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Glioblastoma (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in part, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive drug delivery route to the brain, but has been severely limited by the blood-brain barrier (BBB). Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD. SPNPs containing siRNA against Signal Transducer and Activation of Transcription 3 factor (STAT3 i ) result in in vitro and in vivo downregulation of STAT3, a central hub associated with GBM progression. When combined with the standard of care, ionized radiation, STAT3 i SPNPs result in tumor regression and long-term survival in 87.5% of GBM-bearing mice and prime the immune system to develop anti-GBM immunological memory. The lack of effective drug delivery strategies has impaired the therapeutic progress in the treatment of glioblastoma (GBM). Here, the authors engineer synthetic protein nanoparticle based on polymerized human serum albumin equipped with the cell-penetrating peptide iRGD to deliver siRNA against STAT3 and report improved survival in a mouse model of GBM.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8 + T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8 + T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.

ETFs combine features of open-end and closed-end funds. In this paper, we investigate how the unique characteristics affect ETFs’ response to investor sentiment. We employ a novel identification strategy to distinguish between the response of liquidity traders, short-term arbitrageurs and long-term arbitrageurs. We find that liquidity traders respond positively to sentiment, which results in a subsequent cumulative 12-month return of −8%. Long-term arbitrageurs who go long the ETF, and short the underlying asset benefit from this return reversal. Finally, short-term arbitrageurs respond negatively to the Baker and Wurgler (2006) sentiment measure. Their actions are profitable in the long-run as ETFs that experience fewer redemptions from short-term arbitrageurs experience weaker returns reversals.

Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.

Purpose The authors study the effect of an exogenous shock in the form of Coronavirus lockdowns on individual default and on default contagion within the microfinance (MF) sector in India. The authors rely on proprietary data obtained from an MF institution for the period from Nov 2019 to Dec 2020. The authors show that default increased to 95.29% in the month of April 2020, when Covid lockdowns were fully in place. However, borrowers bounced back thereafter, either making full or partial payments, so that defaults had fallen to 5.92% by December 2020. Static features of the group lending model like peer monitoring and joint liability help explain 90% of the monthly deficit during Covid lockdowns among uneducated borrowers. Dynamic features such as contingent renewal help explain why defaults were cured quickly through timely repayments. Finally, there is an absence of default contagion at the district level. Indeed, lagged own default explains 96.6% of variation in individual default, rather than contagion through group, village or district-level defaults. The authors conclude that the MF sector is resilient to exogenous shocks like the pandemic. Design/methodology/approach The authors use time series panel regressions, as well as cross-sectional regressions. Findings The authors find that borrower defaults increased significantly to 95.29% during the month of April 2020, when Covid lockdowns were fully in place. However, borrowers bounced back almost immediately, either making full or partial payments, such that defaults had fallen to 5.92% by December 2020. The group lending model does remarkably well in explaining defaults even during Covid lockdowns. Among the majority (92%) of borrowers who are residents of rural districts, the group lending model appears to blunt the impact of the exogenous shock on rates of default. Indeed, panel regressions demonstrate that the group lending model helps explain 90% of the monthly deficit among uneducated borrowers. Logistic regressions indicate that the group lending model is less persuasive among relatively affluent borrowers residing in semi-urban or urban areas who have some formal schooling. Contingent renewal is shown to be an effective disciplining mechanism when a group does default due to the Covid lockdowns. The authors find that groups who defaulted in April 2020 but repaid the outstanding balance within the next two months were more likely to receive subsequent loans from the lender. On the other hand, groups who defaulted in April 2020 and did not repay the outstanding balance until December 2020 did not receive follow-on financing. Finally, the authors find that lagged individual default is the primary source of individual default, rather than contagion through group, village or district-level defaults. Research limitations/implications The limitation of the study is that it is confined to a single MF institution in India. Social implications The authors conclude that the social capital that is the foundation of the group lending model succeeds in limiting both the risk and contagion of default from an exogenous shock, such as the Covid pandemic. Originality/value To the best of the authors’ knowledge, the authors are the first to examine defaults in the Indian MF sector during the Covid lockdowns in April 2020.

The author compares the relative response of Treasury fund flows to the sentiment-prone Michigan Survey of Inflation Expectations and to the Blue Chip Survey of Financial Forecasts, a professional forecast of inflation. The Treasury market is an ideal subject for examining whether or not sentiment affects flows: it is highly liquid, making it unlikely that it is hard to arbitrage, and inflation is the primary factor affecting its returns. Using mutual fund inflows into TIPs and Treasury mutual funds that occurred between January 1991 and June 2011, the author finds that the Michigan Survey is insignificantly related to flows into inflation-indexed TIPs and is positively related to flows into nominal Treasury funds. The Blue Chip Survey does not have incremental explanatory power. The evidence is consistent with a combination of a hedging motive and a flight to liquidity triggered by information in the Michigan Survey about households’ perception of financial market risk. The two motives reinforce each other in driving flows into nominal Treasury funds when the Michigan forecast of inflation is high, while they appear to cancel each other out in determining flows into the illiquid TIPS market.

OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse primary patient derived GBM model and human glioma biopsies. We evaluated the molecular landscape of oncostreams by laser capture microdissection (LCM) followed by RNA-Sequencing and bioinformatics analysis. RESULTS/ANTICIPATED RESULTS: Oncostreams are multicellular structures of 10-20 cells wide and 2-400 μm long. They are distributed throughout the tumors in mouse and human GBM. Oncostreams are heterogeneous structures positive for GFAP, Nestin, Olig2 and Iba1 cells and negative for Neurofilament. Using GEMM we found a negative correlation between oncostream density and animal survival. Moreover, examination of patient’s glioma biopsies evidenced that oncostreams are present in high grade but no in low grade gliomas. This suggests that oncostreams may play a role in tumor malignancy. Our data also indicated that oncostreams aid local invasion of normal brain. Transcriptome analysis of oncostreams revealed 43 differentially expressed (DE) genes. Functional enrichment analysis of DE genes showed that “collagen catabolic processes”, “positive regulation of cell migration”, and “extracellular matrix organization” were the most over-represented GO biological process. Network analysis indicated that Col1a1, ACTA2, MMP9 and MMP10 are primary target genes. These genes were also overexpressed in more malignant tumors (WT-IDH) compared to the less malignant (IDH1- R132H) tumors. Confocal time lapse imagining of 3D tumor slices demonstrated that oncostreams display a collective motion pattern within gliomas that has not been seen before. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, oncostreams are anatomically and molecularly distinctive, regulate glioma growth and invasion, display collective motion and are regulated by the extracellular matrix. We propose oncostreams as novel pathological markers valuable for diagnosis, prognosis and designing therapeutics for GBM patients.

Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM. [Display omitted] Kamran and colleagues provide compelling evidence that shows that inhibiting the critical immunosuppressive myeloid network in the glioma (GBM) tumor microenvironment enhances the efficacy of the immune stimulatory gene therapy, thereby enabling robust anti-GBM immunity to inhibit brain cancer progression and elicit long-term survival of GBM-bearing mice.