Faculty Bibliography

Adipose tissue is composed of a variety of cells distributed in different depots and playing various metabolic roles. In a recent issue of Nature, Sun et al. (2020) use snRNA-seq and functional studies to identify a population of adipocytes that can suppress the thermogenic activity of neighboring adipocytes by secretion of acetate.

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.

OBJECTIVE:The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo. SUMMARY OF BACKGROUND DATA/BACKGROUND:Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo. METHODS:To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells. RESULTS:Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds. CONCLUSION/CONCLUSIONS:Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

SUMMARY/CONCLUSIONS:The authors present indocyanine green angiography to assess the effects of hyperbaric oxygen therapy and as a potential biomarker to predict healing of chronic wounds. They hypothesize that favorable initial response to hyperbaric oxygen therapy (improved perfusion) would be an early indicator of eventual response to the treatment (wound healing). Two groups were recruited: patients with chronic wounds and unwounded healthy controls. Inclusion criteria included adults with only one active wound of Wagner grade III diabetic foot ulcer or caused by soft-tissue radionecrosis. Patients with chronic wounds underwent 30 to 40 consecutive hyperbaric oxygen therapy sessions, once per day, 5 days per week; controls underwent two consecutive sessions. Indocyanine green angiography was performed before and after the sessions, and perfusion patterns were analyzed. Healing was determined clinically and defined as full skin epithelialization with no clinical evidence of wound drainage. Fourteen chronic-wound patients and 10 controls were enrolled. Unlike unwounded healthy volunteers, a significant increase in indocyanine green angiography perfusion was found in chronic-wound patients immediately after therapy (p < 0.03). Moreover, the authors found that 100 percent of the wounds that demonstrated improved perfusion from session 1 to session 2 went on to heal within 30 days of hyperbaric oxygen therapy completion, compared with none in the subgroup that did not demonstrate improved perfusion (p < 0.01). This study demonstrates a beneficial impact of hyperbaric oxygen therapy on perfusion in chronic wounds by ameliorating hypoxia and improving angiogenesis, and also proposes a potential role for indocyanine green angiography in early identification of those who would benefit the most from hyperbaric oxygen therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE/METHODS:Therapeutic, IV.

Balancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone-like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx-Cre:FNDC5/irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early-stage to adulthood. Our phenotypical analysis exhibited decreased osteoblast-related gene expression and increased osteoclast-related gene expression in bone tissues, and reduced adipose tissue browning due to bone-born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gain-of-function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.

The purpose of this study was to determine the feasibility of using mouse models for translational study of flexor tendon repair and reconstruction.

The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.

OBJECTIVE:Although some eye-tracking studies demonstrate atypical attention to faces by 6 months of age in autism spectrum disorder (ASD), behavioral studies in early infancy return largely negative results. We examined the effects of context and diagnosis on attention to faces during face-to-face live interactions in infants at high familial risk (HR) and low familial risk (LR) for ASD. METHOD:Participants were 6-, 9-, and 12-month-old siblings of children with ASD who were later determined to have ASD (n = 21), other developmental challenges (HR-C; n = 74), or typical development (TD) (HR-TD; n = 32), and low-risk, typically developing controls (LR-TD; n = 49). Infants were administered the social orienting probes task, consisting of five conditions: dyadic bid, song, peek-a-boo, tickle, and toy play. Attention to an unfamiliar examiner's face was coded by blinded raters from video recordings. RESULTS:At all ages, the ASD group spent less time looking at the examiner's face than the HR-C, HR-TD, and LR-TD groups during the Dyadic Bid and Tickle conditions (all p <.05), but not during the Song, Peek-a-Boo, or Toy Play conditions (all p >.23). Lower attention to faces during Dyadic Bid and Tickle conditions was significantly correlated with higher severity of autism symptoms at 18 months. CONCLUSION:During the prodromal stages of the disorder, infants with ASD exhibited subtle impairments in attention to faces of interactive partners during interactions involving eye contact and child-directed speech (with and without physical contact), but not in contexts involving singing, familiar anticipatory games, or toy play. Considering the convergence with eye-tracking findings on limited attention to faces in infants later diagnosed with ASD, reduced attention to faces of interactive partners in specific contexts may constitute a promising candidate behavioral marker of ASD in infancy.