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Indexes are commonly used to combine multivariate information into a single number for monitoring, communicating, and decision-making. They are applied in many areas including the environment (e.g. drought index, Southern Oscillation Index), and the economy (e.g. Consumer Price Index, FTSE). Developers, analysts, and policymakers tend to have their favorite indexes, but there is little transparency about their performance. Indexes are used like black boxes---raw data is entered and a single number is returned---with scarce attention paid to diagnostics. Interestingly, though, all indexes can be constructed using a data pipeline in a series of well-defined steps, regardless of their origin. This talk will explain this, and how you can use this structure to inspect the behavior of indexes in different scenarios. Our work coordinates the vast array of index research and development into a simple set of building blocks. This modular data pipeline is implemented in an R package, which contains some standard indexes, and allows others to be easily coded. We will illustrate the benefits of this framework using the drought index, and show how different versions, created by different parameter choices, can lead to potentially varied decisions.

Movie S1 shows timelapse of cells undergoing failure of abscission and becoming multinucleated. Nuclei are in red.

Figures S1-S5 show how stiffness-mediated signaling downstream of Snail is affected by proliferation and expression of septin-6. Tables S1-S2 list primers for qPCR and binding sites in the septin-6 promoter. Legends for Movies S1-S2, which show abscission failure, are also included.

The attainment of both high strength and high toughness is an essential requirement for most structural materials. However, these properties are generally mutually exclusive. To address the conflict between strength and toughness in polyvinyl alcohol (PVA) fibre reinforced cement composites (FRCCs), in this study, we introduced relatively weak interfaces in FRCCs while enhancing the cement matrix in vicinity of the fibre by coating oxidized graphene nanosheets (OGNs) on PVA fibre surfaces. Weak interfaces were introduced due to the sliding between OGNs, while cement matrix in the vicinity of fibre was densified by the strong interaction of OGNs with cement. As a result, this OGNs coating simultaneously improved tensile strength and toughness by 32.0% and 10.0% in the PVA FRCCs. Further investigation also indicated that the oxidation level of the coated OGNs had a significant influence on their interaction with cement. Reduction of OGNs, using l -ascorbic acid for 1 min and 60 min, resulted in 18.6% and 21.7% decrease in interfacial shear strength between fibre and cement, respectively. These reductions also correspondingly caused 114.9% and 117.3% increase in porosity and 36.5% and 35.0% decrease in the stiffness of the cement matrix in the vicinity of fibre.

Tai Chi Chuan is an ancient Chinese body-mind practice. People practice it for different perspectives. The benefits and potential of Tai Chi Chuan for general health, alternative treatments for chronic diseases, anti- aging and social wellbeing, have being recognized by extensive research. Tai Chi Chuan is an art of living pursuit for a healthy, harmonious and happy life. As a lifestyle, Tai Chi performance is not just a simple exercise but an art of living. It deeply connects the Chinese cultures of Taoism, Confucianism and Traditional Chinese Medicine, among others.

This prognostic study evaluates the use of plasma D-dimer concentrations to rule out pulmonary embolism among patients hospitalized with COVID-19.

In adults, data support the utility and acceptance of home HIV testing; however, in youth, particularly in the US, this has not been well studied. In this exploratory study, we surveyed Tampa Bay youth aged 16−27 and attending sexual health clinics between 1 June and 31 June 2018 (n = 133) regarding attitudes and perceptions towards HIV self-testing. While most indicated the clinic over home when asked for preferred testing location, study population and subgroup analysis demonstrated a positive response (agree) to Likert-scale questions regarding the use of home HIV self-testing kits and negative responses (strongly disagree) to “would not use self-testing kit”. There was a significant difference between genders in testing location preference (p = 0.031) for those respondents that specified gender (n = 123), with males more likely to prefer home testing than females. This study suggests an openness of youth towards HIV home testing that could help to expand the number of youth aware of their HIV status.

Background The Philadelphia chromosome is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). While hematopoietic stem cell transplantation (HSCT) has been regarded as a favorable treatment option in adult Philadelphia‐positive (Ph+) ALL, its benefit is less clear in the era of newer generation tyrosine kinase inhibitors (TKIs) like dasatinib. Methods This was a retrospective study that analyzed the outcomes of adult patients with Ph+ ALL treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib followed by allogeneic HSCT. Results A total of 70 patients were included; 30 (42.9%) underwent allogeneic HSCT while 40 (57.1%) received only chemotherapy plus dasatinib. In comparing overall survival (OS) rates, results between the 2 groups were similar with a 1‐year OS of 93.3% versus 100% (P = 0.20), 2‐year OS of 89.8% versus 86.2% (P = 0.72), and 3‐year OS of 76% versus 71.3% (P = 0.56) in the transplant versus nontransplant groups, respectively. The 3‐year relapse‐free survival (RFS) rates were also similar at 70.5% in the transplant group and 80.1% in the nontransplant group (P = 0.94). Subgroup analyses were performed for patients with specific poor prognostic factors (higher white blood count, older age, positive minimal residual disease status), but results again showed no significant survival difference between transplant and nontransplant patients. Conclusions While HSCT has historically led to a survival advantage in Ph+ ALL, the results of our study demonstrate that it may have a less beneficial role in the era of newer generation TKIs such as dasatinib.

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer., Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression.

The molecular events involved in the development of bronchial premalignant lesions (PMLs), and their progression to lung squamous cell carcinoma, are not well understood. Prior work characterized lung PML molecular subtypes by identifying co-expressed gene modules associated with histologic severity and progression/persistence. The proliferative subtype was enriched for PMLs with dysplasia. Genes related to interferon signaling and antigen processing/presentation (Module 9) were decreased in progressive/persistent lesions within this subtype, suggesting early immune suppression is related to PML progression. However, the mechanisms that drive these alterations are unclear. We investigated the role of microRNAs (miRNAs) in regulating gene expression associated with PML outcomes. mRNA and miRNA were extracted and sequenced from longitudinally collected endobronchial biopsies from patients with PMLs (148 samples, 30 patients). miRNAs targeting each gene co-expression module were identified based on target gene enrichment and the degree of negative correlation between the miRNA expression and its targets. Expression association with outcome within the proliferative subtype was tested with a mixed effects model adjusting for batch and patient as random effect. Cell type specificity of miRNA expression was tested based on cell type specific sequencing data from FANTOM5 and cell type marker correlation analysis. Genes regulated by NLRC5 were identified with ChIPseq data from Ludigs et al. Target gene suppression was confirmed by transfecting SW900 cells with miR-149-5p. miR-149-5p level in PML biopsies was examined by miRNA in situ hybridization (miR-ISH). miR-149-5p is identified as potential regulator of Module 9 gene expression and is significantly up-regulated in progressive/persistent PMLs. Its expression is highly enriched in epithelial cells in FANTOM5 and positively correlates with basal cell markers within PMLs. Predicted targets of miR-149-5p are down-regulated in the progressive PMLs in both our and data from Merrick et al. MHC-I and related gene expressions are down-regulated in progressing/persistent PMLs. These genes are regulated by the transcriptional coactivator NLRC5 which is a predicted target gene of miR-149-5p. We find that overexpressing miR-149-5p in SW900 cells decreases the expression levels of both NLRC5 and NLRC5 regulated genes. Additionally, miR-ISH targeting miR-149-5p in proliferative biopsy samples confirm its expression in epithelium compartment and association with outcome. Our data suggest epithelial miR-149-5p might be a key regulator of gene expression contributing to PML progression. We hypothesize that by suppressing NLRC5, miR-149-5p inhibits MHC-I gene expression of epithelial cells, promoting early immune depletion and lesion progression. miR-149-5p might therefore be a therapeutic target for preventing PML progression. Citation Format: Boting Ning, Roxana M. Pfefferkorn, Gang Liu, Sherry Zhang, Hanqiao Liu, Christopher Stevenson, Sarah A. Mazzilli, Avrum E. Spira, Marc E. Lenburg, Jennifer E. Beane. The role of epithelial miR-149 in immune modulation and progression of bronchial premalignant lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1488.

Background: Bronchial pre-malignant lesions (PMLs) are the putative precursors for bronchial squamous cell carcinoma. PMLs represent a spectrum of histologies, from low-grade lesions (hyperplasia, metaplasia) to high-grade lesions (dysplasia, carcinoma in situ). The majority of these lesions will regress or remain stable without clinical intervention while a subset of lesions will progress to invasive carcinoma. We performed single-cell RNA sequencing (scRNAseq) of these lesions to elucidate the cross-talk between epithelial, stromal, and immune populations in lesions of increasing histological grade. Methods: Thirty lesions from seventeen participants were biopsied via bronchoscopy. Cells were sorted by CD45+/- FACS gating and sequenced with the Cel-Seq2 protocol. Celda was used to bi-cluster genes into modules and cells into clusters. Cells were filtered by mitochondrial percentage (%mito < 50%), minimum UMI counts (nUMI > 300), and doublet detection. Cell types were labeled by marker gene expression. Results: After filtering low quality cells, we analyzed 4,382 cells. We observed expected smoking related shifts in epithelial cell type proportions, including an increase in secretory cells (χ2 = 31.39, p = 2.11 X 10-8) and a decrease in ciliated cells (χ2 = 4.83, p = 0.028) among current smokers. Distinct differences in expression of transcriptional modules were observed between KRT5+ (basal) cells from different histologic grades. Basal cells from high grade lesions expressed smoking detoxification and cell cycle gene programs, while low grade lesion basal cells expressed differentiation gene programs. We also identified a group of cells from CIS lesions involved in an epithelial-to-mesenchymal transition, marked by an increase in SPARC and COL4A1 expression and a decrease in CDH1 expression. Subpopulations of immune cells identified include macrophages, CD4/8+ T, B, dendritic cells, and natural killer cells. Several clusters of CD4+ and CD8+ T cells displayed an exhausted phenotype, marked by the expression of PD-1, CTLA4, LAG3, and TIGIT. Samples with high grade histology (dysplasia, carcinoma in situ) were enriched in CD4+ Tregs and myeloid cells compared to low grade histology samples (hyperplasia, metaplasia), which were enriched in Natural Killer and cytotoxic CD8+ T cells (χ2 = 298.95, p = 0.001). Discussion: Our results suggest that changes in specific transcriptional programs are associated with the transition of epithelial cells to more invasive states and that changes in immune populations are associated with increasing histological grade. These signatures can suggest novel avenues for chemoprevention and cancer interception. Citation Format: Conor Shea, Lukas Kalinke, Kitty De Jong, Kate Gowers, Diane Ding, Sherry Zhang, Gang Liu, Jack Cunningham, Ipsita Dey-Guha, Mark Hennon, Sai Yendamuri, Christopher Stevenson, Avrum Spira, Mary E. Reid, Marc E. Lenburg, Sam M. Janes, Jennifer E. Beane, Sarah A. Mazzilli, Joshua D. Campbell. Epithelial, stromal, and immune changes associated with lung squamous premalignant lesion severity identified by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2201.

ObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (i.e., found in one patient only) and public (i.e., found in two or more patients) TCRs was quantified and the CDR3 sequences were compared to those found in curated databases with known antigen specificities.ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman’s rho −0.34, p < 0.001) associated with PML outcome.Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3,396 (8.6%) found in more than one sample and 1,057 (2.7%) found in two or more patients (i.e. public), however, when compared to a public database of CDR3 sequences, 4,543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among Public TCRs (p < 0.001).ConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

Introduction: Although three randomized control trials have proven mortality benefit of CT lung cancer screening (CTLS)

Objective To investigate the effects of GH signaling on Kupffer cells and the resulting changes in lipid homeostasis and their underlying mechanism(s) in the livers of diet-induced obese (DIO) mice. Design Male macrophage specific-growth hormone receptor knockout mice (MacGHR KO) and their litter mate controls were fed a high fat diet containing 60% calories from fat for 26 weeks. Lipid content and lipid profiles in the liver and circulation were analyzed. Expression levels of CD36 in the liver were quantified by RT-PCR and Western Blot. Results Increased hepatic lipid content and abundance of long-chain unsaturated fatty acids were observed in the liver of MacGHR KO mice. These findings were associated with increased steady state levels of CD36 mRNA and protein in MacGHR KO mice when compared with their litter mate controls. Conclusion GH action in Kupffer cells is required for maintaining hepatic lipid homeostasis, in part via regulation of hepatic CD36 expression.

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial–mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277–89. ©2018 AACR.

The myosin heavy chain 7 ( MYH7 ) gene encodes a beta-myosin heavy chain isoform that is expressed primarily in the heart. MYH7 mutations are inherited in an autosomal dominant manner and are believed to cause familial hypertrophic cardiomyopathy (HCM) in about 30% of cases [(1)][1]. Compared with

ObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and PML outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (ie, found in one patient only) and public (ie, found in two or more patients) TCRs was quantified, and the CDR3 sequences were compared with those found in curated databases with known antigen specificities.ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T cell mediated immune activation (p=4e-4) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3396 (8.6%) found in more than one sample and 1057 (2.7%) found in two or more patients (ie, public); however, when compared with a public database of CDR3 sequences, 4543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among public TCRs (pConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

Background: Sampling the bronchial airway during bronchoscopies in screening populations at high risk for lung cancer has increased detection of squamous bronchial pre-malignant lesions (PML). The majority of these lesions will regress or remain stable without any clinical intervention. However, a subset of lesions will progress to invasive malignancy. In this work, we investigate the gene expression changes in epithelial cell states and immune cell proportion shifts associated with premalignant histologic stage using single-cell RNA sequencing to begin to identify molecular features associated with PML regression or progression. Methods: Cells (n=3,325) were isolated from 11 endobronchial biopsies from 9 patients, where biopsy histology range from normal, dysplasia, carcinoma in situ (CIS) and squamous cell carcinoma. Immune cells (CD45+) and epithelial cells (CD45− EPCAM+) were sorted into separate 96-well plates using fluorescence activated cell sorting (FACS) and sequenced using CEL-Seq2 single cell RNA seq protocol. Results: After filtering low quality cells, we profiled 2,998 cells (1,052 CD45+ and 1,946 CD45−) with an average of 1,190 genes per cell. Within the epithelial cells, we focused on basal cells as they are the airway progenitor cells. We observed distinct differences in expression of KRT5+ (basal) cells between different histologic grades, where KRT5+ cells present in a hyperplasic lesion expressed multiple secretory cell markers suggesting they were transitioning to a secretory cell phenotype and KRT5+ cells from a CIS lesion from a current smoker expressed higher levels of smoking inducible genes, such as GSTM1 and CYP1A1. Lastly, KRT5+ cells from a lung squamous carcinoma tumor expressed higher levels of many genes related to cell cycle progression. Among the immune populations, low-grade PMLs with non-dysplastic histology were enriched for CD8+ T cells, whereas higher-grade PMLs and an invasive tumor were enriched for myeloid cells. Conclusions: To date, we have begun to identify histology-associated cellular and molecular profiles in bronchial premalignancy and early-stage carcinoma. Future resampling of these patients and expansion of cases will allow us to discover biomarkers associated with lesion progression and molecular targets for lung cancer interception. Citation Format: Conor Shea, Lukas Kalinke, Kitty De Jong, Kate Gowers, Diane Ding, Sherry Zhang, Gang Liu, Jack Cunningham, Ipsita Dey-Guha, Mark Hennon, Sai Yendumuri, Christopher Stevenson, Steven Dubinett, Avrum Spira, Marc Lenburg, Samuel Janes, Mary Reid, Jennifer Beane, Sarah Mazzilli, Joshua D. Campbell. Cellular and molecular changes associated with lung squamous premalignant lesion severity identified by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2212.

Syphilis is a sexually transmitted infection with rising incidence in recent years due to increased rates of highrisk sexual behaviors. Often called “the great imitator,” syphilis can have many different presentations in its various stages: latent, primary, secondary and tertiary. One form of secondary syphilis is ulceronodular syphilis, also known as lues maligna. We report a case of a 48-year-old Filipino man who presented with a diffuse, ulcerating, papular rash and was subsequently diagnosed concurrently with both lues maligna and human immunodeficiency virus.

As part of the California Air Resources Board's effort to confirm the ability of the vehicular particulate matter (PM) reference method (RM) to measure PM emissions at sub-one milligram per mile (mg/mi), and to explore alternative methods, we evaluated a combination method (CM) that utilizes both gravimetric and real-time particle quantification. PM, collected on a single composite filter is apportioned to the three Federal Test Procedure (FTP) cycle phases using real-time equivalent black carbon (EBC) measurements, reducing the need to carry out separate gravimetric filter measurements for each of the test phases. Four light-duty gasoline vehicles, emitting PM at or below one mg/mi, were dynamometer tested repeatedly on the FTP cycle. PM was quantified by the RM and by two variants of the CM. One variant used photoacoustic spectroscopy to measure EBC (CM-MSS), and the other used an Aethalometer (CM-AE51). The CM was evaluated on repeatability, bias, and correlation with the RM. For the tested vehicles, the observed repeatability of the CM was superior to the RM regardless of the mode of EBC measurement or the test vehicle considered (σCM−MSS = 0.08 mg/mi, σCM−AE51 = 0.07 mg/mi, σRM ≈ 0.11 mg/mi). However, the CM was negatively biased by −0.08 mg/mi, versus the RM, in one of the test vehicles. We attribute the bias in this vehicle's data to organic carbon emissions that were not equivalently collected on the composite filter of the CM. When all data were combined, the correlation between the methods was good (R = 0.90 for CM-MSS vs. RM and R = 0.91 for CM-AE51 vs. RM).

Introduction The Philadelphia chromosome is associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). While modern day therapies including allogeneic hematopoietic stem cell transplantation (HSCT) have led to significant improvements in overall survival (OS) for this population, these treatments have variable accessibility in patients with limited to no health insurance. Methods We performed a single-center, retrospective study to investigate outcomes in Ph+ ALL adults with different types of health insurance. Health insurance options included Medicare, private insurance, Medicaid, or no insurance. Allogeneic HSCT was performed in patients who met transplant eligibility criteria of insurance coverage and caregiver availability at home. Patient OS was defined as the time from diagnosis of Ph+ ALL until patient death. Statistical analysis was performed using the Fisher's exact probability test with two-tailed p-values Results A total of 81 patients with Ph+ ALL were included in this study. Two groups of patients were compared: those with either Medicare or private insurance (M/P) versus those with Medicaid or no insurance (M/N). Thirty-three patients (40.7%) were included in the M/P group and 48 patients (59.2%) in the M/N group. Twenty patients (60.6%) in the M/P group were able to undergo allogeneic HSCT in contrast to 15 patients (31.3%) in the M/N group (p = 0.012). There were similar rates of caregiver availability to support HSCT between both groups; 24 M/P patients (72.7%) lived with a caregiver versus 33 M/N patients (68.8%) in comparison (p = 0.806). In analyzing rates of OS, the 1-year OS was 100% vs. 85.1% (p = 0.038), 2-year OS was 96.2% vs. 75.8% (p = 0.033), and 3-year OS was 88.2% vs. 59.2% (p = 0.049) for M/P patients compared to M/N patients, respectively. Conclusion With the emergence of allogeneic HSCT, the rates of OS in the Ph+ ALL population improved dramatically from the prior era. However, barriers still exist to undergoing transplant, one of the most formidable being appropriate insurance coverage. This study demonstrated that a significantly higher percentage of Ph+ ALL patients in the M/P group were able to undergo allogeneic HSCT compared to those in the M/N group. While eligibility for transplant depended on caregiver availability in addition to insurance status, there were similar rates of caregivers between the two groups, thus implying that this factor had no major impact on the differing rates of HSCT. Furthermore, M/P patients were found to have significantly higher rates of OS at the 1-year, 2-year, and 3-year marks compared to those in the M/N group. Given that broader health insurance coverage was correlated with increased rates of both allogeneic HSCT and OS, it remains a critical point of discussion in the treatment of Ph+ ALL patients from all socioeconomic backgrounds.

Introduction: The Philadelphia chromosome is associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior to the use of hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitors (TKIs), Philadelphia-positive (Ph+) ALL patients were found to have an overall survival (OS) rate of less than 20% over the course of 3 years (Thomas et al., Blood 2004). While modern day therapies including allogeneic HSCT and newer-generation TKIs such as dasatinib have led to significant improvements in OS for this population, these treatments have variable accessibility due to costs for patients with limited to no health insurance. Methods: We performed a retrospective study at the Norris Comprehensive Cancer Center and Los Angeles County Hospital, both associated with the University of Southern California, to investigate outcomes in Ph+ ALL adults with different types of health insurance. Individuals included in the study were diagnosed with Ph+ ALL between 2004-2019. Health insurance options included private insurance, Medicare, Medicaid, or no insurance. Treatment modalities included allogeneic HSCT followed by maintenance TKI therapy or combination chemotherapy plus a TKI. The former was preferred if patients met the key transplant eligibility criteria of insurance coverage and caregiver availability at home. Patient OS was defined as the time from diagnosis of Ph+ ALL until patient death. Statistical analysis was performed using the Fisher's exact probability test with two-tailed p-values Results: A total of 81 patients with Ph+ ALL were included in this study. Forty-seven patients (58%) were male and the median age at the time of diagnosis was 45 years (range 20-70). Two groups of patients were compared: those with either Medicare or private insurance (M/P) versus those with Medicaid or no insurance (M/N). Thirty-three patients (40.7%) were included in the M/P group and 48 patients (59.2%) in the M/N group. In comparing rates of OS, the 1-year OS was 100% vs. 85.1% (p = 0.038), 2-year OS was 96.2% vs. 75.8% (p = 0.033), and 3-year OS was 88.2% vs. 59.2% (p = 0.049) for M/P patients compared to M/N patients, respectively (Figure 1). In terms of treatment, there was a significant difference in the number of patients eligible to undergo allogeneic HSCT as 20 patients (60.6%) in the M/P group were able to be transplanted in contrast to 15 patients (31.3%) in the M/N group (p = 0.012). There were similar rates of caregiver availability to support HSCT between both groups; 24 M/P patients (72.7%) lived with a caregiver versus 33 M/N patients (68.8%) in comparison (p = 0.806). Furthermore, there were significantly more patients in the M/P group who were able to be treated with the newer-generation TKI dasatinib instead of the older agent imatinib compared to M/N patients (100% vs. 85.4%, p = 0.038). Conclusion: With the emergence of allogeneic HSCT and newer-generation TKIs, the rates of OS in the Ph+ ALL population improved dramatically from the prior era (Fielding et al., Blood 2009). However, barriers still exist to receiving these modern therapies, one of the most formidable being sufficient insurance coverage of costs. This study demonstrated that the Ph+ ALL population in the M/P group had significantly higher rates of OS at the 1-year, 2-year, and 3-year marks compared to those in the M/N group. Furthermore, there were also a greater percentage of patients in the former group who were able to undergo allogeneic HSCT during the study period. While eligibility for allogeneic HSCT depended on caregiver availability in addition to insurance status, there were similar rates of caregivers between the two groups, thus implying that this factor had no major impact on the differing rates of HSCT. Dasatinib was previously shown to have increased potency in inhibiting the in vitro growth of cells with wild-type BCR-ABL compared to imatinib, making it a preferred choice for TKI therapy (Li, Leukemia & Lymphoma 2008). There were again significantly more M/P patients than M/N patients who were able to be treated with dasatinib rather than imatinib. Given that health insurance status was found to be correlated with rates of OS, allogeneic HSCT, and the availability of newer-generation TKIs, it remains a critical point of discussion in the treatment of Ph+ ALL patients from all socioeconomic backgrounds. Disclosures No relevant conflicts of interest to declare.

The California Air Resources Board (ARB) adopted the low emission vehicle (LEV) III particulate matter (PM) standards in January 2012, which require, among other limits, vehicles to meet 1 mg/mi over the federal test procedure (FTP). One possible alternative measurement approach evaluated to support the implementation of the LEV III standards is integrated particle size distribution (IPSD), which reports real-time PM mass using size distribution and effective density. The IPSD method was evaluated using TSI's engine exhaust particle sizer (EEPS, 5.6-560 nm) and gravimetric filter data from more than 250 tests and 34 vehicles at ARB's Haagen-Smit Laboratory (HSL). IPSD mass was persistently lower than gravimetric mass by 56-75% over the FTP tests and by 81-84% over the supplemental FTP (US06) tests. Strong covariance between the methods suggests test-to-test variability originates from actual vehicle emission differences rather than measurement accuracy, where IPSD offered no statistical improvement over gravimetric measurement variability.

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT) provides protection in a rat model for Alzheimer’s disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2PP2A or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic β-amyloid protein. Dietary supplementation with EHT for 6–12 months resulted in substantial amelioration of all of these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiological studies indicating the coffee drinkers have substantially lowered risk of developing AD.

Hepatitis C virus (HCV) intergenotypic recombinant forms have been reported for various HCV genotypes/subtypes in several countries worldwide. In a recent study, four patients living in Austria had been identified to be possibly infected with a recombinant HCV strain. To clarify results and determine the point of recombination, full-genome next-generation sequencing using the Illumina MiSeq v2 300 cycle kit (Illumina, San Diego, CA, USA) was performed in the present study. Samples of all of the patients contained the recombinant HCV strain 2k/1b. The point of recombination was found to be within the HCV NS2 gene between nucleotide positions 3189-3200 based on H77 numbering. While three of four patients were male and had migration background from Chechnya (n = 2) and Azerbaijan (n = 1), the forth patient was a female born in Austria. Three of the four patients including the female had intravenous drug abuse as a risk factor for HCV transmission. While sequencing techniques are limited to a few specialized laboratories, a genotyping assay that uses both ends of the HCV genome should be employed to identify patients infected with a recombinant HCV strain. The correct identification of recombinant strains also has an impact considering the tailored choice of anti-HCV treatment.

Foreign acquirers own private information about domestic targets in cross-border M&As. Has this led to more aggressive insider trading by foreign insiders on domestic markets due to barriers to cross-border law enforcement? Using a sample of 10,600 M&As around the world between 1990 and 2017, we find that the answer is yes. Abnormal trading in target firm securities before the announcements of cross-border deals, in which foreigners are known to possess insider information, is systematically higher than that before the announcements of domestic deals, in which foreigners are less likely to possess insider information. The difference is mainly driven by cross-border deals in which the acquirer is from a country with high corruption and low social norms, and where the target is in a country with stricter insider trading law enforcement. Using the staggered entering into the Multilateral Memorandum of Understanding (MMoU) of 2002 by securities regulators around the world as a shock to increased coordination among securities regulators, we find that the entering into the MMoU by a country pair significantly reduces abnormal trading before cross-border deals between the country pair relative to other country pairs. Our evidence reveals a dark side of globalization and suggests that maintaining integrity in domestic securities markets cannot be done by a single country in this globalization era.