Commercial Delta-8 THC Products: an Analysis of Content and Labeling.

INTRODUCTION: ∆-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid and structural isomer of ∆-9 THC that is technically legal under United States Federal law. Commercial ∆-8-THC products being sold are currently unregulated. This study aims to (1) describe the advertising and labeling of Δ-8 THC retail products; (2) compare the advertised amount of Δ-8 THC for each product to that found during independent laboratory analysis; and (3) evaluate the presence and amount of other cannabinoids in those products. METHODS: Twenty ∆-8 THC products were purchased from retail stores in Pittsburgh, PA, USA. Samples were analyzed to determine cannabinoid content using a validated UPLC-MS/MS method. Descriptive statistics were calculated for all variables. Spearman's rank order correlation was calculated for the labeled ∆-8 THC content compared to ∆-8 THC content found on our analysis. Differences in continuous variables were compared using ANOVA, Wilcoxon Rank Sum, or Kruskal-Wallis tests. RESULTS: ∆-8 THC was detected in 95% (N=19) of the sample products. A weakly positive correlation (Spearman's rho =0.40) was found between the advertised ∆-8 THC content and our analysis results. Factors associated with decreased difference in these variables included (1) solid matrix (chocolate, gummies) and (2) absence of a "lab-tested" label. Δ-9 THC was found in 35% (N=7) of the products, and CBD was found in one. CONCLUSION: A majority of the products analyzed contained ∆-8 THC in amounts that could cause intoxication. The range of ∆-8 THC content on independent analysis was wide and weakly correlated to the advertised content. ∆-8 THC, ∆-9 THC, and CBD were the only cannabinoids detected.

Measuring the monetization strategies of websites with application to pro- and anti-vaccine communities.

Anti-vaccine content and other kinds of misinformation are hypothesized to be more heavily monetized than other kinds of online content. We test this hypothesis by applying several novel and scalable measures of website monetization strategies to more than 400,000 links shared by 261 anti-vaccine Facebook pages and 190 pro-vaccine ones. Contrary to expectations, websites promoted in pro-vaccine venues do more to monetize attention than those promoted in anti-vaccine venues. This is a consequence of how intensely monetized news websites are-pro-vaccine venues share more links to news. The specific news sites shared by anti-vaccine venues are rated less credible by fact-checking organizations, but we find little substantive difference in their monetization strategies. These results emphasize the need to interpret measures of monetization within the context of the broader "attention economy".

Rising tension in the Himalayas: A geospatial analysis of Chinese border incursions into India.

The China-India border is the longest disputed border in the world. The countries went to war in 1962 and there have been recurring border skirmishes ever since. Reports of Chinese incursions into Indian territory are now a frequent occurrence. This rising tension between the world's most populous countries not only poses risks for global security and the world economy, but also has a negative impact on the unique ecology of the Himalayas, because of the expanding military infrastructure. We have assembled a unique data set of the dates and locations of the major incursions over the past 15 years. We find that the conflict can be separated into two independent conflicts, the western and eastern sectors. The incursions in these sectors are statistically independent. However, major incidents do lead to an increased tension that persists for years all along the entire Line of Actual Control (LAC). This leads us to conclude that an agreement on the exact location of a limited number of contested regions, such as the Doklam plateau on the China-Bhutan border, has the potential to significantly defuse the conflict, and could potentially settle the dispute at a further date. Building on insights from game theory, we find that the Chinese incursions in the west are strategically planned and may aim for a more permanent control over specific contested areas. This finding is in agreement with other studies into the expansionist strategy of the current Chinese government.

The Potential Proconvulsant Effects of Cannabis: a Scoping Review.

INTRODUCTION: Cannabis' effect on seizure activity is an emerging topic that remains without consensus and merits further investigation. We therefore performed a scoping review to identify the available evidence and knowledge gaps within the existing literature on cannabis product exposures as a potential cause of seizures in humans. METHODS: A scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews guidelines. The PubMed and Scopus databases were searched over a 20-year period from the date of the database query (12/21/2020). Inclusion criteria were (1) English language original research articles, (2) inclusion of human subjects, and (3) either investigation of seizures as a part of recreational cannabinoid use OR of exogenous cannabinoids as a cause of seizures. RESULTS: A total of 3104 unique articles were screened, of which 68 underwent full-text review, and 13 met inclusion/exclusion criteria. Ten of 11 studies evaluating acute cannabis exposures reported a higher seizure incidence than would be expected based on the prevalence of epilepsy in the general and pediatric populations (range 0.7-1.2% and 0.3-0.5% respectively). The remaining two studies demonstrated increased seizure frequency and/or seizure-related hospitalization in recreational cannabis users and those with cannabis use disorder. CONCLUSIONS: This scoping review demonstrates that a body of literature describing seizures in the setting of cannabis exposure exists, but it has several limitations. Ten identified studies showed a higher than expected incidence of seizures in populations exposed to cannabis products. Based on the Bradford Hill criteria, delta-9 tetrahydrocannabinol (THC) may be the causative xenobiotic for this phenomenon.

Using impression data to improve models of online social influence.

Influence, the ability to change the beliefs and behaviors of others, is the main currency on social media. Extant studies of influence on social media, however, are limited by publicly available data that record expressions (active engagement of users with content, such as likes and comments), but neglect impressions (exposure to content, such as views) and lack "ground truth" measures of influence. To overcome these limitations, we implemented a social media simulation using an original, web-based micro-blogging platform. We propose three influence models, leveraging expressions and impressions to create a more complete picture of social influence. We demonstrate that impressions are much more important drivers of influence than expressions, and our models accurately identify the most influential accounts in our simulation. Impressions data also allow us to better understand important social media dynamics, including the emergence of small numbers of influential accounts and the formation of opinion echo chambers.

CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner.

BACKGROUND & AIMS: Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions. METHODS: Liver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches. RESULTS: Deletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001). CONCLUSIONS: Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.

Rab27a plays a dual role in metastatic propensity of pancreatic cancer.

Pancreatic cancer is an aggressive malignancy, often diagnosed at metastatic stages. Several studies have implicated systemic factors, such as extracellular vesicle release and myeloid cell expansion, in the establishment of pre-metastatic niches in cancer. The Rab27a GTPase is overexpressed in advanced cancers, can regulate vesicle trafficking, and has been previously linked to non-cell autonomous control of tumor growth and metastasis, however, the role of Rab27a itself in the metastatic propensity of pancreatic cancer is not well understood. Here, we have established a model to study how Rab27a directs formation of the pre-metastatic niche. Loss of Rab27a in pancreatic cancer cells did not decrease tumor growth in vivo, but resulted in altered systemic myeloid cell expansion, both in the primary tumors and at the distant organ sites. In metastasis assays, loss of Rab27a expression in tumor cells injected into circulation compromised efficient outgrowth of metastatic lesions. However, Rab27a knockdown cells had an unexpected advantage at initial steps of metastatic seeding, suggesting that Rab27a may alter cell-autonomous invasive properties of the tumor cells. Gene expression analysis of gene expression revealed that downregulation of Rab27a increased expression of genes involved in epithelial-to-mesenchymal transition pathways, consistent with our findings that primary tumors arising from Rab27a knockdown cells were more invasive. Overall, these data reveal that Rab27a can play divergent roles in regulating pro-metastatic propensity of pancreatic cancer cells: by generating pro-metastatic environment at the distant organ sites, and by suppressing invasive properties of the cancer cells.

B cell-Derived IL35 Drives STAT3-Dependent CD8+ T-cell Exclusion in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.

Chronic epigastric pain associated with gastric anisakidosis.

Anisakidosis is an acute and, less commonly, chronic gastrointestinal tract disease caused by the ingestion of nematode larvae contained within raw or undercooked seafood. We describe a case of chronic gastric anisakidosis diagnosed by endoscopic resection of submucosal nodules in a patient with a multi-year history of epigastric abdominal pain. This case illustrates the importance of maintaining a high index of suspicion for this diagnosis, even in patients with a remote history of seafood consumption or a chronic presentation of abdominal pain.

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells.

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer.

Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4+ effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8+ T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically "cold" to "hot" tumor. Although PDA is typically resistant to anti-PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti-PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy. Cancer Immunol Res; 6(9); 1014-24. ©2018 AACR.

Determinants of HIV Incidence Disparities Among Young and Older Men Who Have Sex with Men in the United States.

This study sought to determine why young men who have sex with men (MSM) have higher HIV incidence rates than older MSM in the United States. We developed hypotheses that may explain this disparity. Data came from peer-reviewed studies published during 1996-2016. We compared young and older MSM with respect to behavioral, clinical, psychosocial, and structural factors that promote HIV vulnerability. Compared with older MSM, young MSM were more likely to have HIV-discordant condomless receptive intercourse. Young MSM also were more likely to have "any" sexually transmitted infection and gonorrhea. Among HIV-positive MSM, young MSM were less likely to be virally suppressed, use antiretroviral therapy, and be aware of their infection. Moreover, young MSM were more likely than older MSM to experience depression, polysubstance use, low income, decreased health care access, and early ages of sexual expression. These factors likely converge to exacerbate age-associated HIV incidence disparities among MSM.

Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has been proposed to standardize salivary gland fine-needle aspiration (FNA) diagnoses. This study assessed salivary gland FNA results and risk of malignancy (ROM) rates at the University of North Carolina as well as the interobserver reliability (IOR) of the atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP) categories. METHODS: The electronic medical record was searched for FNA cases from 2010 to 2017 with subsequent surgical resections. Histologic diagnosis was used for gold-standard comparison. The original cytologic results were then converted into MSRSGC categories (nondiagnostic, nonneoplastic, AUS, benign neoplasm, SUMP, suspicious, and malignant). For the assessment of IOR, 23 cases were selected with enrichment for cases diagnosed as AUS (n = 11) or SUMP (n = 9). Six boarded cytopathologists and 1 cytopathology fellow assessed representative slides and provided an MSRSGC diagnosis for each case. Fleiss' κ coefficients were calculated to determine IOR. RESULTS: The ROM was 33% for both AUS and SUMP cases; however, the risk of neoplasia was 56% for AUS cases and 100% for SUMP cases. Fleiss' κ for the AUS category was 0.217 (P < .05), and Fleiss' κ for the SUMP category was 0.024 (P = .74). CONCLUSIONS: In this study assessing the IOR of MSRSGC categories, fair agreement and slight agreement were found for the AUS and SUMP categories, respectively. Observers preferentially used the AUS or benign neoplasm category for SUMP cases, perhaps because of unfamiliarity with SUMP as a diagnostic option. The initial adoption of a new reporting system will require a quality assessment to ensure that the system is reliable and useful for clinicians. Cancer Cytopathol 2018;126:390-6. © 2018 American Cancer Society.

Intraosseous Rosai-Dorfman disease diagnosed by touch imprint cytology evaluation: A case series.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD) is a rare benign disorder that primarily affects the lymph nodes. Localized lymphadenopathy is the most common clinical manifestation of this disorder. However, RDD has been described in several extra-nodal sites including the head and neck region, soft tissue, skin, upper respiratory tract, gastro-intestinal tract and central nervous system (CNS). Involvement of the bone is considered very rare, occurring in less than 10% patients. RDD is one of the histiocytoses and the differential diagnosis includes entities such as Langerhans cell histiocytosis and Erdheim-Chester disease. In the rare intraosseous variant, the clinical and radiologic differential diagnosis is broader and includes neoplasms such as osteosarcoma and Ewing sarcoma. In this report, we describe three cases of extra-nodal, intraosseous RDD where touch imprint cytology played a crucial role in diagnosis. Two of the cases initially presented with involvement of the head and neck region and later developed intraosseous disease; while the third patient presented with primary bone involvement. The diagnosis was established by core biopsy with touch imprints of the bone lesions. The cytologic samples showed numerous histiocytes, often with neutrophils within their cytoplasm (emperipolesis) in addition to lymphocytes and plasma cells. The diagnosis of RDD was confirmed with appropriate immunohistochemical stains. Our account of these three cases of intraosseous Rosai-Dorfman disease highlights the role of cytology in the diagnosis of this rare entity.

Social Determinants of Health Associated with HBV Testing and Access to Care among Foreign-born Persons Residing in the United States: 2009 - 2012.

OBJECTIVES: To describe how select Social Determinants of Health (SDH) are associated with the burden of hepatitis B virus (HBV) infection among foreign-born persons residing in the United States. METHODS: Multivariate logistic regression was used to examine the Racial and Ethnic Approaches to Community Health (REACH) 2010 Risk Factor Survey data to investigate the independent relationship between SDH and HBV testing and access to care. RESULTS: HBV infected persons with insurance were more likely to see a physician than those without. Respondents worried about money to pay rent or mortgage were more likely to report HBV infection than individuals who reported they never worry. Compared to English speakers, Spanish-speakers were less likely to report HBV infection, Vietnamese-speakers were more likely to see a physician for HBV infection, and Khmer-speakers were less likely to be tested. CONCLUSIONS: Health insurance coverage, worries about paying rent, and language of interview all differentially affect HBV testing and linkages to care among foreign-born persons. Multi-sectorial stakeholder collaborative efforts should integrate resources to provide culturally sensitive health promotion campaigns which may improve HBV related outcomes.

Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.

Serrated neoplasia of the colon: what do we really know?

Colonoscopy offers incomplete protection from colorectal cancer, particularly in the right colon. Part of this inadequacy may be related to serrated neoplasia. Serrated polyps of the colorectum are now understood to be a heterogeneous group of polyps, some of which are cancer precursors, such as the sessile serrated adenoma (SSA) and the traditional serrated adenoma (TSA). In contrast to conventional adenomas, there is limited published literature on the epidemiology and natural history of these lesions. Furthermore, existing guidelines regarding screening and surveillance practices for these polyps are based largely on expert opinion without firm evidence. In this review, we describe the current understanding of the molecular biology, histopathology, and endoscopic features of serrated neoplasia of the colorectum, with an emphasis on aspects relevant to the practicing gastroenterologist.