Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient\u27s hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual\u27s TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing

A Divergent Synthetic Approach to Diverse Molecular Scaffolds: Assessment of Lead-Likeness using LLAMA, an Open-Access Computational Tool

Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient\u27s hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual\u27s TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing

Integrating plant physiology into simulation of fire behavior and effects

Wildfires are a global crisis, but current fire models fail to capture vegetation response to changing climate. With drought and elevated temperature increasing the importance of vegetation dynamics to fire behavior, and the advent of next generation models capable of capturing increasingly complex physical processes, we provide a renewed focus on representation of woody vegetation in fire models. Currently, the most advanced representations of fire behavior and biophysical fire effects are found in distinct classes of fine-scale models and do not capture variation in live fuel (i.e. living plant) properties. We demonstrate that plant water and carbon dynamics, which influence combustion and heat transfer into the plant and often dictate plant survival, provide the mechanistic linkage between fire behavior and effects. Our conceptual framework linking remotely sensed estimates of plant water and carbon to fine-scale models of fire behavior and effects could be a critical first step toward improving the fidelity of the coarse scale models that are now relied upon for global fire forecasting. This process-based approach will be essential to capturing the influence of physiological responses to drought and warming on live fuel conditions, strengthening the science needed to guide fire managers in an uncertain future

Carbon stored in live ponderosa pines in the Sierra Nevada will not return to pre-drought (2012) levels during the 21st century due to bark beetle outbreaks

Outbreaks of several bark beetle species can develop rapidly in response to drought and may result in large transfers of carbon (C) stored in live trees to C stored in dead trees (10s of Tg C yr-1 in the western U.S. alone), which over time will be released back to the atmosphere. The western pine beetle (WPB) outbreak incited by the 2012–2015 mega-drought in the Sierra Nevada, California, U.S., could portend more frequent and/or severe bark beetle outbreaks as the temperature warms and drought frequency and intensity increase in the future. However, changes in the frequency and/or severity (resultant levels of host tree mortality) of beetle outbreaks are difficult to predict as outbreaks are complex with non-linear and eruptive processes primarily driven by interactions among beetle populations, the demography of hosts and other tree species, and climate and weather. Using an insect phenology and tree defense model, we projected the future likelihood of WPB outbreaks in the Sierra Nevada with climate drivers from different Earth System Models. Our goal was to understand how host (ponderosa pine, PIPO) recovery and future warming and drought affect the frequency and severity of WPB outbreaks and their C consequences. Our projections suggested that by 2100 the C stored in live PIPO (mean: 1.98 kg C m-2, 95% CI: 1.74–2.21 kg C m-2) will not return to levels that occurred before the 2012–2015 drought (2012: ∼2.30 kg C m-2) due to future WPB outbreaks. However, differences in climate models indicate a wide range of possible WPB outbreak frequencies and severities. Our results suggest that total plot basal area is the most significant factor in the mortality rate of PIPO by WPB in any given year, followed by drought severity and temperature. High levels of host basal area, higher temperature, and extreme drought all contribute to the frequency and severity of future WPB outbreaks. While PIPO basal area may decline under increased drought and warming, limiting high-stand basal area (>60 m2 ha-1) may reduce the severity of future WPB outbreaks in the Sierra Nevada

AmphibiCare: Providing Medical Supplies and Urgent Care to South Sudan

South Sudan with its swampy, desolate terrain, has only 50 km of paved roads making it hard to travel and distribute medical supplies to remote areas, which are susceptible to numerous diseases. We have designed a prototype, all-terrain vehicle, that can overcome these harsh terrains[4] . Our prototype was able to traverse simulated terrain similar to that found in South Sudan[2]

Lymph Node Metastases from Non-Melanoma Skin Cancer of the Head and Neck

Non-melanoma skin cancer (NMSC) represents the most common malignancy in the world, comprising exceedingly common lesions such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) and rare lesions such as Merkel cell carcinoma. Risk factors are widely recognized and include ultraviolet (UV) light exposure, radiation exposure, immunosuppression, and many others. As a whole, survival and functional outcomes are favorable, but each histopathological subtype of NMSC behaves differently. Treatment regimens for the primary site usually include wide surgical excision and neck dissection in cases of clinically involved metastatic lymph nodes. The elective management of draining nodal basins, however, is a contested topic. Nearly all subtypes, excluding BCC, have a significant risk of lymphatic metastases, and have been studied with regard to sentinel lymph node biopsy (SLNB) and elective neck dissection. To date, no studies have definitively established a true single standard of care, as exists for melanoma, for any of the NMSCs. As a result, the authors have sought to summarize the current literature and identify indications and management options for the management of the cervical lymphatics for each major subtype of NMSC. Further research remains critically necessary in order to develop complete treatment algorithms

A new hero emerges: another exceptional mammalian spine and its potential adaptive significance

The hero shrew's (Scutisorex somereni) massive interlocking lumbar vertebrae represent the most extreme modification of the vertebral column known in mammals. No intermediate form of this remarkable morphology is known, nor is there any convincing theory to explain its functional significance. We document a new species in the heretofore monotypic genus Scutisorex; the new species possesses cranial and vertebral features representing intermediate character states between S. somereni and other shrews. Phylogenetic analyses of DNA sequences support a sister relationship between the new species and S. somereni. While the function of the unusual spine in Scutisorex is unknown, it gives these small animals incredible vertebral strength. Based on field observations, we hypothesize that the unique vertebral column is an adaptation allowing these shrews to lever heavy or compressive objects to access concentrated food resources inaccessible to other animals