PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity.

Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.

Conservative Quantization of Covariance Matrices with Applications to Decentralized Information Fusion.

Information fusion in networked systems poses challenges with respect to both theory and implementation. Limited available bandwidth can become a bottleneck when high-dimensional estimates and associated error covariance matrices need to be transmitted. Compression of estimates and covariance matrices can endanger desirable properties like unbiasedness and may lead to unreliable fusion results. In this work, quantization methods for estimates and covariance matrices are presented and their usage with the optimal fusion formulas and covariance intersection is demonstrated. The proposed quantization methods significantly reduce the bandwidth required for data transmission while retaining unbiasedness and conservativeness of the considered fusion methods. Their performance is evaluated using simulations, showing their effectiveness even in the case of substantial data reduction.

Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report.

Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944). For two months post-infusion, the patient experienced dramatic regression of subcutaneous nodules of DLBCL. Unfortunately, her CAR T exhibited kinetics unassociated with remission, and she died of DLBCL-related sequelae. Serial phenotypic analysis of peripheral blood alongside sequencing of the ß-peptide variable region of the T cell receptor (TCRß) revealed distinct waves of oligoclonal T cell expansion with dynamic expression of immune checkpoint molecules. One week prior to CAR T cell contraction, T cell immunoglobulin mucin domain 3 (Tim-3) and programmed cell death protein 1 (PD-1) exhibited peak expressions on both the CD8 T cell (Tim-3 ≈ 50%; PD-1 ≈ 17%) and CAR T cell subsets (Tim-3 ≈ 78%; PD-1 ≈ 40%). These correlative observations draw attention to Tim-3 and PD-1 signaling pathways in context of CAR T cell exhaustion.

A large-scale evaluation of computational protein function prediction.

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.

The Moral Frameworks and Foundations of Contesting Orientations.

According to contesting theory (Shields & Bredemeier, 2011), people conceptualize competition either through a metaphor of partnership or war. These two alternate metaphors suggest differing sociomoral relationships among the participants. In the current study of intercollegiate athletes (n = 610), we investigated the two approaches to contesting in relation to formalist and consequentialist moral frameworks (Brady & Wheeler, 1996) and individualizing and binding moral foundations (Haidt, 2001). Correlational analysis indicated that the partnership approach correlated significantly with all four moral dimensions, while the war approach correlated with formalist and consequentialist frameworks and binding foundations (i.e., appeals to in-group loyalty, authority, and purity). Multiple regressions demonstrated that the best predictors of a partnership approach were formalist thinking and endorsement of individualizing moral foundations (i.e., appeal to fairness and welfare). Among our primary variables, the best predictors of a war orientation were consequentialist thinking and endorsement of binding foundations.

Fresh whole blood transfusion capability for Special Operations Forces.

Fresh whole blood (FWB) transfusion is an option for providing volume and oxygen carrying capacity to bleeding Special Operations soldiers who are injured in an austere environment and who are far from a regular blood bank. Retrospective data from recent conflicts in Iraq and Afghanistan show an association between the use of FWB and survival. We reviewed the literature to document the issues surrounding FWB transfusion to Special Operations soldiers in the austere environment and surveyed the literature regarding best practice guidelines for and patient outcomes after FWB transfusions. Most literature regarding FWB transfusion is retrospective or historical. There is limited prospective evidence currently to change transfusion practice in tertiary care facilities, but FWB remains an option in the austere setting.

Predictors of Moral Disengagement in Sport.

Researchers have made productive use of Bandura's (1991) construct of moral disengagement (MD) to help explain why sport participants deviate from ethical ideals. In this study of intercollegiate athletes from diverse sports (N = 713), we examined MD in relation to other character-related variables: empathy, moral identity, moral attentiveness, and contesting orientations. We also examined whether moral attentiveness conforms to the pattern of "bracketed morality" found in moral reasoning (Shields & Bredemeier, 1995) and moral behavior (Kavussanu, Boardley, Sagar, & Ring, 2013). Results indicated that MD correlated positively with perceptual moral attentiveness and war contesting orientation; MD correlated negatively with empathy, moral identity, reflective moral attentiveness, and partnership contesting orientation. Results of hierarchical regression demonstrated that gender, contesting orientations, moral identity, and one form of moral attentiveness were significant predictors of MD. Finally, sport participants were found to be less morally attentive in sport than in everyday life.

Large-scale biomedical concept recognition: an evaluation of current automatic annotators and their parameters.

BACKGROUND: Ontological concepts are useful for many different biomedical tasks. Concepts are difficult to recognize in text due to a disconnect between what is captured in an ontology and how the concepts are expressed in text. There are many recognizers for specific ontologies, but a general approach for concept recognition is an open problem. RESULTS: Three dictionary-based systems (MetaMap, NCBO Annotator, and ConceptMapper) are evaluated on eight biomedical ontologies in the Colorado Richly Annotated Full-Text (CRAFT) Corpus. Over 1,000 parameter combinations are examined, and best-performing parameters for each system-ontology pair are presented. CONCLUSIONS: Baselines for concept recognition by three systems on eight biomedical ontologies are established (F-measures range from 0.14-0.83). Out of the three systems we tested, ConceptMapper is generally the best-performing system; it produces the highest F-measure of seven out of eight ontologies. Default parameters are not ideal for most systems on most ontologies; by changing parameters F-measure can be increased by up to 0.4. Not only are best performing parameters presented, but suggestions for choosing the best parameters based on ontology characteristics are presented.

The chemical composition and sources of road dust, and of tire and road wear particles-A review.

To gain better understanding of how the transition to electric vehicles affects road dust (RD) composition, and potential health and environmental risks, it is crucial to analyze the chemical composition of RD and identify its sources. Sources of RD include wear of tire tread (TT), brake wear (BW) and road wear (RW). A relevant component of RD are tire and road wear particles (TRWPs). This literature review compiles data on the chemical bulk composition of RD sources, RD in Asia, Europe and North America and TRWP as a RD component. The focus is on elements such as Cd, Co, Cr, Cu, Ni, Pb, V, and Zn. Although the comparability of global RD data is limited due to differences in sampling and analytical methods, no significant differences in the composition from Asia, Europe, and North America were found for most of the investigated elements studied, except for Cd, Co, and V. Sources of RD were analyzed using elemental markers. On average TT, BW, and RW contributed 3 %, 1 %, and 96 %, respectively. The highest concentrations of TT (9 %) and BW (2 %) were observed in the particle size fraction of RD ≤ 10 µm. It is recommended that these results be verified using additional marker compounds. The chemical composition of TRWPs from different sources revealed that (i) TRWPs isolated from a tunnel dust sample are composed of 31 % TT, 6 % BW, and 62 % RW, and (ii) test material from tire test stands show a similar TT content but different chemical bulk composition likely because e.g., of missing BW. Therefore, TRWPs from test stands need to be chemically characterized prior to their use in hazard testing to validate their representativeness.

Combining heterogeneous data sources for accurate functional annotation of proteins.

Combining heterogeneous sources of data is essential for accurate prediction of protein function. The task is complicated by the fact that while sequence-based features can be readily compared across species, most other data are species-specific. In this paper, we present a multi-view extension to GOstruct, a structured-output framework for function annotation of proteins. The extended framework can learn from disparate data sources, with each data source provided to the framework in the form of a kernel. Our empirical results demonstrate that the multi-view framework is able to utilize all available information, yielding better performance than sequence-based models trained across species and models trained from collections of data within a given species. This version of GOstruct participated in the recent Critical Assessment of Functional Annotations (CAFA) challenge; since then we have significantly improved the natural language processing component of the method, which now provides performance that is on par with that provided by sequence information. The GOstruct framework is available for download at http://strut.sourceforge.net.

Disseminated Peritoneal Tuberculosis Initially Misdiagnosed as Nephrogenic Ascites.

A middle-aged immigrant male from a region with endemic tuberculosis who had a history of end-stage kidney disease presented to the emergency room for routine hemodialysis and abdominal swelling. He was admitted to the medicine service for suggested daily dialysis to improve his volume overload, which was attributed to nephrogenic ascites. He was found to have several findings concerning for systemic illness, including fevers, night sweats, hypercalcemia, lymphadenopathy, omental thickening, ascitic fluid with a serum ascites albumin gradient of less than 1.1 gm/dL, and exudative pleural effusions. Our suspicion for hematologic malignancy versus disseminated infection was high. During admission, there were many diagnostic challenges in obtaining histologic and bacteriologic confirmation of our leading suspected diagnosis, disseminated tuberculosis. Ultimately, tuberculosis infection was confirmed with histologic evidence of granulomatous inflammation of cervical lymph node and sputum culture positive for Mycobacterium tuberculosis. This case highlights the necessity for every patient presenting with new ascites to undergo diagnostic paracentesis. Nephrogenic ascites is a rare syndrome that is possible in volume overloaded states but is a diagnosis of exclusion that should be supported by an exudative serum ascites albumin gradient and no evidence of an alternate etiology.

Detection of pneumothorax on ultrasound using artificial intelligence.

BACKGROUND: Ultrasound (US) for the detection of pneumothorax shows excellent sensitivity in the hands of skilled providers. Artificial intelligence may facilitate the movement of US for pneumothorax into the prehospital setting. The large amount of training data required for conventional neural network methodologies has limited their use in US so far. METHODS: A limited training database was supplied by Defense Advanced Research Projects Agency of 30 patients, 15 cases with pneumothorax and 15 cases without. There were two US videos per patient, of which we were allowed to choose one to train on, so that a limited set of 30 videos were used. Images were annotated for ribs and pleural interface. The software performed anatomic reconstruction to identify the region of interest bounding the pleura. Three neural networks were created to analyze images on a pixel-by-pixel fashion with direct voting determining the outcome. Independent verification and validation was performed on a data set gathered by the Department of Defense. RESULTS: Anatomic reconstruction with the identification of ribs and pleura was able to be accomplished on all images. On independent verification and validation against the Department of Defense testing data, our program concurred with the SME 80% of the time and achieved a 86% sensitivity (18/21) for pneumothorax and a 75% specificity for the absence of pneumothorax (18/24). Some of the mistakes by our artificial intelligence can be explained by chest wall motion, hepatization of the underlying lung, or being equivocal cases. CONCLUSION: Using learning with limited labeling techniques, pneumothorax was identified on US with an accuracy of 80%. Several potential improvements are controlling for chest wall motion and the use of longer videos. LEVEL OF EVIDENCE: Diagnostic Tests; Level III.

Passenger pathogens on physicians.

BACKGROUND: Hospital acquired infections pose a significant risk for patients undergoing hematopoietic stem cell transplantation. Horizontal transfer of antimicrobial resistance genes contributes to prevalence of multidrug-resistant infections in this patient population. METHODS: At an academic bone marrow transplantation center, we performed whole genome DNA sequencing (WGS) on commonly used physician items, including badges, stethoscopes, soles of shoes, and smart phones from 6 physicians. Data were analyzed to determine antimicrobial resistance and virulence factor genes. RESULTS: A total of 1,126 unique bacterial species, 495 distinct bacteriophages, 91 unique DNA viruses, and 175 fungal species were observed. Every item contained bacteria with antibiotic and/or antiseptic resistance genes. Stethoscopes contained greatest frequency of antibiotic resistance and more plasmid-carriage of antibiotic resistance. DISCUSSION AND CONCLUSIONS: These data indicate that physician examination tools and personal items possess potentially pathogenic microbes. Infection prevention policies must consider availability of resources to clean physical examination tools as well as provider awareness when enacting hospital policies. Additionally, the prevalence of antimicrobial resistance genes (eg, encoding resistance to aminoglycosides, ß-lactams, and quinolones) reinforces need for antimicrobial stewardship, including for immunocompromised patients. Further research is needed to assess whether minute quantities of microbes on physician objects detectable by WGS represents clinically significant inoculums for immunocompromised patients.

A corpus of full-text journal articles is a robust evaluation tool for revealing differences in performance of biomedical natural language processing tools.

BACKGROUND: We introduce the linguistic annotation of a corpus of 97 full-text biomedical publications, known as the Colorado Richly Annotated Full Text (CRAFT) corpus. We further assess the performance of existing tools for performing sentence splitting, tokenization, syntactic parsing, and named entity recognition on this corpus. RESULTS: Many biomedical natural language processing systems demonstrated large differences between their previously published results and their performance on the CRAFT corpus when tested with the publicly available models or rule sets. Trainable systems differed widely with respect to their ability to build high-performing models based on this data. CONCLUSIONS: The finding that some systems were able to train high-performing models based on this corpus is additional evidence, beyond high inter-annotator agreement, that the quality of the CRAFT corpus is high. The overall poor performance of various systems indicates that considerable work needs to be done to enable natural language processing systems to work well when the input is full-text journal articles. The CRAFT corpus provides a valuable resource to the biomedical natural language processing community for evaluation and training of new models for biomedical full text publications.

KIT Mutations Correlate with Higher Galectin Levels and Brain Metastasis in Breast and Non-Small Cell Lung Cancer.

To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the mutation status of 50 known cancer-critical genes, which were determined using multiplex PCR in tumors of the same patients. Mutations in the KIT proto-oncogene, which codes for the c-Kit protein, a receptor tyrosine kinase, correlated with higher levels of galectins -1, -3, -8, and -9 in breast cancer patients and galectin-1 in non-small cell lung cancer patients. Mutations in the KIT gene were more likely found in brain metastases from both of these primary cancers. The most common KIT mutation in our panel was p.M541L, a missense mutation in the transmembrane domain of the c-Kit protein. These results demonstrate an association between KIT oncogenic signaling and elevated serum galectins in patients with metastatic disease. Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments.

Splenic injury following endoscopic drainage of a large pancreatic pseudocyst: a case report.

BACKGROUND: Many pancreatic pseudocysts spontaneously resolve, but larger or symptomatic pseudocysts may require procedural management. Though endoscopic ultrasound guided approaches are standard of care and have high success rates, complications can include bleeding, infection, and splenic perforation. This patient case report details an unusual series of complications of endoscopic cystogastrostomy that should encourage clinicians to evaluate for anatomic disruptions caused by mass effects of pancreatic pseudocysts prior to endoscopic pseudocyst drainage. CASE PRESENTATION: A 53-year-old African American male with a past medical history notable for alcohol use disorder, chronic pancreatitis, and insulin dependent diabetes presented with a 4-day history of left upper quadrant abdominal pain. Computed tomography imaging with contrast revealed enlargement of a known pancreatic pseudocyst to 15.9 × 10.4 cm. Due to pseudocyst size and the patient's symptoms, endoscopic cystogastrostomy stent placement was performed. However, postprocedurally, he developed leukocytosis to 19,800 cells/m3 (from 14,100 cells/m3 preoperatively) as well as acute hypoxemic respiratory failure with a large left pleural effusion. Postprocedural computed tomography with contrast demonstrated a new large subcapsular splenic hematoma in communication with a new subdiaphragmatic fluid collection. Due to suspicion of endoscopic procedural complication, he underwent open laparotomy which revealed grade 4 splenic laceration, septic splenic hematoma, and a subdiaphragmatic abscess. CONCLUSIONS: While endoscopic drainage of pancreatic pseudocyst was technically successful, this case demonstrates complications from mass effect of a large pancreatic pseudocyst which putatively tore the splenorenal ligament, leading to excessive separation of the left kidney and spleen. If anatomic disruptions caused by mass effect from a pancreatic pseudocyst are recognized through preprocedural abdominal imaging, such cases may be considered for early open repair versus cystogastrostomy.

Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and -γ.

PI3K-δ and PI3K-γ are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-δ and PI3K-γ signaling can contribute to T-cell inhibition via intrinsic mechanisms and regulation of suppressor cell populations, including regulatory T-cells and myeloid derived suppressor cells in the tumor. We examine an exciting new role for using selective inhibitors of the PI3K δ- and γ-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-δ and -γ inhibition in T-cell biology, discuss existing challenges in adoptive T-cell therapies and checkpoint blockade inhibitors, and highlight ongoing efforts and future directions to incorporate PI3K-δ and PI3K-γ as synergistic T-cell modulators in immunotherapy.

Increased Circulating Levels of Galectin Proteins in Patients with Breast, Colon, and Lung Cancer.

Galectins are proteins with high-affinity ß-galactoside-binding sites that function in a variety of signaling pathways through interactions with glycoproteins. The known contributions of galectins-1, -3, -7, -8, and -9 to angiogenesis, metastasis, cell division, and evasion of immune destruction led us to investigate the circulating levels of these galectins in cancer patients. This study compares galectin concentrations by enzyme-linked immunosorbent assay (ELISA) from each stage of breast, lung, and colon cancer. Galectins-1 and -7, which share a prototype structure, were found to have statistically significant increases in breast and lung cancer. Of the tandem-repeat galectins, galectin-8 showed no statistically significant change in these cancer types, but galectin-9 was increased in colon and lung cancer. Galectin-3 is the only chimera-type galectin and was increased in all stages of breast, colon, and lung cancer. In conclusion, there were significant differences in the galectin levels in patients with these cancers compared with healthy controls, and galectin levels did not significantly change from stage to stage. These findings suggest that further research on the roles of galectins early in disease pathogenesis may lead to novel indications for galectin inhibitors.

Galectins in the Pathogenesis of Cerebrovascular Accidents: An Overview.

Due to limitations of neuroimaging, such as the isodense appearance of blood to neuronal tissue in subacute hemorrhagic stroke, a body of studies have been performed to evaluate candidate biomarkers which may aid in accurate determination of cerebrovascular accident type. Beyond aiding in the delineation of stroke cause, biomarkers could also confer useful prognostic information to help clinicians plan use of resources. One of the candidate biomarkers studied for detection of cerebrovascular accident (CVA) includes a class of proteins called galectins. Galectins bind ß-galactoside through a highly conserved carbohydrate recognition domain, endowing an ability to interact with carbohydrate moieties on glycoproteins, some of which are relevant to CVA response. Furthermore, galectins-1, -2, -3, -9, and -12 are expressed in tissues relevant to CVA, and some exhibit characteristics (eg, extracellular secretion) that could render feasible their detection in serum. Galectins-1 and -3 appear to have the largest amounts of preclinical evidence, consistently demonstrating increased activity and expression levels during CVA. However, a lack of standardization of biochemical assays across cohort studies limits further translation of these basic science studies. This review aims to increase awareness of the biochemical roles of galectins in CVA, while also highlighting challenges and remaining questions preventing the translation of basic science observations into a clinically useful test.

Financing agricultural drought risk through ex-ante cash transfers.

Despite advances in drought early warning systems, forecast information is rarely used for triggering and financing early actions, such as cash transfer. Scaling up cash transfer pay-outs, and overcoming the barriers to actions based on forecasts, requires an understanding of costs resulting from False Alarms, and the potential benefits associated with appropriate early interventions. On this study, we evaluate the potential cost-effectiveness of cash transfer responses, comparing the relative costs of ex-ante cash transfers during the maize growing season to ex-post cash transfers after harvesting in Kenya. For that, we developed a forecast model using Fast-and Frugal Trees that unravels early warning relationships between climate variability, vegetation coverage, and maize yields at multiple lead times. Results indicate that our models correctly forecast low maize yield events 85% of the time across the districts studied, some already six months before harvesting. The models' performance improves towards the end of the growing season driven by a decrease of 29% in the probability of False Alarms. Overall, we show that timely cash transfers ex-ante to a disaster can often be more cost-effective than investing in ex-post expenditures. Our findings suggest that early response can yield significant cost savings, and can potentially increase the effectiveness of existing cash transfer systems.