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Comorbidity of disordered eating (DE) behaviors and nonsuicidal self-injury (NSSI) is linked to increased functional impairment. The present study identified subtypes of DE and NSSI comorbidity in a non-Western, low- and middle-income country where there has been particularly little research in this area.Latent profile analyses (LPA) were conducted to identify patterns of subgroup comorbidity in self-reported DE behaviors and NSSI behaviors, in a sample of Vietnamese high-school students (N = 1451, 51% female). Parallel-process LPA was used to predict NSSI subgroup membership from DE subgroup membership.A seven-class LPA model was identified for DE: (1) Low frequencies of all DE behaviors; (2) Frequent levels of all DE behaviors; (3) Frequent fasting and purging behaviors; (4) Frequent binge eating only; (5) Moderate binge eating; (6) Moderate fasting and purging behaviors; (7) Exercise and fasting. A two-class (high versus low) model was identified for NSSI. Odds of membership in the high-NSSI class were significantly increased for all DE classes except the class characterized by moderate binge eating. Odds of belonging to the high-NSSI class were highest for those in DE classes involving purging behaviors. Males predominated in classes characterized by high behavior dysregulation.DE and NSSI represent important clinical concerns among Vietnamese youth in urban contexts, and males may show particular vulnerability for certain risk behaviors. The association of classes of DE behaviors to NSSI was particularly strong for classes that involved purging, highlighting the importance of this specific behavior for understanding comorbidity of DE and NSSI.Disordered eating and nonsuicidal self-injury (NSSI; hurting oneself without intending to die) commonly co-occur. There has been less research on disordered eating and NSSI among individuals from non-Western or low/middle-income countries. We examined patterns of these behaviors in a school-based sample of Vietnamese adolescents. We found that patterns of disordered eating distinguished by purging showed particular links to NSSI, which could have implications for screening and treatment.

Graph theory provides a convenient framework for modeling and solving structured optimization problems. Under this framework, the modeler can arrange/assemble the components of an optimization model (variables, constraints, objective functions, and data) within nodes and edges of a graph, and this representation can be used to visualize, manipulate, and solve the problem. In this work, we present a ${\tt Julia}$ framework for modeling and solving graph-structured nonlinear optimization problems. Our framework integrates the modeling package ${\tt Plasmo.jl}$ (which facilitates the construction and manipulation of graph models) and the nonlinear optimization solver ${\tt MadNLP.jl}$ (which provides capabilities for exploiting graph structures to accelerate solution). We illustrate with a simple example how model construction and manipulation can be performed in an intuitive manner using ${\tt Plasmo.jl}$ and how the model structure can be exploited by ${\tt MadNLP.jl}$. We also demonstrate the scalability of the framework by targeting a large-scale, stochastic gas network problem that contains over 1.7 million variables., 30 pages, 14 figures

Background 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. Methods We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. Results Chronic MDMA users showed elevated GLX levels in the striatum, but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. Conclusion Our findings suggest that MDMA use affects not only serotonin, but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

Figure S1. Blockade of IL-7 but not IL-2 reduces engraftment of IL-12 conditioned (Tc1) CD8+ T cells in lymphodepleted mice. Figure S2. Blockade of cytokine signaling does not reduce the functionality of donor CD8+ T cells. Figure S3. Activated CD8+ T cells do not require TCR engagement for engraftment in an irradiated host. Figure S4. IL-7 mediated proliferation of Tc1 is STAT5 and PI3K dependent. Figure S5. Tc1 cells generated from IL-7Ralpha+/- and wildtype mice exhibit a similar profile except for IL-7Ralpha expression. Figure S6. The level of TCR stimulation, costimulation, and IL-12 drive IL-7Ralpha expression after CD8+ T cell activation.

PyMT tumor versus spleen fold change, acute infection day 6 versus spleen fold change.

Selected phosphatases up-regulated in PyMT tumor CD8+ T cells.

PyMT tumor CD8+ versus day 5 effector OT-I gene expression and fold change.

Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8+ T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhanced IL7 responsiveness was conferred by elevated IL7Rα expression, which was critical for antitumor immunity. Elevated IL7Rα expression was achievable without IL12, as polyclonal CD8+ T cells activated with high T-cell receptor (TCR) stimulation depended on T-cell IL7Rα expression and host IL7 for maximal engraftment. Finally, IL12 conditioning during the activation of human CD8+ T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL7Rα expression. Our results demonstrate the importance of the donor IL7Rα/host IL7 axis for effector CD8+ T-cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment. Cancer Immunol Res; 3(12); 1364–74. ©2015 AACR.

Despite clinical potential and recent advances, durable immunotherapeutic ablation of solid tumors is not routinely achieved. IL15 expands natural killer cell (NK), natural killer T cell (NKT) and CD8+ T-cell numbers and engages the cytotoxic program, and thus is under evaluation for potentiation of cancer immunotherapy. We found that short-term therapy with IL15 bound to soluble IL15 receptor α–Fc (IL15cx; a form of IL15 with increased half-life and activity) was ineffective in the treatment of autochthonous PyMT murine mammary tumors, despite abundant CD8+ T-cell infiltration. Probing of this poor responsiveness revealed that IL15cx only weakly activated intratumoral CD8+ T cells, even though cells in the lung and spleen were activated and dramatically expanded. Tumor-infiltrating CD8+ T cells exhibited cell-extrinsic and cell-intrinsic resistance to IL15. Our data showed that in the case of persistent viral or tumor antigen, single-agent systemic IL15cx treatment primarily expanded antigen-irrelevant or extratumoral CD8+ T cells. We identified exhaustion, tissue-resident memory, and tumor-specific molecules expressed in tumor-infiltrating CD8+ T cells, which may allow therapeutic targeting or programming of specific subsets to evade loss of function and cytokine resistance, and, in turn, increase the efficacy of IL2/15 adjuvant cytokine therapy. Cancer Immunol Res; 4(9); 799–811. ©2016 AACR.

PyMT tumor CD8+ versus day 1 effector OT-I gene expression and fold change.

Supplemental Figure 1: Five day IL-15cx treatment results in splenic CD8+ T cell activation and up-regulation of cytotoxic molecule expression in PyMT tumor-bearing mice. Supplemental Figure 2: PyMT tumor single-cell suspensions induce IL-2 / IL-15 resistance in CD8+ T cells. Supplemental Figure 3: Abundance of IL-2 / IL-15 cytokine receptor chains in PyMT tumor, acute/persistent infection, and TRM CD8+ T cells. Supplemental Figure 4: Gene expression in tumor versus acute infection CD8+ T cells. Supplemental Figure 5: Differentially-regulated transcripts in PyMT tumor CD8+ T cells versus naive, early effector, peak effector and memory T cells. Supplemental Figure 6: Human breast cancer CD8+ T cell infiltrate. Supplemental Figure 7: TRM "core signature" gene expression and transcriptional regulator TOX correlation with IL-15 resistance. Supplemental Figure 8: IL-15cx treatment of persistent virus-infected mice results in decreased relative abundance of exhausted antigen-specific CD8+ T cells. Supplemental Figure 9: Combined in vivo IL-15cx and αPD-L1 antibody treatment does not rescue PyMT CD8+ T cell cytokine non-responsiveness. Supplemental Figure 10: Expression of CD80 and CD200R on CD8+ T cells from PyMT tumor and persistent viral infection. Supplemental Figure 11: Activated and expanded tumor-specific CD8+ T cells adoptively transferred to tumor-bearing mice localize to tumor, but rapidly up-regulate PD-1 and CD244.

Transcripts up-regulated {greater than or equal to}2-fold in PyMT tumor versus splenic CD8+ T cells.

PyMT tumor CD8+ versus naive gene expression and fold change.

Supplemental Figure S5. Priming Tc17 cells with IL-12 does not increase their engraftment in the spleen.

Effector CD8+ T cells conditioned with IL12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL7-consuming host cells and improve the persistence and antitumor activity of IL12-conditioned CD8+ T cells. Using cyclophosphamide, fludarabine, and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T-cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as posttransfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared with TBI alone. Similarly, IL7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or antitumor immunity. However, IL15 or IL2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing posttransfer support with IL2 or IL15.Significance: The relationship between lymphodepletion and cytokine support plays a critical role in determining donor T-cell engraftment and antitumor efficacy. Cancer Res; 78(11); 3067–74. ©2018 AACR.

This file contains the following figures: Supplemental Figure 1. The return of host lymphocytes is affected by the type of donor CD8+ T cells. Supplemental Figure 2. Return of myeloid cells after CTX leads to more rapid host cell reconstitution than TBI-containing regimens. Supplemental Figure 3. CTX and TBI differentially affect host T cells and NK cells. Supplemental Figure 4. Donor CD8+ T cells transferred into a TBI-conditioned host maintain functional efficacy. Supplemental Figure 5. ALT-803 (IL-15/IL-15Ra complexes) augment the persistence of Tc1 cells in irradiated hosts.

Supplementary Table 1 from An Innovative Microarray Strategy Identities Informative Molecular Markers for the Detection of Micrometastatic Breast Cancer

There is increasing evidence that molecular detection of micrometastatic breast cancer in the axillary lymph nodes (ALN) of breast cancer patients can improve staging. Molecular analyses of samples obtained from the Minimally Invasive Molecular Staging of Breast Cancer Trial (n = 489 patients) indicate that whereas the majority of molecular markers are informative for the detection of metastatic breast cancer (significant disease burden), only a few are sensitive for the detection of micrometastatic disease (limited disease burden). Frequency distribution and linear regression analyses reveal that relative levels of gene expression are highly correlated with apparent sensitivity for the detection of micrometastic breast cancer (P < 0.05). These data provides statistical validation of the concept that the most informative markers for detection of micrometastatic disease are those that are most highly expressed in metastatic disease. To test this hypothesis, we developed an innovative microarray strategy. RNA from a metastatic breast cancer ALN was diluted into RNA from a normal lymph node and analyzed using Affymetrix microarrays. Expression analysis indicated that only two genes [mammaglobin (mam) and trefoil factor 1 (TFF1)] were significantly overexpressed at a dilution of 1:50. Real-time reverse transcription-PCR analysis of pathology-negative ALN (n = 72) confirm that of all the markers tested, mam and TFF1 have the highest apparent sensitivity for detection of micrometastatic breast cancer. We conclude that a dilutional microarray approach is a simple and reliable method for the identification of informative molecular markers for the detection of micrometastatic cancer.

Supplementary Figure 1 from An Innovative Microarray Strategy Identities Informative Molecular Markers for the Detection of Micrometastatic Breast Cancer

Details for comparative characterization of phenotype and anti-tumor function between the p53-KO vs. WT T cells are included.

Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor–mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope–reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229–40. ©2016 AACR.

Details for comparative characterization of the phenotype, and anti-tumor function of p53-KO vs Wt T cells is included.