Impact of United States 2017 Immigration Policy changes on missed appointments at two Massachusetts Safety-Net Hospitals

Introduction

Studies have shown mixed findings regarding the impact of immigration policy changes on immigrants’ utilization of primary care.

Methods

We used a difference-in-differences analysis to compare changes in missed primary care appointments over time across two groups: patients who received care in Spanish, Portuguese, or Haitian Creole, and non-Hispanic, white patients who received care in English.

Results

After adjustment for age, sex, race, insurance, hospital system, and presence of chronic conditions, immigration policy changes were associated with an absolute increase in the missed appointment prevalence of 0.74 percentage points (95% confidence interval: 0.34, 1.15) among Spanish, Portuguese and Haitian-Creole speakers. We estimated that missed appointments due to immigration policy changes resulted in lost revenue of over $185,000.

Conclusions

We conclude that immigration policy changes were associated with a significant increase in missed appointments among patients who receive medical care in languages other than English.

     

Blocking the Adhesion Cascade at the Premetastatic Niche for Prevention of Breast Cancer Metastasis

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)^–/CD44⁺ hormone-independent breast cancer cells, but not of the ER⁺/CD44^-/low hormone-dependent breast cancer cells. Coincidentally, CD44⁺ breast cancer cells were abundant in metastatic lung and brain lesions in ER^– breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER^–/CD44⁺ breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44⁺ cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER^–/CD44⁺ breast cancer.     

Exposure to Air Pollution in Relation to Risk of Dementia and Related Outcomes: An Updated Systematic Review of the Epidemiological Literature

Background: Dementia is a devastating neurologic condition that is common in older adults. We previously reviewed the epidemiological evidence examining the hypothesis that long-term exposure to air pollution affects dementia risk. Since then, the evidence base has expanded rapidly.Objectives: With this update, we collectively review new and previously identified epidemiological studies on air pollution and late-life cognitive health, highlighting new developments and critically discussing the merits of the evidence.Methods: Using a registered protocol (PROSPERO 2020 CRD42020152943), we updated our literature review to capture studies published through 31 December 2020, extracted data, and conducted a bias assessment.Results: We identified 66 papers (49 new) for inclusion in this review. Cognitive level remained the most commonly considered outcome, and particulate matter (PM) remained the most commonly considered air pollutant. Since our prior review, exposure estimation methods in this research have improved, and more papers have looked at cognitive change, neuroimaging, and incident cognitive impairment/dementia, though methodological concerns remain common. Many studies continue to rely on administrative records to ascertain dementia, have high potential for selection bias, and adjust for putative mediating factors in primary models. A subset of 35 studies met strict quality criteria. Although high-quality studies of fine particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) and cognitive decline generally supported an adverse association, other findings related to PM2.5 and findings related to particulate matter with aerodynamic diameter ≤10μm (PM10, NO2, and NOx) were inconclusive, and too few papers reported findings with ozone to comment on the likely direction of association. Notably, only a few findings on dementia were included for consideration on the basis of quality criteria.Discussion: Strong conclusions remain elusive, although the weight of the evidence suggests an adverse association between PM2.5 and cognitive decline. However, we note a continued need to confront methodological challenges in this line of research. https://doi.org/10.1289/EHP8716     

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.Rod and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone–rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph.uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransduction-associated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotide-gated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7, 8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long (M, green) and short (S, blue) wavelengths of light (9, 10). In mouse, M- and S-opsins are expressed in opposing gradients such that varying amounts of both opsins are coexpressed in cones in midretinal regions, whereas M-opsin predominates in dorsal (superior) regions and S-opsin predominates in ventral (inferior) regions (10, 11) (Fig. S1). During development and in the adult postmitotic retina, TH signaling via its receptor type β2 (TRβ2) suppresses expression of S-opsin, induces expression of M-opsin, and promotes the dorsal–ventral opsin patterning (7, 8). Importantly, TH signaling has been associated with cone viability. Triiodothyronine (T3) treatment was shown to cause cone death in mice and this effect was reversed by deletion of TRβ2 gene (12). Excessive TH signaling was also shown to induce auditory defects and cochlear degeneration in mice (13). TH signaling has been associated with apoptosis of a variety of human cell lines, including lymphocytes (14), breast cancer cells (15), HeLa cells (16), and pituitary tumor cells (17), and TH signaling has been well documented in apoptotic tissue remodeling during anuran metamorphosis (18, 19). To determine whether TH signaling affects cone viability in inherited retinal degeneration, we investigated cone death/survival in retinal degeneration mouse models following TH signaling suppression and stimulation. Retinol isomerase RPE65-deficient (Rpe65^−/−) (a model of Leber congenital amaurosis, LCA) (20, 21) and cone photoreceptor function loss type 1 (cpfl1) mice (PDE6C mutation, a model of achromatopsia) (22), displaying fast and severe cone degeneration, were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone degeneration. Cone cyclic nucleotide-gated channel B subunit-deficient (Cngb3^−/−) (a model of achromatopsia) (23) and guanylate cyclase 2e-deficient (Gucy2e^−/−) (another model of LCA) mice (24), displaying relatively slow progressive and moderate cone degeneration, were used to determine whether stimulating TH signaling (with T3 treatment) deteriorates cones. We report here that cone survival was greatly improved in Rpe65^−/− and cpfl1 mice following TH signaling suppression, whereas cone degeneration was significantly increased in Cngb3^−/− and Gucy2e^−/− mice following TH signaling stimulation, demonstrating a protective role of suppressing TH signaling in cones.     

Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy

Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2-4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials.     

Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway

The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.     

Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics

The role of Notch signaling in cervical cancer is seemingly controversial. To confirm the function of Notch signaling in this type of cancer, we established a stable Notch1-activated cervical cancer HeLa cell line. We found that Notch1 activation resulted in apoptosis, cell cycle arrest, and tumor suppression. At the molecular level, we found that a variety of genes associated with cyclic AMP, G protein-coupled receptor, and cancer signaling pathways contributed to Notch1-mediated tumor suppression. We observed that the expression of somatostatin (SST) was dramatically induced by Notch1 signaling activation, which was accompanied by enhanced expression of the cognate SST receptor subtype 1 (SSTR1) and SSTR2. Certain genes, such as tumor protein 63 (TP63, p63), were upregulated, whereas others, such as B-cell lymphoma 2 (BCL-2), Myc, Akt, and STAT3, were downregulated. Subsequently, knockdown of Notch1-induced SST reversed Notch1-induced decrease of BCL-2 and increase of p63, indicating that Notch1-induced tumor suppression may be partly through upregulating SST signaling. Our findings support a possible crosstalk between Notch signaling and SST signaling. Moreover, Notch-induced SSTR activation could enhance SSTR-targeted cancer chemotherapy. Valproic acid (VPA), a histone deacetylase inhibitor, suppressed cell growth and upregulated the expression of Notch1 and SSTR2. A combination therapy with VPA and the SSTR2-targeting cytotoxic conjugate CPT-SST strongly led to greater suppression, as compared to each alone. Our findings thus provide us with a promising clinical opportunity for enhanced cancer therapy using combinations of Notch1-activating agents and SSTR2-targeting agents.     

Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.