Social Threat Reduces Alcohol Consumption among College Students.

AIMS: Past research suggests that people report a greater desire to consume alcohol when they experience social threat-or threats to their social selves, such as social exclusion. Nevertheless, experimental research on the role of social threat in alcohol consumption is limited. The present study examined the causal relationship between social threat and wine consumption. METHODS: Undergraduate students (N = 83; Mage = 21.8 years old, SDage = 1.62 years old; 72.3% women; 61.4% Latinx/Hispanic) participated in a study under the pretense that they were in a focus group gauging students' opinions of a bar being constructed at their university. During the study, participants and two confederate researchers completed a group activity in which they selected design elements for the bar. Participants were randomly assigned to one of two conditions. In the social threat condition, confederates rejected participants' design choices and socially excluded them during a follow-up task. In the social acceptance condition, confederates supported participants' choices and did not socially exclude them. All participants then completed a wine taste test. RESULTS: Contrary to predictions, an independent-samples t-test revealed that participants who experienced social threat consumed significantly less wine than those who were socially accepted, t(81) = -2.22, P = 0.03, d = -0.49. Furthermore, a linear regression test revealed that this effect persisted even when controlling for typical alcohol-consumption behavior, b = 56.09, t = -2.50, P = 0.02, d = -0.61. CONCLUSION: The relationship between social threat and alcohol consumption may be more nuanced than anticipated. Discussion centers around two potential moderators including positive affect and identity.

Empirical identification and validation of tumor-targeting T cell receptors from circulation using autologous pancreatic tumor organoids.

BACKGROUND: Tumor-specific cytotoxic T cells and T cell receptors are effective tools for cancer immunotherapy. Most efforts to identify them rely on known antigens or lymphocytes that have infiltrated into the tumor bed. Approaches to empirically identify tumor-targeting T cells and T cell receptors by exploiting all antigens expressed on tumor cell surfaces are not well developed for most carcinomas, including pancreatic cancer. METHODS: Autologous tumor organoids were stimulated with T cells from the patients' peripheral blood for 2 weeks to generate the organoid-primed T (opT) cells. opT cell phenotype was analyzed by monitoring changes in the expression levels of 28 cell surface and checkpoint proteins. Expression of ligands of the immune checkpoints was investigated by immunohistochemistry staining. T cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) and assayed by flow cytometry to monitor tumor-induced T cell proliferation changes. opT cell-mediated killing of three-dimensional organoids was measured using an M30 ELISA kit. T cell receptors (TCRs) were identified by deep sequencing of gDNA isolated from T cells, and the TCR specificity was confirmed by transferring TCRs to the T cell line SKW-3 or donor T cells. RESULTS: The co-culture was effective in the generation of CD8 + or CD4+opT cells. The opT cells killed autologous tumors in a granzyme B or Fas-Fas ligand-dependent manner and expressed markers of tissue-resident memory phenotype. Each patient-derived opT cell culture displayed a unique complement of checkpoint proteins. Interestingly, only NKG2A blockade showed a potent increase in the interferon-γ production compared with blocking programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) or TIM3 or TIGIT or LAG3. Importantly, TCR sequencing demonstrated a dramatic clonal expansion of T cells with a restricted subset of TCRs. Cloning and transferring the TCRs to heterologous T cells was sufficient to confer tumor cell recognition and cytotoxic properties in a patient-specific manner. CONCLUSION: We report a platform for expanding tumor-targeting T cells from the peripheral blood of patients with pancreatic cancer. We identify the NKG2A-HLA-E axis as a potentially important checkpoint for CD8 +T cells for pancreatic cancer. Lastly, we demonstrate empirical identification of tumor-targeting TCRs that can be used for TCR-therapeutics.

PDX-derived organoids model in vivo drug response and secrete biomarkers.

Patient-derived organoid models are proving to be a powerful platform for both basic and translational studies. Here we conduct a methodical analysis of pancreatic ductal adenocarcinoma (PDAC) tumor organoid drug response in paired patient-derived xenograft (PDX) and PDX-derived organoid (PXO) models grown under WNT-free culture conditions. We report a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth, irrespective of the drug treatment. In addition, we analyzed the glycome of PDX and PXO models and demonstrate that PXOs recapitulate the in vivo glycan landscape. In addition, we identify a core set of 57 N-glycans detected in all 10 models that represent 50%-94% of the relative abundance of all N-glycans detected in each of the models. Last, we developed a secreted biomarker discovery pipeline using media supernatant of organoid cultures and identified potentially new extracellular vesicle (EV) protein markers. We validated our findings using plasma samples from patients with PDAC, benign gastrointestinal diseases, and chronic pancreatitis and discovered that 4 EV proteins are potential circulating biomarkers for PDAC. Thus, we demonstrate the utility of organoid cultures to not only model in vivo drug responses but also serve as a powerful platform for discovering clinically actionable serologic biomarkers.