Applying an alternative test of herding behavior: a case study of the Indian stock market

The paper presents an alternative approach to test the herding behavior in the Indian equity market using symmetric properties of the cross sectional return distribution instead of the traditional standard deviation of the portfolio-based approach. Using the proposed approach, we find evidence of herding in the Indian market during the sample period. We also observe pronounced herding during the 2007 crash in the Indian equity market. Finally, we also observe that the rate of increase in security return dispersion as a function of the aggregate market return is lower in up market, relative to down market days, which stands contrary to the directional asymmetry documented by McQueen, Pinegar, and Thorley (1996)

Applying an alternative test of herding behavior: a case study of the Indian stock market

The paper presents an alternative approach to test the herding behavior in the Indian equity market using symmetric properties of the cross sectional return distribution instead of the traditional standard deviation of the portfolio-based approach. Using the proposed approach, we find evidence of herding in the Indian market during the sample period. We also observe pronounced herding during the 2007 crash in the Indian equity market. Finally, we also observe that the rate of increase in security return dispersion as a function of the aggregate market return is lower in up market, relative to down market days, which stands contrary to the directional asymmetry documented by McQueen, Pinegar, and Thorley (1996)

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche and metabolic reprogramming via regulation of their target genes. However, the role of miRNA in breast cancer brain metastasis (BCBM) is poorly explored. Thus, identification and understanding of miRNAs in the pathobiology of BCBM may identify a novel candidate miRNA for the early diagnosis and prevention of this devastating process. In this review, we focus on understanding the role of candidate miRNAs in the regulation of BC brain metastatic processes as well as designing novel miRNA-based therapeutic strategies for BCBM

Investigating the Anti-tumorigenic Properties of Synthetic Inhibitors of B7-H3 in Group 3 Medulloblastoma

Medulloblastomas (MB) are devastating brain tumors originating in the cerebellum most commonly in children. There are four distinct subgroups of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. The most malignant tumors possess an aggressive phenotype characterized by c-Myc amplification and deletions to chromosome 17p; they belong to group 3. Prior investigations into the significance of genes on 17p revealed that miR-1253, which is found on locus 17p13.3, is significantly downregulated in medulloblastoma and has important tumor suppressive properties. Amongst its oncogenic targets is B7-H3 (CD276), a highly deregulated oncoprotein that attenuates the immune response to MB tumors. We chose to elucidate the oncogenic properties of B7-H3 in group 3 MB using synthetic inhibitors. After screening 100,000 different compounds for: 1) docking ability, 2) oral bioavailability, 3) potential CNS activity, and 4) number of metabolic side reactions, we selected two N-terminal inhibitors: B7-H3-Ni1 and B7-H3-Ni3. In HDMB03 cells (with c-Myc amplification and i17q), we found an IC50 of 3.7 M for B7-H3-Ni1 and no discernible effect of B7-H3-Ni3. We confirmed CD276 expression inhibition using B7-H3-Ni1 via Western blotting and concurrently noted elevations in cleaved PARP (apoptosis) and reduction in p-Akt (proliferation marker), providing us preliminary insights into the mechanism of inhibition. Notably, a remarkable decline in migration and wound healing and abrogation of colony formation were observed with B7-H3-Ni1. Collectively, our findings substantiate the inhibitory properties of B7-H3-Ni1 in vitro, potentially serving as a therapeutic agent for in vivo group 3 MB tumors.https://digitalcommons.unmc.edu/surp2021/1049/thumbnail.jp

MiR-1253 Potentiates Cisplatin Response in Pediatric Medulloblastoma by Regulating Ferroptosis

Introduction Among CNS tumors, medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four subgroups, group 3 (G3MB) tumors fare the worst. Haploinsufficiency of 17p13.3 is a hallmark of these high-risk tumors; included within this locus is miR-1253, which has tumor suppressive properties in medulloblastoma. Therapeutic strategies capitalizing on the anti-neoplastic properties of miRNAs can provide promising adjuncts that can improve efficacy while mitigating toxicity of current chemotherapeutic drugs. Objective In this study, we explored the potentiation of miR-1253 on cisplatin cytotoxicity in group 3 MB. Methods We used RNA Sequencing to isolate a putative target for miR-1253 that is upregulated in G3MB, has a poor prognostic profile, and is involved in iron balance/ferroptosis. Calein AM quenching, COX IV staining and multiple stains for iron were used to study mitochondrial vs. free cytosolic iron generation. Confocal microscopy and FACs analyses were used to examine ROS generation and lipid peroxidation. Using 2 classical group 3 MB cell lines, possessing c-Myc amplification and i17q, we determined the IC50 of cisplatin in the presence of miR-1253 expression using MTT assay. We also studied colony formation, apoptosis and oxidative stress, as cisplatin is an inducer of both. Finally, ROS and ferroptosis inhibitors were used to study effects on tumor cell rescue from miR-1253 and cisplatin therapy. Results In silico and in vitro analyses revealed upregulation of ABCB7 in G3MB cancer cells and tumors. Overexpressing miR-1253, in turn, suppressed ABCB7, revealing it as a putative target with poor survival in high-expressing MB tumors. Overexpression also led to a suppression of GPX4, a ferroptosis regulator, consequently increasing labile iron pool within the mitochondria and resulting in mtROS induction. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. In miR-1253-overexpressing cancer cells, we observed a cumulative effect on cell death and colony formation with cisplatin; treatment with ROS and ferroptosis inhibitors abrogated these effects. Conclusions We conclude that miR-1253 potentiates the ferroptotic effects of cisplatin via targeting miR-1253/ABCB7/GPX4 axis.https://digitalcommons.unmc.edu/chri_forum/1010/thumbnail.jp

Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate and Improved Temozolomide Efficacy for Glioblastoma

BACKGROUND: Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. METHODS: We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM\u27s specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. RESULTS: We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTEN CONCLUSION: PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation

MiR-212-3p Functions as a Tumor Suppressor Gene in Group 3 Medulloblastoma via Targeting Nuclear Factor I/B (NFIB)

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC

MicroRNA-1 Attenuates the Growth and Metastasis of Small Cell Lung Cancer through CXCR4/FOXM1/RRM2 Axis

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis