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Marie M Plante,1 ErinMarie O Kimbrough,2 Amit K Agarwal,3 Liuyan Jiang,4 Kirk Bourgeois,4 Greta C Stamper,5 Michael W Stewart,6 Han W Tun2 1Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA; 2Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Radiology, Mayo Clinic, Jacksonville, FL, USA; 4Department of Pathology, Mayo Clinic, Jacksonville, FL, USA; 5Department of Otolaryngology and Audiology, Mayo Clinic, Jacksonville, FL, USA; 6Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Han W Tun, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, USA, Tel +1 904 953 7290, Fax +1 904 953 2315, Email Tun.Han@mayo.eduAbstract: Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton’s tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.Keywords: hyperviscosity syndrome, Waldenström macroglobulinemia, central retinal vein occlusion, exudative maculopathy, serous macular detachment, cochlear hemorrhage, plasma exchange, genomic sequencing, CXCR4

Lyndsey L Fournier,1 ErinMarie O Kimbrough,1 Muhamad Alhaj Moustafa,1 Ke Li,2 Madiha Iqbal,1 Vivek Gupta,3 Han W Tun1 1Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Pathology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Radiology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Han W Tun, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA, Tel +1 904 953 2693, Fax +1 904 953 2315, Email Tun.Han@mayo.eduAbstract: Secondary central nervous system involvement by systemic diffuse large B-cell lymphoma (DLBCL) carries a very poor prognosis. We present a female patient who had two episodes of intracerebral central nervous system (CNS)-only relapse of systemic non-germinal center diffuse large B-cell lymphoma (NGC-DLBCL). Her treatment at initial diagnosis consisted of induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and intrathecal (IT) - methotrexate (MTX) followed by consolidation with autologous stem cell transplant (ASCT) after high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy. She had the first CNS-only relapse 1.5 years post-ASCT and received whole brain radiation therapy (WBRT). She developed the second intracerebral CNS-only relapse 2 years post-WBRT. A CNS-centric therapeutic approach with salvage chemoimmunotherapy incorporating rituximab, high-dose methotrexate (HD-MTX), high-dose cytarabine (HiDAC), and ibrutinib was utilized for her second CNS-only relapse. She underwent consolidation with a second ASCT following high-dose carmustine (BCNU) and thiotepa chemotherapy. Given her high risk of CNS recurrence, she was started on maintenance ibrutinib. To date, she has remained in complete remission for 3 years. In our experience, multiply relapsed secondary CNS lymphoma (SCNSL) with this response is very rare. We suggest one CNS-centric therapeutic approach that can potentially salvage patients with SCNSL who have not had prior exposure to adequate CNS-directed therapies but acknowledge that additional research is necessary to validate our findings.Keywords: SCNSL, relapsed CNS lymphoma, CNS lymphoma, secondary CNS DLBCL

ErinMarie O Kimbrough,1 Vivek Gupta,2 Liuyan Jiang,3 Han W Tun1 1Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Radiology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Pathology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Han W Tun, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road S., Jacksonville, FL, 32224, USA, Tel +1 904 953 2693, Fax +1 904 953 2315, Email Tun.Han@mayo.eduAbstract: Primary pituitary diffuse large B-cell lymphoma (PPL) has been regarded as a subtype of primary central nervous system lymphoma (PCNSL); however, the pituitary gland is located outside the blood brain barrier (BBB) with neural and vascular connections to the brain. Given its unique anatomic location, a combination of non-central nervous system (CNS)-penetrating and CNS-penetrating therapeutic agents can be employed to treat PPL. We report a female patient with PPL who was successfully managed with anatomy-adapted therapy incorporating non-CNS penetrating chemoimmunotherapy [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] alternating with CNS-penetrating chemoimmunotherapy [rituximab, high-dose methotrexate, and high-dose cytarabine (RMA)]. She received a total of eight cycles of treatment with four cycles of each regimen following partial transsphenoidal resection. She achieved a complete response after two cycles and has remained in complete remission for the last eight years. To our knowledge, this is the longest documented survival in a patient with PPL. Targeted genomic profiling with Next-Generation Sequencing (NGS) was recently performed on the lymphoma tissue. The genomic profile of PPL in this patient is quite different from the findings typically associated with PCNSL. We suggest that PPL may be biologically distinct from PCNSL and should be treated with an anatomy adapted approach. Additional research is necessary to confirm our findings.Keywords: primary central nervous system lymphoma, pituitary gland, primary pituitary lymphoma, endocrine dysfunction

Jordan Davis,1 ErinMarie O Kimbrough,1 Muhamad Alhaj Moustafa,1 Liuyan Jiang,2 Vivek Gupta,3 Ephraim Parent,3 Han W Tun1 1Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Pathology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Radiology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Han W Tun, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA, Tel +1 904 953 7290, Fax +1 904 953 2315, Email Tun.Han@mayo.eduAbstract: Primary cranial vault lymphoma (PCVL) is a rare lymphoma involving the skull with or without extra- and intracranial extension. Most cases of PCVL are diffuse large B-cell lymphoma (DLBCL). We report a case of primary cranial vault diffuse large B-cell lymphoma (PCV-DLBCL) that was successfully treated with anthracycline-based chemoimmunotherapy (CIT) alternating with central nervous system (CNS)-directed CIT with high-dose methotrexate and high-dose cytarabine. CNS-centric therapy was given for suspected cerebral cortical involvement and presumed elevated risk of CNS recurrence. The patient has remained in complete remission for 4.25 years following treatment. We suggest that PCV-DLBCL is potentially curable with CNS-directed therapy. Additionally, we provide genomic profiling results indicating an indeterminate cell of origin and multiple genetic mutations which are not frequently seen in DLBCL.Keywords: diffuse large B-cell lymphoma, central nervous system, calvarium, chemotherapy, scalp lesions

ErinMarie O Kimbrough,1 Liuyan Jiang,2 Ephraim E Parent,3 Kirk Bourgeois,2 Muhamad Alhaj Moustafa,1 Han W Tun,1 Madiha Iqbal1 1Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Pathology, Mayo Clinic, Jacksonville, FL, USA; 3Department of Radiology, Mayo Clinic, Jacksonville, FL, USACorrespondence: Madiha Iqbal, Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA, Tel +1 904 953 2795, Fax +1 904 953 2315, Email Iqbal.Madiha@mayo.eduAbstract: Diffuse large B-cell lymphoma (DLBCL) is well known for selectively involving certain extranodal locations such as the central nervous system (CNS), testes, and skin. DLBCL or high-grade B-cell lymphoma selectively involving the bone marrow is rare and has been sparsely reported in the medical literature. We report two cases of lymphoma presenting with primary bone marrow involvement without evidence of involvement of any other sites. The first case represents de novo DLBCL. The patient achieved complete remission with initial treatment, had a bone marrow-only relapse three years later, and achieved a second complete remission following non-transplant salvage therapy. The second case had findings consistent with “double hit” Richter’s transformation of chronic lymphocytic leukemia with translocation of c-MYC and BCL-2. This patient had an aggressive clinical course characterized by rapid progression with CNS involvement within three months resulting in the demise of the patient. These two cases represent two distinct subtypes of primary bone marrow lymphoma: de novo and transformed. Further research is necessary to gain a better understanding of this rare lymphoma entity and develop novel therapies.Keywords: diffuse large B-cell lymphoma, high-grade B-cell lymphoma with MYC and BCL-2 rearrangements, bone marrow involvement, cytopenias

Recent research has shown how norms shape political and economic decision-making. Much of this work assumes that a single norm influences the behavior of all people, but in fact, many situations are characterized by the existence of competing normative viewpoints. We apply a method for measuring belief in the simultaneous existence of multiple norms. Such multiplicity arises naturally when norms are associated with distinctive groups, and thus political polarization can be characterized, in part, as a product of diverging norms between groups. We thus assess the validity of our measurement technique by testing whether it can recover polarization on seven salient political issues on which US Democrats and Republicans tend to hold different views. We then compare the norms elicited by our method to the norms of Democrats and Republicans elicited in a separate sample using an established and validated-but methodologically less rich-measurement approach. Our study uncovers a wide range of co-existing views between and within political groups. Partisans understand their group's norms and hold personal views that align with them. They can also recognize the diversity and polarization in US public opinion by identifying norms specific to political parties and acknowledging the variety of views within their own parties, which may indicate internal divisions. This research underscores the importance of nuanced approaches to political norms that go beyond party lines. By acknowledging a plurality of views, we can encourage productive discussions and bridge ideological divides., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR , KRAS , ALK , ROS1 , BRAF , NTRK , ERBB2 , RET , MET , PIK3CA , STK11 , and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53 . Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK , ROS1 , BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53 . Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA . We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC., Competing Interests: Leylah M. Drusbosky is an employee and stockholder of Guardant Health. Yujie Zhao discloses research funding support from PDS Biotechnology, Zai Lab, Incyte, Mirati, Alpine, Pfizer, Merck, and Elucida Oncology. Rami Manochakian has previously participated on an advisory board for AstraZeneca, Takeda, Guardant Health, Janssen, Novocure, Turning Point, and OncoHost. Yanyan Lou has participated on an advisory board for AstraZeneca, Takeda, Guardant Health, Janssen, Novocure, Turning Point Therapeutics, Cardinal Health, Clinical Education Alliance, Oncohost, Mirati Therapeutics Honorarium to Mayo Clinic; Research Funding Support: Merck, Tolero Pharmaceuticals, AstraZeneca, Blueprint Medicines, Sun Pharma, Mirati Therapeutics, Genmab, EMD Serono, Jacobio pharma, TOPALLIAN, Daiichi Sankyo. ErinMarie O. Kimbrough, Julian A. Marin-Acevedo, and Ariana Mooradian declare no conflicts of interest.

The rapid growth of cultural evolutionary science, its expansion into numerous fields, its use of diverse methods, and several conceptual problems have outpaced corollary developments in theory and philosophy of science. This has led to concern, exemplified in results from a recent survey conducted with members of the Cultural Evolution Society, that the field lacks 'knowledge synthesis', is poorly supported by 'theory', has an ambiguous relation to biological evolution and uses key terms (e.g. 'culture', 'social learning', 'cumulative culture') in ways that hamper operationalization in models, experiments and field studies. Although numerous review papers in the field represent and categorize its empirical findings, the field's theoretical challenges receive less critical attention even though challenges of a theoretical or conceptual nature underlie most of the problems identified by Cultural Evolution Society members. Guided by the heterogeneous 'grand challenges' emergent in this survey, this paper restates those challenges and adopts an organizational style requisite to discussion of them. The paper's goal is to contribute to increasing conceptual clarity and theoretical discernment around the most pressing challenges facing the field of cultural evolutionary science. It will be of most interest to cultural evolutionary scientists, theoreticians, philosophers of science and interdisciplinary researchers., Competing Interests: The authors declare none., (© The Author(s) 2024.)

Norm-based accounts of social behavior in economics typically reflect tradeoffs between maximization of own consumption utility and conformity to social norms. Theories of norm-following tend to assume that there exists a single, stable, commonly known injunctive social norm for a given choice setting and that each person has a stable propensity to follow social norms. We collect panel data on 1468 participants aged 11-15 years in Belfast, Northern Ireland and Bogotá, Colombia in which we measure norms for the dictator game and norm-following propensity twice at 10 weeks apart. We test these basic assumptions and find that norm-following propensity is stable, on average, but reported norms show evidence of change. We find that individual-level variation in reported norms between people and within people across time has interpretable structure using a series of latent transition analyses (LTA) which extend latent class models to a panel setting. The best fitting model includes five latent classes corresponding to five sets of normative beliefs that can be interpreted in terms of what respondents view as "appropriate" (e.g. equality vs. generosity) and how they view deviations (e.g. deontological vs. consequentialist). We also show that a major predictor of changing latent classes over time comes from dissimilarity to others in one's network. Our application of LTA demonstrates how researchers can engage with heterogeneity in normative perceptions by identifying latent classes of beliefs and deepening understanding of the extent to which norms are shared, stable, and can be predicted to change. Finally, we contribute to the nascent experimental literature on the economic behavior of children and adolescents., Supplementary Information: The online version contains supplementary material available at 10.1007/s10683-024-09821-5., (© The Author(s) 2024.)

Introduction: The development of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) concurrently or sequentially in the same patient is a rare clinical scenario and can be labeled as a poly-lymphomatous syndrome (PLS)., Methods: We report clinico-pathologic characteristics and survival outcomes of 7 such cases from our institution. In concurrent PLS, HL is present with NHL in the same location (composite PLS) or in separate locations (discordant PLS). Sequential presentations were seen with HL following NHL or vice versa (sequential PLS)., Conclusions: It is essential to perform adequate biopsies in supposedly relapsed or refractory settings to diagnose PLS. We suggest that the incidence of PLS is likely underestimated due to the under-utilization of repeat biopsies. In patients with concurrent PLS, the treatment should ideally cover both types of lymphoma with an emphasis on tailoring the treatment towards the more aggressive lymphoma. In patients with sequential PLS, the treatment should target the new lymphoma. Consolidation treatments such as autologous hematopoietic cell transplant should be considered when there is a component of relapsed cHL or aggressive NHL. Based on our experience, PLS does not appear to be associated with a poor prognosis. Further research is necessary for better understanding of the biology and management of PLS., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR -mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR -mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.

Co-stimulatory and co-inhibitory molecules play a critical role in T cell function. Tumor cells escape immune surveillance by promoting immunosuppression. Immunotherapy targeting inhibitory molecules like anti-CTLA-4 and anti-PD-1/PD-L1 were developed to overcome these immunosuppressive effects. These agents have demonstrated remarkable, durable responses in a small subset of patients. The other mechanisms for enhancing anti-tumor activities are to target the stimulatory pathways that are expressed on T cells or other immune cells. In this review, we summarize current phase I/II clinical trials evaluating novel immunotherapies targeting stimulatory pathways and outline their advantages, limitations, and future directions.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

Many adolescent smoking prevention programmes target social norms, typically evaluated with self-report, susceptible to social desirability bias. An alternative approach with little application in public health are experimental norms elicitation methods. Using the Mechanisms of Networks and Norms Influence on Smoking in Schools (MECHANISMS) study baseline data, from 12-13 year old school pupils (n = 1656) in Northern Ireland and Bogotá (Colombia), we compare two methods of measuring injunctive and descriptive smoking and vaping norms: (1) incentivized experiments, using monetary payments to elicit norms; (2) self-report scales. Confirmatory factor analysis (CFA) examined whether the methods measured the same construct. Paths from exposures (country, sex, personality) to social norms, and associations of norms with (self-reported and objectively measured) smoking behavior/intentions were inspected in another structural model. Second-order CFA showed that latent variables representing experimental and survey norms measurements were measuring the same underlying construct of anti-smoking/vaping norms (Comparative Fit Index = 0.958, Tucker Lewis Index = 0.951, Root Mean Square Error of Approximation = 0.030, Standardized Root Mean Square Residual = 0.034). Adding covariates into a structural model showed significant paths from country to norms (second-order anti-smoking/vaping norms latent variable: standardized factor loading [β] = 0.30, standard error [SE] = 0.09, p < 0.001), and associations of norms with self-reported anti-smoking behavior (β = 0.40, SE = 0.04, p < 0.001), self-reported anti-smoking intentions (β = 0.42, SE = 0.06, p < 0.001), and objectively measured smoking behavior (β = - 0.20, SE = 0.06, p = 0.001). This paper offers evidence for the construct validity of behavioral economic methods of eliciting adolescent smoking and vaping norms. These methods seem to index the same underlying phenomena as commonly-used self-report scales.

This proof of concept study harnesses novel transdisciplinary insights to contrast two school-based smoking prevention interventions among adolescents in the UK and Colombia. We compare schools in these locations because smoking rates and norms are different, in order to better understand social norms based mechanisms of action related to smoking. We aim to: (1) improve the measurement of social norms for smoking behaviors in adolescents and reveal how they spread in schools; (2) to better characterize the mechanisms of action of smoking prevention interventions in schools, learning lessons for future intervention research. The A Stop Smoking in Schools Trial (ASSIST) intervention harnesses peer influence, while the Dead Cool intervention uses classroom pedagogy. Both interventions were originally developed in the UK but culturally adapted for a Colombian setting. In a before and after design, we will obtain psychosocial, friendship, and behavioral data (e.g., attitudes and intentions toward smoking and vaping) from ~300 students in three schools for each intervention in the UK and the same number in Colombia (i.e., ~1,200 participants in total). Pre-intervention, participants take part in a Rule Following task, and in Coordination Games that allow us to assess their judgments about the social appropriateness of a range of smoking-related and unrelated behaviors, and elicit individual sensitivity to social norms. After the interventions, these behavioral economic experiments are repeated, so we can assess how social norms related to smoking have changed, how sensitivity to classroom and school year group norms have changed and how individual changes are related to changes among friends. This Game Theoretic approach allows us to estimate proxies for norms and norm sensitivity parameters and to test for the influence of individual student attributes and their social networks within a Markov Chain Monte Carlo modeling framework. We identify hypothesized mechanisms by triangulating results with qualitative data from participants. The MECHANISMS study is innovative in the interplay of Game Theory and longitudinal social network analytical approaches, and in its transdisciplinary research approach. This study will help us to better understand the mechanisms of smoking prevention interventions in high and middle income settings., (Copyright © 2020 Hunter, Montes, Murray, Sanchez-Franco, Montgomery, Jaramillo, Tate, Kumar, Dunne, Ramalingam, Kimbrough, Krupka, Zhou, Moore, Bauld, Llorente, Sarmiento and Kee.)

Introduction: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors. Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase. Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.

Background: Toll-like receptors (TLRs) have been shown to be involved in cerebral ischemia/reperfusion (I/R) injury. TLR9 is located in intracellular compartments and recognizes CpG-DNA. This study examined the effect of CpG-ODN on cerebral I/R injury., Methods and Results: C57BL/6 mice were treated with CpG-ODN by i.p. injection 1 hour before the mice were subjected to cerebral ischemia (60 minutes) followed by reperfusion (24 hours). Scrambled-ODN served as control-ODN. Untreated mice, subjected to cerebral I/R, served as I/R control. The effect of inhibitory CpG-ODN (iCpG-ODN) on cerebral I/R injury was also examined. In addition, we examined the therapeutic effect of CpG-ODN on cerebral I/R injury by administration of CpG-ODN 15 minutes after cerebral ischemia. CpG-ODN administration significantly decreased cerebral I/R-induced infarct volume by 69.7% (6.4±1.80% vs 21.0±2.85%, P<0.05), improved neurological scores, and increased survival rate, when compared with the untreated I/R group. Therapeutic administration of CpG-ODN also significantly reduced infarct volume by 44.7% (12.6±2.03% vs 22.8±2.54%, P<0.05) compared with untreated I/R mice. Neither control-ODN, nor iCpG-ODN altered I/R-induced cerebral injury or neurological deficits. Nissl staining showed that CpG-ODN treatment preserved neuronal morphology in the ischemic hippocampus. Immunoblot showed that CpG-ODN administration increased Bcl-2 levels by 41% and attenuated I/R-increased levels of Bax and caspase-3 activity in ischemic brain tissues. Importantly, CpG-ODN treatment induced Akt and GSK-3β phosphorylation in brain tissue and cultured microglial cells. PI3K inhibition with LY294002 abolished CpG-ODN-induced protection., Conclusion: CpG-ODN significantly reduces cerebral I/R injury via a PI3K/Akt-dependent mechanism. Our data also indicate that CpG-ODN may be useful in the therapy of cerebral I/R injury.

We model competition between two firms selling identical goods to customers who arrive in the market stochastically. Shoppers choose where to purchase based upon both price and the time cost associated with waiting for service. One seller provides two separate queues, each with its own server, while the other seller has a single queue and server. We explore the market impact of the multi-server seller engaging in waiting cost-based-price discrimination by charging a premium for express checkout. Specifically, we analyze this situation computationally and through the use of controlled laboratory experiments. We find that this form of price discrimination is harmful to sellers and beneficial to consumers. When the two-queue seller offers express checkout for impatient customers, the single queue seller focuses on the patient shoppers thereby driving down prices and profits while increasing consumer surplus.

Donations and volunteerism can be conceived as market transactions with a zero explicit price. However, evidence suggests people may not view zero as just another price when it comes to pro-social behavior. Thus, while markets might be expected to increase the supply of assets available to those in need, some worry such financial incentives will crowd out altruistic giving. This paper reports laboratory experiments directly investigating the degree to which market incentives crowd out large, discrete charitable donations in a setting related to deceased organ donation. The results suggest markets increase the supply of assets available to those in need. However, as some critics fear, market incentives disproportionately influence the relatively poor.

Spiteful, antisocial behavior may undermine the moral and institutional fabric of society, producing disorder, fear, and mistrust. Previous research demonstrates the willingness of individuals to harm others, but little is understood about how far people are willing to go in being spiteful (relative to how far they could have gone) or their consistency in spitefulness across repeated trials. Our experiment is the first to provide individuals with repeated opportunities to spitefully harm anonymous others when the decision entails zero cost to the spiter and cannot be observed as such by the object of spite. This method reveals that the majority of individuals exhibit consistent (non-)spitefulness over time and that the distribution of spitefulness is bipolar: when choosing whether to be spiteful, most individuals either avoid spite altogether or impose the maximum possible harm on their unwitting victims.