The Pitfalls of Global Hemostasis Assays in Myeloproliferative Neoplasms and Future Challenges.

Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies.

Estimating county-level flu vaccination in the United States.

In the United States, influenza vaccines are an important part of public health efforts to blunt the effects of seasonal influenza epidemics. This in turn emphasizes the importance of understanding the spatial distribution of influenza vaccination coverage. Despite this, high quality data at a fine spatial scale and spanning a multitude of recent flu seasons are not readily available. To address this gap, we develop county-level counts of vaccination across five recent, consecutive flu seasons and fit a series of regression models to these data that account for bias. We find that the spatial distribution of our bias-corrected vaccination coverage estimates is generally consistent from season to season, with the highest coverage in the Northeast and Midwest but is spatially heterogeneous within states. We also observe a negative relationship between a county's vaccination coverage and social vulnerability. Our findings stress the importance of quantifying flu vaccination coverage at a fine spatial scale, as relying on state or region-level estimates misses key heterogeneities.

Sorting nexins: role in the regulation of blood pressure.

Sorting nexins (SNXs) are a family of proteins that regulate cellular cargo sorting and trafficking, maintain intracellular protein homeostasis, and participate in intracellular signaling. SNXs are also important in the regulation of blood pressure via several mechanisms. Aberrant expression and dysfunction of SNXs participate in the dysregulation of blood pressure. Genetic studies show a correlation between SNX gene variants and the response to antihypertensive drugs. In this review, we summarize the progress in SNX-mediated regulation of blood pressure, discuss the potential role of SNXs in the pathophysiology and treatment of hypertension, and propose novel strategies for the medical therapy of hypertension.

Characterizing the Spatiotemporal Heterogeneity of the COVID-19 Vaccination Landscape.

As variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged throughout 2021-2022, the need to maximize vaccination coverage across the United States to minimize severe outcomes of coronavirus disease 2019 (COVID-19) has been critical. Maximizing vaccination requires that we track vaccination patterns to measure the progress of the vaccination campaign and target locations that may be undervaccinated. To improve efforts to track and characterize COVID-19 vaccination progress in the United States, we integrated Centers for Disease Control and Prevention and state-provided vaccination data, identifying and rectifying discrepancies between these data sources. We found that COVID-19 vaccination coverage in the United States exhibits significant spatial heterogeneity at the county level, and we statistically identified spatial clusters of undervaccination, all with foci in the southern United States. We also identified vaccination progress at the county level as variable through summer 2021; the progress of vaccination in many counties stalled in June 2021, and few had recovered by July, with transmission of the SARS-CoV-2 delta variant rapidly rising. Using a comparison with a mechanistic growth model fitted to our integrated data, we classified vaccination dynamics across time at the county scale. Our findings underline the importance of curating accurate, fine-scale vaccination data and the continued need for widespread vaccination in the United States, especially with the continued emergence of highly transmissible SARS-CoV-2 variants.

Isolation of Lipid Rafts by the Detergent-Based and Non-detergent-Based Methods for Localization of GPCRs with Immunoblotting and Laser Scanning Confocal Microscopy.

The understanding of how biological membranes are organized and how they function has constantly been evolving over the past decades. Instead of just serving as a medium in which specific proteins are located, certain parts of the lipid bilayer contribute to platforms that assemble signaling complexes by providing a microenvironment that facilitates effective protein-protein interactions. G protein-coupled receptors (GPCRs) and relevant signaling molecules, including the heterotrimeric G proteins, key enzymes such as kinases and phosphatases, trafficking proteins, and secondary messengers, preferentially partition to these highly organized cell membrane microdomains, called lipid rafts. Lipid rafts are essential for the trafficking and signaling of GPCRs. The study of GPCR biology in the context of lipid rafts involves the localization of the GPCR of interest in lipid rafts, at the basal state and upon receptor agonism, and the evaluation of the biological functions of the GPCR in appropriate cell lines. The lack of standardized methodologies to study lipid rafts, in general, and of the workings of GPCRs in lipid rafts, in particular, and the inescapable drawbacks of current methods have hampered the complete understanding of the underlying molecular mechanisms. Newer methodologies that allow the study of GPCRs in their native form are needed. The use of complementary approaches that produce mutually supportive results appears to be the best way for drawing conclusions with regard to the distribution and activity of GPCRs in lipid rafts.

Survival Disparities of Diffuse Large B-Cell Lymphoma in a Community-Based Inner-City Cancer Center.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) comprises approximately 30% of all non-Hodgkin lymphomas. Multiple studies have demonstrated race-based disparities in survival among patients with DLBCL across all stages of disease, in the era both before and after rituximab. The etiology for the racial disparities in survival among patients with DLBCL is still unknown. Moreover, the Revised International Prognostic Index (R-IPI), a tool that predicts the DLBCL patients' outcome, has not yet been validated in African Americans (AA). PATIENTS AND METHODS: We conducted a cohort study of patients diagnosed with DLBCL from January 1, 2007, to December 31, 2017, from our tumor registry in a single community-based inner-city cancer center. We abstracted demographic, clinical, histopathologic, treatment, and R-IPI variables. A total of 181 patients (47.5%) with biopsy-proven DLBCL were included in the retrospective analysis. The median age was 65 years, 47% were men, 41% were AA, and 44% were white. RESULTS: The AA group had a younger median age, higher lactate dehydrogenase levels, higher frequency of B symptoms, and higher HIV infection than the non-AA group. The AA group had significantly decreased median overall survival than the non-AA group (15.7 months; 95% confidence interval, 10.3 to 23.9, vs. 93.6 months; 95% confidence interval, 61.5 to 142.6, respectively; P < .001). The survival disparities persisted after excluding patients with HIV and who did not receive chemotherapy. In addition, AA race predicts a reduced survival by univariate and multivariate analysis. CONCLUSION: AA with DLBCL may have a poorer prognosis than the non-AA population. Further studies should investigate the biology of DLBCL in the AA population.

Lipid Rafts and Dopamine Receptor Signaling.

The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine receptors, and their signaling process offers an opportunity to unravel potential treatment targets that could halt the progression of hypertension, chronic kidney disease (CKD), and their complications.

Lipid rafts are required for effective renal D1 dopamine receptor function.

Effective receptor signaling is anchored on the preferential localization of the receptor in lipid rafts, which are plasma membrane platforms replete with cholesterol and sphingolipids. We hypothesized that the dopamine D1 receptor (D1 R) contains structural features that allow it to reside in lipid rafts for its activity. Mutation of C347 palmitoylation site and Y218 of a newly identified Cholesterol Recognition Amino Acid Consensus motif resulted in the exclusion of D1 R from lipid rafts, blunted cAMP response, impaired sodium transport, and increased oxidative stress in renal proximal tubule cells (RPTCs). Kidney-restricted silencing of Drd1 in C57BL/6J mice increased blood pressure (BP) that was normalized by renal tubule-restricted rescue with D1 R-wild-type but not the mutant D1 R 347A that lacks a palmitoylation site. Kidney-restricted disruption of lipid rafts by ß-MCD jettisoned the D1 R from the brush border, decreased sodium excretion, and increased oxidative stress and BP in C57BL/6J mice. Deletion of the PX domain of the novel D1 R-binding partner sorting nexin 19 (SNX19) resulted in D1 R partitioning solely to non-raft domains, while silencing of SNX19 impaired D1 R function in RPTCs. Kidney-restricted silencing of Snx19 resulted in hypertension in C57BL/6J mice. Our results highlight the essential role of lipid rafts for effective D1 R signaling.

Trends in the prevalence of malignancy among patients admitted with acute heart failure and associated outcomes: a nationwide population-based study.

Cancer is the second leading cause of death in the USA, and cardiovascular disease is the second leading cause of morbidity and mortality among cancer survivors. Cancer survivors share common risk factors for cardiovascular disease with non-cancer patients. With improved survival, cancer patients become susceptible to treatment-related toxicity often involving the heart. The impact of concurrent malignancy on outcomes particularly among heart failure patients is an area of active research. We studied the trends in the prevalence of a concurrent diagnosis of breast, prostate, colorectal, and lung cancer among admissions for acute heart failure and the associated trends for in-hospital mortality. Patients aged ≥ 18 years who were admitted with a primary diagnosis of "congestive heart failure" (CCS codes 99 and 108) from years 2003 to 2014 were included. We analyzed the rate of admission and in-hospital mortality among patients who had a concurrent diagnosis for either lung cancer, colorectal cancer, breast cancer (among females), or prostate cancer (among males). We performed a multivariate analysis to assess the role of a concurrent diagnosis of any cancer in predicting in-hospital mortality among HF admissions. From 2003 to 2014 across over 12 million HF admissions, ≈ 7% had a concurrent diagnosis of either lung, breast, colorectal, or prostate cancer. The prevalence was highest for breast cancer (2.3%) followed by prostate cancer (2.1%) and colorectal cancer (1.5%) and lowest with lung cancer (1.1%). The prevalence of cancer increased over the duration of study among all four cancer types with the largest increase in prevalence of breast cancer. Baseline comorbidities including hypertension, diabetes, smoking, chronic kidney disease, and coronary artery disease increased over time among patients with and without cancer. In-hospital mortality was higher among those with a diagnosis of lung cancer (5.9%) followed by colorectal cancer (4.0%), prostate cancer (3.5%), no diagnosis of cancer (3.3%), and breast cancer (3.2%). In-hospital mortality declined across HF admissions with and without a cancer diagnosis from 2003 to 2014. Decline in such mortality among heart failure was highest for patients with lung cancer (8.1 to 4.6% from 2003 to 2014; p < 0.001). Multivariate analysis showed that a concurrent diagnosis of cancer was associated with a marginally lower hospital mortality compared with controls (adjusted odds ratio 0.95, 95% confidence interval 0.94-0.96; p < 0.001). Among HF admissions, the prevalence of a concurrent cancer diagnosis increased over time for breast, lung, colorectal, and prostate cancer. Baseline in-hospital mortality was higher among HF admissions with either lung cancer, colorectal cancer, or prostate cancer and lower with breast cancer compared with controls without a cancer diagnosis. Adjusted analysis revealed no evidence for higher hospital mortality among HF admissions with any accompanying cancer diagnosis.

Colorectal cancer in young African Americans: clinical characteristics and presentations.

PURPOSE: Colorectal cancer (CRC) is the third most common cancer in the USA, and the incidence in young adults has been increasing over the past decade. We studied the clinical characteristics and presentations of CRC in young African American (AA) adults because available data on how age and ethnicity influence its pattern of presentation is limited. PATIENTS AND METHODS: We conducted a retrospective study of 109 young adults (75 African Americans) below 50 years, who were diagnosed with CRC between 1 January 1997 and 31 December 2016. Proximal CRC was defined as lesions proximal to the splenic flexure. Independent t-tests and χ-test or Fisher's exact test were performed where appropriate to determine the differences between AA and non-AA patients. RESULTS: The mean age at diagnosis was 42 years (range: 20-49 years). Compared with non-AAs, AAs had more frequent proximal CRC (38.7 vs. 14.7%, P=0.003), lower hemoglobin (10.5 vs. 12.7 g/dl, P<0.001), and more frequent weight loss (21.3 vs. 2.9% P=0.014). Non-AAs presented more frequently with rectal bleeding (52.9 vs. 32.0% P=0.037). There was no statistically significant difference in histology, stage, grade, tumor size, and carcinoembryonic antigen level between groups. When we stratified between proximal and distal disease among patients with CRC, we found larger tumor size in distal disease, which presented more with rectal bleeding and bowel habit changes. Proximal disease presented more as abdominal pain and weight loss. CONCLUSION: There should be a higher index of suspicion for CRC in young AA adults presenting with anemia, abdominal pain, and weight loss. Early screening colonoscopy should be advocated in AAs because of the predominance of proximal disease.

Multiple Liver Nodules Mimicking Metastatic Disease as Initial Presentation of Multiple Myeloma.

Multiple myeloma is a malignant clonal proliferation of plasma cells in the bone marrow preceded by monoclonal gammopathy of undetermined significance. Initial presentation of multiple myeloma as extramedullary spread in soft tissues particularly in the liver is uncommon. We report a case of a 74-year-old African American female who presented with epigastric pain, hematemesis, elevated alkaline phosphatase, and gamma-glutamyl transferase. Initial impression was peptic ulcer disease; however, ultrasound and CT scan of the abdomen showed multiple liver nodules and perihepatic lymphadenopathy suggestive of metastatic disease. Biopsy of the liver nodules showed CD138 and kappa light chain-restricted positive cells consistent with extramedullary spread of multiple myeloma to the liver. The patient achieved partial response after 6 months of treatment with Velcade, cyclophosphamide, and dexamethasone (VCD). Due to severe neutropenia from cyclophosphamide, regimen was switched to Velcade, Revlimid, and dexamethasone (VRD) which resulted to very good partial response in 1 year which eventually persisted after 4 years. No controlled prospective studies have defined the standard treatment for multiple myeloma with extramedullary spread particularly to the liver. Treatment of multiple myeloma with extramedullary disease follows guidelines for multiple myeloma.

Clinical outcomes of African American patients with advanced or metastatic non-small cell lung cancer on Nivolumab in a single community-based cancer center.

African Americans (AA) have the highest incidence and mortality rates with lung cancer. They are diagnosed at an earlier age with more advanced disease. Programmed cell death protein-1 inhibitor, Nivolumab, was approved as a second-line agent after failure of platinum-based therapy for advanced or metastatic non-small cell lung cancer (NSCLC). The original studies leading to the approval of Nivolumab had insufficient AA patients, thus there is still inadequate knowledge on treatment outcomes among AA patients. Our primary study endpoints were to determine the median overall survival, 1-year overall survival rate, median progression-free survival, and 1-year progression-free survival rate of patients with advanced or metastatic non-small cell lung cancer on Nivolumab. Our secondary study endpoints were to determine the overall tumor response rate, median time to response, median duration of response, and incidence of treatment-related adverse events of grade 3 or 4. In this retrospective study, we reviewed the charts of 38 patients, 29 of which were AA, with advanced or metastatic NSCLC who received Nivolumab from March 1, 2015 until November 30, 2017 from a single community-based cancer center and compared our results with historical data. Adenocarcinoma was the most common histology (71%) among all patients. Seven (18%) continued to use Nivolumab while 21 (55%) discontinued the treatment mainly due to progression of the disease. The median overall survival was 21.4 months (95% CI 13.5-27.4) and 17.6 months (95% CI 11.5-27.6) for all the patients and AA, respectively. Both have statistically significant difference (P < 0.001) compared to the historical studies of Borghaei et al. and Brahmer et al. At 1 year, the overall survival rate was 73% (95% CI 50-86) and 66% (95% CI 40-82) for all patients and AA, respectively. The median progression-free survival was also statistically significant (P < 0.001) between all the patients 6.3 months (95% CI 2.8-8), AA 6.0 months (95% CI 2.3-8.0), and the said historical studies. The 1-year progression-free survival rate was 23% (95% CI 10-39) and 28% (95% CI 12-47) for all patients and AA, respectively. Overall tumor response rate which includes complete and partial responses was 21% (95% CI 10-37) and 24% (95% CI 10-43) for all patients and AA, respectively. The median time to response was 3 and 2.8 months for all patients and AA, respectively. The median duration of response was 3.8 and 4.0 months for all patients and AA, respectively. Treatment-related adverse events of grade 3 or 4 were reported in 8 and 10% in all patients and AA, respectively, similar to the rates previously shown. AA patients with advanced or metastatic NSCLC on Nivolumab had increased overall survival and progression-free survival with similar grade 3 or 4 treatment-related adverse events. Providing adequate access to immunotherapy is indispensable to maximize survival benefit for AA patients.

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes.

Leptin is a pro-inflammatory cytokine secreted by the adipose tissue. Dopamine D2 receptors (D2Rs) have anti-inflammatory effects in the brain and kidney tissues. Mouse and human adipocytes express D2R; D2R protein was 10-fold greater in adipocytes from human visceral tissue than subcutaneous tissue. However, the function of D2R in adipocytes is not well understood. 3T3-L1 cells were treated with D2-like receptor agonist quinpirole, and immunoblot and quantitative PCR were performed. Quinpirole increased the protein and mRNA expression of leptin and IL-6, but not adiponectin and visfatin (24 h). It also increased the mRNA expression of TNF-α , MCP1, and NFkB-p50. An acute increase in the protein expression of leptin and TNF-α was also found in the cells treated with quinpirole. The leptin concentration in the culture media was increased by quinpirole-bathing the 3T3-L1 adipocytes. These quinpirole effects on leptin and IL-6 expression were prevented by the D2R antagonist L741,626. Similarly, siRNA-mediated silencing of Drd2 decreased the leptin, IL-6, mRNA, and protein expressions. The D2R-mediated increase in leptin expression was prevented by the phosphoinositide 3-kinase inhibitor LY294002. Acute quinpirole treatment in C57Bl/6J mice increased serum leptin concentration and leptin mRNA in visceral adipocyte tissue but not in subcutaneous adipocytes, confirming the stimulatory effect of D2R on leptin in vivo. Our results suggest that the stimulation of D2R increases leptin production and may have a tissue-specific pro-inflammatory effect in adipocytes.

Right orbital edema masquerading a hematologic malignancy.

INTRODUCTION: Multiple myeloma is caused by abnormal proliferation of plasma cells that affects more commonly African Americans. It classically presents with hypercalcemia, renal failure, anemia, and lytic bone lesions. The aim of this article is to present an unusual case of a 63-year-old African-American female with multiple myeloma who presented with worsening right-sided eye swelling for the past 3 weeks and to briefly review ophthalmologic manifestations of multiple myeloma. CASE DESCRIPTION: Our patient's presentation was associated with a throbbing frontal headache, nasal congestion, malaise, and weight loss. Differential diagnosis on admission included giant cell arteritis, conjunctivitis, preseptal cellulitis, glaucoma, acute sinusitis, or cavernous sinus thrombosis. Extensive ophthalmologic evaluation did not show any intraocular abnormality. However, a magnetic resonance imaging of the brain showed hyperintense foci in the right frontal calvarium leading to the eye swelling. Further evaluation revealed pancytopenia, elevated protein levels, and inverse albumin-globulin ratio suggestive of a plasma cell dyscrasia. A skeletal survey revealed multiple osteolytic lesions. Serum and urine protein electrophoresis revealed elevated immunoglobulin G Kappa monoclonal gammopathy. Bone marrow biopsy demonstrated a hypercellular marrow comprised at least 70% mature appearing plasma cells staining positive for CD138. Chemotherapy with cyclophosphamide, bortezomib, and dexamethasone was initiated. After 2 months of chemotherapy, orbital swelling has resolved with decrease in M-spike, immunoglobulin G, and serum kappa light chains. CONCLUSION: This case illustrates an unusual presentation of multiple myeloma which was eye swelling caused by bony infiltration in the calvarium. Although hematologic malignancies tend to have more specific signs and symptoms, they should be included in the differentials of unilateral orbital edema.

Acute Left Internal Carotid Artery and Right Popliteal Artery Occlusion Related to Cisplatin-Gemcitabine Based Chemotherapy.

OBJECTIVES: The increased risk of thromboembolic complications with active cancer is well known. We present this case to highlight that chemotherapy may increase the risk of thromboembolic events even further in cancer patients. METHODS: We report a case of a 64-year-old male with Diffuse Large B-Cell Non-Hodgkin's Lymphoma who presented with left-sided headache and right calf pain two weeks after starting Rituximab/Gemcitabine/Cisplatin/Dexamethasone chemotherapy. Neurological examination was normal, but there was an absent right dorsalis pedis pulse. He subsequently developed left vision loss. CT angiogram of the head and neck revealed occlusion of his left internal carotid artery and poor opacification of the left ophthalmic artery. An angiogram of the right leg further revealed acute occlusion of the popliteal artery. RESULTS: The patient underwent intra-arterial Tissue Plasminogen Activator injection to his lower limb and was started on Low Molecular Weight Heparin. His vision gradually recovered with time. His chemotherapy regimen was changed to RICE (Rituximab, Ifosfamide, Carboplatin, Etoposide). CONCLUSION: Based on literature review, there are numerous similar presentations of arterial thromboembolism in patients on Cisplatin-based chemotherapy. A high index of suspicion for such events should be maintained for patients on chemotherapy presenting with unusual symptoms.

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts.

The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.