Biology subjects

George, B.

Publications and source records attributed to George, B..

23 records · Page 2Linked to original sources

bioRxiv2019

Cellular Fitness Phenotype of Cancer Target Genes in Repurposing Cancer Therapeutics

To define the growing significance of cellular targets of cancer drugs, we examined the fitness dependency of cellular targets or effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular mediators or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules were approved. Additionally, our analysis recognized 43 cellular targets as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues repurposing approved oncology drugs in cancer types. For example, we found the widespread upregulation and fitness dependency of the components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these targets and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the in-tended cellular effectors of drug might not be fitness genes and offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

cancer biology↗

bioRxiv2019

Community driven dynamics of oscillatory network responses to threat

Physiological responses to threat stimuli involve neural synchronized oscillations in cerebral networks with distinct organization properties. Community architecture within these networks and its dynamic adaptation could play a critical role in achieving optimal physiological responses.\n\nHere we applied dynamic network analyses to address the early phases of threat processing at the millisecond level, describing multi-frequency (theta and alpha) integration and basic reorganization properties (flexibility and clustering) that drive physiological responses. We quantified cortical and subcortical network interactions and captured illustrative reconfigurations using community allegiance as essential fingerprints of large-scale adaptation.\n\nA theta band driven community reorganization of key anatomical regions forming the threat network (TN) along with transitions of nodes from the dorsal attention (DAN) and salience (SN) circuits predict the optimal physiological response to threat. We show that increase flexibility of the community network architecture drives the physiological responses during instructed threat processing. Nodal switches modulate the directionality of information flows in the involved circuits.\n\nThese results provide a captivating perspective of flexible network responses to threat and shed new light on basic physiological principles relevant for the development of stress- and threat-related mental disorders.

neuroscience↗

bioRxiv2019

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ long-term hematopoietic stem cells

Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single-cell transplants (1-3) and lineage tracing (4, 5) suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs) (6). We show that NEO1+Hoxb5+ LT-HSCs expand with age and respond to myeloablative stress, while NEO1-Hoxb5+ LT-HSCs exhibit no significant change in number. NEO1+Hoxb5+ LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1-Hoxb5+ LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+Hoxb5+ LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution, while NEO1-Hoxb5+ LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression comparison reveals increased expression of cell cycle genes and evidence of lineage-priming in the NEO1+ fraction. Finally, transplanted NEO1+Hoxb5+ LT-HSCs rarely generate NEO1-Hoxb5+ LT-HSCs, while NEO1-Hoxb5+ LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced, NEO1-Hoxb5+ LT-HSCs can hierarchically precede active, myeloid-biased NEO1+Hoxb5+ LT-HSCs.\n\nSIGNIFICANCE STATEMENTHematopoietic stem cells (HSCs) are rare cells that have the unique ability to regenerate themselves and produce all blood cells throughout life. However, HSCs are functionally heterogeneous and several studies have shown that HSCs can differ in their contribution to major blood lineages. In this study, we discovered that the surface marker, Neogenin-1, can divide mouse HSCs into two subpopulations--one that is more active but biased towards producing myeloid cells and another that is more dormant and capable of equally producing all blood lineages. Neogenin-1 reveals the diversity and hierarchical relationship of HSCs in the mouse bone marrow, enables the prospective isolation of myeloid-biased and balanced HSCs, and opens opportunities to do the same in humans.

cell biology↗

bioRxiv2019

Enabling MHC-mismatched hematopoietic stem cell transplants and organ graft tolerance without chemotherapy or radiation

Hematopoietic stem cell (HSC) transplantation can replace diseased blood systems with a healthy one, thereby treating or curing genetic blood and immune disorders including autoimmune diseases and immunodeficiencies. However, toxic chemotherapy or radiation is necessary to ablate an animals existing blood system prior to HSC transplantation, leading to significant morbidity. To accomplish safer blood-system replacement we developed a combination of six monoclonal antibodies to safely and specifically deplete the HSCs, T cells and NK cells of immune-competent mice. Remarkably, immunologically-foreign (allogeneic) HSCs mismatched at half or all the MHC genes could engraft these antibody-treated mice, generating donor blood systems that stably co-existed with host blood cells. These chimeric immune systems were immunologically tolerant to heart tissue from the HSC donor, providing a safe platform for HSC transplantation as a means to solid organ transplantation. The ability to transplant MHC-mismatched HSCs without chemotherapy or radiation has significant ramifications for regenerative medicine.

immunology↗

bioRxiv2017

Effects of mechanical loading on cortical defect repair using a novel mechanobiological model of bone healing

Mechanical loading is an important aspect of post-surgical care. The timing of load application relative to the injury event is thought to differentially regulate repair depending on the stage of healing. Here, we show using a novel mechanobiological model of cortical defect repair that daily loading (5 N peak load, 2 Hz, 60 cycles, 4 consecutive days) during hematoma consolidation and inflammation disrupts the injury site and activates cartilage formation on the periosteal surface adjacent to the defect. We also show that daily loading during the matrix deposition phase enhances both bone and cartilage formation at the defect site, while loading during the remodeling phase results in an enlarged woven bone regenerate. All loading regimens resulted in abundant cellular proliferation within the regenerate and at the periosteal surface and fibrous tissue formation directly above the defect. Stress was concentrated at the edges of the defect during exogenous loading, and finite element (FE)-modeled longitudinal strain ({varepsilon}zz) values along the anterior and posterior borders of the defect (~2200 {varepsilon}) were an order of magnitude larger than strain values on the proximal and distal borders (~50-100 {varepsilon}). These findings demonstrate that all phases of cortical defect healing are sensitive to physical stimulation. In addition, the proposed novel mechanobiological model offers several advantages including its technical simplicity and its well-characterized and spatially confined repair program, making effects of physical and biological interventions more easily assessed.

bioengineering↗