gap between in vitro cell cultures and in vivo responses by more accurately simulating the natural in vivo environment, shape, tissue stiffness, stressors, gradients and cellular response while avoiding the costs and ethical concerns associated with animal models. The inclusion of the third dimension in 3D cell culture influences the spatial organization of cell surface receptors that interact with other cells and imposes physical restrictions on cells in compared to Two-dimensional (2D) cell cultures. Spheroids' distinctive cyto-architecture mimics in vivo cellular structure, gene expression, metabolism, proliferation, oxygenation, nutrition absorption, waste excretion, and drug uptake while preserving cell-extracellular matrix (ECM) connections and communication, hence influencing molecular processes and cellular phenotypes. This protocol describes the in vitro generation of tumourspheroids using the low attachment plate, hanging drop plate, and cellusponge natural scaffold based methods. The expected results from these protocols confirmed the ability of all these methods to create uniform tumourspheres.

Ear mite infection restructures otic microbial networks in conservation-reliant Santa Catalina Island foxes (Urocyon littoralis catalinae).

Ceruminous gland tumours are highly prevalent in the ear canals of Santa Catalina Island foxes (Urocyon littoralis catalinae). Previous work suggests that tumours may result from a combination of ectoparasites, disruption of the host-associated microbiome, and host immunopathology. More specifically, ear mite infection has been associated with broad-scale microbial dysbiosis marked by secondary bacterial infection with the opportunistic pathogen Staphylococcus pseudintermedius. Together, ear mites and S. pseudintermedius probably sustain chronic inflammation and promote conditions suitable for tumour development. In the present study, we expanded upon this framework by constructing otic microbial community networks for mite-infected and uninfected foxes sampled in 2017-2019. Across sampling years, we observed consistent signatures of microbial dysbiosis in mite-infected ear canals, including reduced microbial diversity and shifted abundance towards S. pseudintermedius. Network analysis further revealed that mite infection disrupts overall community structure. In mite-infected networks, interaction strengths between taxa were generally weaker, and numerous subnetworks disappeared altogether. We also found that two strains of S. pseudintermedius connected to the main network, suggesting that multistrain biofilm formation may be occurring. In contrast, S. pseudintermedius is peripheral in the uninfected network, with its only connections including a second strain of S. pseudintermedius and the possible competitor Acinetobacter rhizosphaerae. Finally, the lineup of potential keystone taxa shifted across disease states. Fusobacteria spp., a carcinogenesis-promoting microbe, assumed a keystone role in the mite-infected community. Considered together, these findings provide insights into how mite infection may destabilize the microbiome and ultimately contribute to tumour development in this island endemic species.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A.

Colorectal cancer is a common cancer with a poor prognosis in both males and females. The influence of bisphenol A (BPA), a widely used environmental contaminant, in colon cancer development and progression is not well identified, in spite of the fact that the most common mode of exposure to BPA is ingestion. The aim of this work is to elucidate the carcinogenic effects of BPA in the colon in vitro. We analyzed BPA's effects on human colon epithelial (HCoEpiC) and colon cancer (HCT116) cells. BPA exerted cytotoxic effects and augmented the 5FU cytotoxicity on both cell lines at high doses, while it did not show this effect at low doses. Therefore, we focused on studying the effects of low-dose (0.0043 nM) exposure on normal colonic epithelial cells for a long period of time (two months), which is more consistent with environmental exposure levels and patterns. BPA increased cellular invasiveness through collagen and the ability to anchorage-independent cell growth, as measured by colony formation in soft agar, which could support oncogenicity. To gain insights into the mechanism of these actions, we performed transcriptomic analysis using next-generation sequencing, which revealed 340 differentially expressed transcripts by BPA in HCT116 and 75 in HCoEpiC. These transcripts belong in many cancer-related pathways such as apoptosis, cell proliferation, signal transduction, and angiogenesis. Some of the significant genes (FAM83H, CXCL12, PITPNA, HMOX1, DGKZ, NR5A2, VMP1, and ID1) were confirmed by quantitative RT-PCR. Furthermore, BPA induced the phosphorylation of protein kinases such as JNK1/2/3, GSK-3α/ß, AMPKα1, AKT1/2/3, AMPKα2, HSP27, ß-catenin, STAT2, Hck, Chk2, FAK, and PRAS40 in HCoEpiC, as well as GSK-3α/ß, p53, AKT1/2/3, p70 S6 kinase, and WNK1 in HCT116. The majority of these proteins are involved in potential carcinogenic pathways. Taken together, these data suggest that BPA plays a role in colon carcinogenesis, and they provide insights into the molecular mechanisms of colon epithelial cell transformation by BPA. Increasing exposure to environmental toxins such as BPA can explain the increasing incidence of colorectal cancer.

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers.

Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.

Physicians' vs patients' global assessments of disease activity in rheumatology and musculoskeletal trials: A meta-research project with focus on reasons for discrepancies.

BACKGROUND: In most rheumatic and musculoskeletal diseases (RMDs), global assessments of disease activity by physicians and patients are 'anchor outcomes' in therapeutic trials evaluating whether a treatment is effective. OBJECTIVES: To compare physicians' vs patients' global assessments of disease activity in RMD trials and explore reasons for discrepancies between them. METHODS: Eligible trials were sampled from systematic reviews of treatments for RMDs by using the Cochrane database of systematic reviews (i.e., reviews from the Cochrane Musculoskeletal Group, [CMSG]). Randomized controlled trials (RCTs) of interventions for RMDs were eligible if they reported quantitative analyses of both physicians´ and patients´ global assessments at the same time point for the comparison of the same experimental intervention against the same comparator (i.e., placebo, no treatment, or other treatment). We accepted data from trial comparisons for each type of outcome, regardless of the type of intervention and type of RMD within the CMSG. Using mixed-effects meta-regression models, we assigned the dependent variable as the ratio of odds ratios (ROR) of global change with the experimental intervention, versus the control comparator. An ROR>1 would indicate that physicians rated the experimental intervention more favorable than their patients did. RESULTS: We were able to estimate the ROR (data from both physicians' and patients' global assessments) across 70 trials (116 randomized comparisons) in 7 diseases (ankylosing spondylitis, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, and gout). The combined ROR across all effectiveness comparisons were rated significantly in favor of the intervention by physicians: ROR=1.15 CI 95% (1.07 to 1.23). This combined ROR was based on a substantial heterogeneity across comparisons (I2=89.1%). Across all the stratified analyses, the type of the RMD was an informative reason for discrepancies, with a statistically significant ROR in rheumatoid arthritis ROR=1.33, CI 95% (1.13 to 1.56), unlike the ROR in all other conditions (ROR=1.04, CI 95% (0.95-1.14). CONCLUSION: In comparative effectiveness research on rheumatology, physicians' global assessments of disease activity, surprisingly, are more in favor of the experimental interventions than are those of the patients.

Mesenchymal Stem Cells-Induced Trophoblast Invasion Is Reduced in Patients with a Previous History of Preeclampsia.

Endometrial stromal cells play an important role in reproductive success, especially in implantation and placentation. Although Mesenchymal stem cells (MSCs) have been studied to assess decidualization disorders in preeclampsia (PE), their role during trophoblast invasion remains unclear. This study aims to determine: (i) whether MSCs isolated from menstrual fluid (MenSCs) from nulliparous, multiparous, and women with a previous history of preeclampsia exhibited different patterns of proliferation and migration and (ii) whether reproductive history (i.e., prior pregnancy or prior history of PE) was able to produce changes in MenSCs, thus altering trophoblast invasion capacity. MenSCs were collected from nulliparous and multiparous women without a history of PE and from non-pregnant women with a history of PE. Proliferation and migration assays were performed on MenSCs with sulforhodamine B and transwell assays, respectively. Trophoblast invasion was analyzed by culturing HTR-8/SVneo trophospheres on a matrigel overlying MenSCs for 72 h at 5% O2, simulating a 3D implantation model. A previous history of pregnancy or PE did not impact the proliferative capacity or migratory behavior of MenSCs. Following exposure to physiological endometrial conditions, MenSCs demonstrated upregulated expression of IGFBP-1 and LIF mRNA, decidualization and window of implantation markers, respectively. The mRNA expression of VIM, NANOG, and SOX2 was upregulated upon trophosphere formation. Relative to co-culture with multiparous MenSCs, co-culture with PE-MenSCs was associated with reduced trophoblast invasion. The findings of this study suggest a potential role for communication between maternal MenSCs and invading trophoblast cells during the implantation process that could be implicated in the etiology of PE.

Obesity and Inflammation: Colorectal Cancer Engines.

The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.

Residential proximity to hydraulically fractured oil and gas wells and adverse birth outcomes in urban and rural communities in California (2006-2015).

BACKGROUND: Prenatal exposure to hydraulic fracturing (HF), a chemically intensive oil and gas extraction method, may be associated with adverse birth outcomes, but no health studies have been conducted in California. METHODS: We conducted a retrospective cohort study of 979,961 births to mothers in eight California counties with HF between 2006 and 2015. Exposed individuals had at least 1 well hydraulically fractured within 1 km of their residence during pregnancy; the reference population had no wells within 1 km, but at least one oil/gas well within 10 km. We examined associations between HF and low birth weight (LBW), preterm birth (PTB), small for gestational age birth (SGA), and term birth weight (tBW) using generalized estimating equations and assessing urban-rural effect modification in stratified models. RESULTS: Fewer than 1% of mothers (N = 1,192) were exposed to HF during pregnancy. Among rural mothers, HF exposure was associated with increased odds of LBW (odds ratio [OR] = 1.74; 95% confidence interval [CI] = 1.10, 2.75), SGA (OR = 1.68; 95% CI = 1.42, 2.27) and PTB (OR = 1.17; 95% CI = 0.64, 2.12), and lower tBW (mean difference: -73 g; 95% CI = -131, -15). Among urban mothers, HF exposure was positively associated with SGA (OR = 1.23; 95% CI = 0.98, 1.55), inversely associated with LBW (OR = 0.83; 95% CI = 0.63, 1.07) and PTB (OR = 0.65; 95% CI = 0.48, 0.87), and not associated with tBW (mean difference: -2 g; 95% CI = -35, 31). CONCLUSION: HF proximity was associated with adverse birth outcomes, particularly among rural Californians.

Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation.

Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis. Interestingly, clinical presentation of CHIKV arthritides have many overlapping features with rheumatoid arthritis including cellular and cytokine pathways that lead to disease development and progression. Currently, there are no specific treatments or vaccines available to treat CHIKV infections therefore advocating the need for the development of novel therapeutic strategies to treat CHIKV rheumatic disease. Herein, we provide an in-depth analysis of an efficacious new treatment for CHIKV arthritis with a semi-synthetic sulphated polysaccharide, Pentosan Polysulfate Sodium (PPS). Mice treated with PPS showed significant functional improvement as measured by grip strength and a reduction in hind limb foot swelling. Histological analysis of the affected joint showed local inflammation was reduced as seen by a decreased number of infiltrating immune cells. Additionally, joint cartilage was protected as demonstrated by increased proteoglycan staining. Using a multiplex-immunoassay system, we also showed that at peak disease, PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5) which may be associated with the reduction in cellular infiltrates. Further characterisation of the local effect of PPS in its action to reduce joint and muscle inflammation was performed using NanoString™ technology. Results showed that PPS altered the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation. Overall, this study shows that PPS is a promising treatment for alphaviral arthritis by reducing inflammation and protecting joint integrity.