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Jain, Rakesh

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Jain

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Rakesh

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Jain, Rakesh
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    Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium
    (Springer Science and Business Media LLC, 2019-01-07) Seano, Giorgio; Nia, Hadi; Emblem, Kyrre E.; Datta, Meenal; Ren, Jun; Krishnan, Shanmugarajan; Kloepper, Jonas; Pinho, Marco C.; Ho, William W.; Ghosh, Mitrajit; Askoxylakis, Vasileios; Ferraro, Gino B.; Riedemann, Lars; Gerstner, Elizabeth; Batchelor, Tracy; Wen, Patrick; Lin, Nancy; Grodzinsky, Alan J.; Fukumura, Dai; Huang, Peigen; Baish, James W.; Padera, Timothy; Munn, Lance; Jain, Rakesh
    The compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function. We demonstrate a causal link between solid stress and neurological dysfunction by applying and removing cerebral compression, which respectively mimic the mechanics of tumour growth and of surgical resection. We also show that, in mice, treatment with lithium reduces solid-stress-induced neuronal death and improves motor coordination. Our findings indicate that brain-tumour-generated solid stress impairs neurological function in patients, and that lithium as a therapeutic intervention could counter these effects.
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    p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis
    (American Association for the Advancement of Science (AAAS), 2009-12-17) Kirsch, David G.; Santiago, Philip M.; Di Tomaso, Emmanuelle; Sullivan, Julie M.; Hou, Wu-Shiun; Dayton, Talya; Jeffords, Laura B.; Sodha, Pooja; Mercer, Kim; Cohen, Rhianna; Takeushi, Osamu; Takeuchi, Osamu; Korsmeyer, Stanley J.; Bronson, Roderick; Kim, Carla; Haigis, Kevin; Jain, Rakesh; Jacks, Tyler
    Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells mediating the GI syndrome are derived from the epithelium or endothelium, and whether the target cells die by apoptosis or other mechanisms, are controversial issues. Studying mouse models, we found that selective deletion of the pro-apoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after subtotal body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by death of GI epithelial cells by a mechanism that is regulated by p53 but independent of apoptosis.
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    Non-Invasive Monitoring of Chronic Liver Disease via Near-Infrared and Shortwave-Infrared Imaging of Endogenous Lipofuscin
    (Springer Science and Business Media LLC, 2020-08) Saif, Mari; Kwanten, Wilhelmus J.; Carr, Jessica A.; Chen, Ivy X.; Posada, Jessica; Srivastava, Amitabh; Zhang, Juanye; Zheng, Yi; Pinter, Matthias; Chatterjee, Sampurna; Softic, Samir; Kahn, C.; van Leyen, Klaus; Bruns, Oliver T.; Jain, Rakesh; Bawendi, Moungi G.
    Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.
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    A metastasis map of human cancer cell lines
    (Springer Science and Business Media LLC, 2020-12-09) Jin, Xin; Demere, Zelalem; Nair, Karthik; Ali, Ahmed; Ferraro, Gino; Natoli, Ted; Deik, Amy; Petronio, Lia; Tang, Andrew A.; Zhu, Cong; Wang, Li; Rosenberg, Danny; Mangena, Vamsi; Roth, Jennifer; Chung, Kwanghun; Jain, Rakesh; Clish, Clary B.; Vander Heiden, Matthew G.; Golub, Todd R.
    Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical due to the complexity of in vivo models. Here, we introduce an in vivo barcoding strategy capable of determining the metastatic potential of human cancer cell lines in murine xenografts at scale. We validated the robustness, scalability and reproducibility of the method, and applied it to 500 cell lines spanning 21 solid cancer types. We created a first-generation Metastasis Map (MetMap) that reveals organ-specific patterns of metastasis and allows relating those patterns to clinical and genomic features. We demonstrated the utility of MetMap by exploring the molecular basis of breast cancers capable of metastasizing to the brain – a principal cause of death in these patients. We found that breast cancers capable of metastasizing to the brain had unexpected evidence of altered lipid metabolism. Perturbing lipid metabolism curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a public resource to support metastasis research.
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    Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors
    (Nature Publishing Group, 2017) Chen, Yunching; Liu, Ya-Chi; Sung, Yun-Chieh; Ramjiawan, Rakesh R.; Lin, Ts-Ting; Chang, Chih-Chun; Jeng, Kuo-Shyang; Chang, Chiung-Fang; Liu, Chun-Hung; Gao, Dong-Yu; Hsu, Fu-Fei; Duyverman, Annique M.; Kitahara, Shuji; Huang, Peigen; Dima, Simona; Popescu, Irinel; Flaherty, Keith; Zhu, Andrew; Bardeesy, Nabeel; Jain, Rakesh; Benes, Cyril; Duda, Dan
    Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.
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    Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2
    (American Association for the Advancement of Science (AAAS), 2018) Incio, Joao; Ligibel, Jennifer; McManus, Daniel T.; Suboj, Priya; Jung, Keehoon; Kawaguchi, Kosuke; Pinter, Matthias; Babykutty, Suboj; Chin, Shan M.; Vardam, Trupti; Huang, Yuhui; Rahbari, Nuh N.; Roberge, Sylvie; Wang, Dannie; Gomes-Santos, Igor L.; Puchner, Stefan B.; Schlett, Christopher L.; Hoffmman, Udo; Ancukiewicz, Marek; Tolaney, Sara; Krop, Ian; Duda, Dan; Boucher, Yves; Fukumura, Dai; Jain, Rakesh
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    Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior
    (Nature Publishing Group, 2017) Li, Suyan; Kumar T, Peeyush; Joshee, Sampada; Kirschstein, Timo; Subburaju, Sivan; Khalili, Jahan S; Kloepper, Jonas; Du, Chuang; ElKhal, Abdallah; Szabó, Gábor; Jain, Rakesh; Köhling, Rüdiger; Vasudevan, Anju
    The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia.
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    Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy
    (2018) Pinter, Matthias; Jain, Rakesh
    Renin-angiotensin system (RAS) inhibitors (RASi)—widely prescribed for the treatment of cardiovascular diseases— have considerable potential in oncology. The RAS plays a crucial role in cancer biology and affects tumor growth and dissemination directly and indirectly by remodeling the tumor microenvironment. We review clinical data on the benefit of RASi in primary and metastatic tumors and propose that, by activating immunostimulatory pathways, these inhibitors can enhance immunotherapy of cancer.
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    Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
    (Nature Pub. Group, 2013) Chauhan, Vikash; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh
    Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics.
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    Differential Effects of Sorafenib on Liver Versus Tumor Fibrosis Mediated by Stromal-Derived Factor 1 alpha/C-X-C Receptor Type 4 Axis and Myeloid Differentiation Antigen-Positive Myeloid Cell Infiltration in Mice
    (Wiley-Blackwell, 2014) Chen, Yunching; Huang, Yuhui; Reiberger, Thomas; Duyverman, Annique M.; Huang, Peigen; Samuel, Rekha; Hiddingh, Lotte; Roberge, Sylvie; Koppel, Christina; Lauwers, Gregory Y.; Zhu, Andrew; Jain, Rakesh; Duda, Dan
    Sorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia—and its consequences on treatment resistance—remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen–positive (Gr-1+) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1+ myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis—despite persistently elevated hypoxia—in part by reducing Gr-1+ myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. Conclusion: Blocking SDF-1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment. (Hepatology 2014;59:1435-1447)