Faculty Bibliography

Animal development entails the organization of specific cell types in space and time, and spatial patterns must form in a robust manner. In the zebrafish spinal cord, neural progenitors form stereotypic patterns despite noisy morphogen signaling and large-scale cellular rearrangements during morphogenesis and growth. By directly measuring adhesion forces and preferences for three types of endogenous neural progenitors, we provide evidence for the differential adhesion model in which differences in intercellular adhesion mediate cell sorting. Cell type-specific combinatorial expression of different classes of cadherins (N-cadherin, cadherin 11, and protocadherin 19) results in homotypic preference ex vivo and patterning robustness in vivo. Furthermore, the differential adhesion code is regulated by the sonic hedgehog morphogen gradient. We propose that robust patterning during tissue morphogenesis results from interplay between adhesion-based self-organization and morphogen-directed patterning.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.

BACKGROUND:There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes. OBJECTIVE:The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies. METHODS:PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13). RESULTS:The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo. CONCLUSIONS:Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.

BACKGROUND:Lipoprotein insulin resistance (LPIR) score is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. It is elevated in obesity and may provide information not captured in glycosylated hemoglobin and homeostatic model assessment for insulin resistance. While bariatric surgery reduces diabetes incidence and resolves metabolic syndrome, the effect of bariatric surgery on LPIR is untested. OBJECTIVES/OBJECTIVE:We sought to assess the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on LPIR in nondiabetic women with obesity. SETTING/METHODS:Nonsmoking, nondiabetic, premenopausal Hispanic women, age ≥18 years, undergoing Roux-en-Y gastric bypass or sleeve gastrectomy at Bellevue Hospital were recruited for a prospective observational study. METHODS:Anthropometric measures and blood sampling were performed preoperatively and at 6 and 12 months postoperatively. LPIR was measured by nuclear magnetic resonance spectroscopy. RESULTS:. LPIR was reduced by 35 ± 4% and 46 ± 4% at 6 and 12 months after surgery, respectively, with no difference by procedure. Twenty-seven of 53 patients met International Diabetes Federation criteria for metabolic syndrome preoperatively and had concomitant higher homeostatic model assessment for insulin resistance, glycosylated hemoglobin, nonhigh-density lipoprotein-cholesterol and LPIR. Twenty-five of 27 patients experienced resolution of metabolic syndrome postoperatively. Concordantly, the preoperative differences in homeostatic model assessment for insulin resistance, glycosylated hemoglobin, and nonhigh-density lipoprotein-cholesterol between those with and without metabolic syndrome resolved at 6 and 12 months. In contrast, patients with metabolic syndrome preoperatively exhibited greater LPIR scores at 6 and 12 months postoperatively. CONCLUSION/CONCLUSIONS:This is the first study to demonstrate improvement in insulin resistance, as measured by LPIR, after bariatric surgery with no difference by procedure. This measure, but not traditional markers, was persistently higher in patients with a preoperative metabolic syndrome diagnosis, despite resolution of the condition.

Myelin loss in the brain is a common occurrence in traumatic brain injury (TBI) that results from impact-induced acceleration forces to the head. Fast and abrupt head motions, either resulting from violent blows and/or jolts, cause rapid stretching of the brain tissue, and the long axons within the white matter tracts are especially vulnerable to such mechanical strain. Recent studies have shown that mechanotransduction plays an important role in regulating oligodendrocyte progenitors cell differentiation into oligodendrocytes. However, little is known about the impact of mechanical strain on mature oligodendrocytes and the stability of their associated myelin sheaths. We used an in vitro cellular stretch device to address these questions, as well as characterize a mechanotransduction mechanism that mediates oligodendrocyte responses. Mechanical stretch caused a transient and reversible myelin protein loss in oligodendrocytes. Cell death was not observed. Myelin protein loss was accompanied by an increase in intracellular Ca²⁺ and Erk1/2 activation. Chelating Ca²⁺ or inhibiting Erk1/2 activation was sufficient to block the stretch-induced loss of myelin protein. Further biochemical analyses revealed that the stretch-induced myelin protein loss was mediated by the release of Ca²⁺ from the endoplasmic reticulum (ER) and subsequent Ca²⁺ -dependent activation of Erk1/2. Altogether, our findings characterize an Erk1/2-dependent mechanotransduction mechanism in mature oligodendrocytes that de-stabilizes the myelination program.

Pancreatic ductal adenocarcinoma carries a dismal prognosis, and outcomes have improved little with modern therapeutics. Checkpoint-based immunotherapy has failed to elicit responses in the vast majority of patients with pancreatic cancer. Alongside tumor cell-intrinsic mechanisms associated with oncogenic KRAS-induced inflammation, the tolerogenic myeloid cell infiltrate has emerged as a critical impediment to adaptive antitumor immune responses. Furthermore, the discovery of an intratumoral microbiome and the elucidation of host-microbe interactions that curtail antitumor immunity also present opportunities for intervention. Here we review the mechanisms of immunotherapy resistance in pancreatic ductal adenocarcinoma and discuss strategies to directly augment T cell responses in parallel with myeloid cell- and microbiome-targeted approaches that may enable immune-mediated control of this malignancy.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.

Objective; To analyze a case of complex multisite carbapenems-resistant Klebsiella pneumoniae (CRKP) infection,and to evaluate the rationality of the treatment scheme,so as to provide reference for rational use of drugs.
Method(s): The clinical and laboratory data of the patient were collected,and the clinical efficacy was observed,laboratory indexes and the results of etiological examination were compared, treatment effect was evaluated and relevant literature was reviewed. Results and
Conclusion(s): In the treatment of the patient,meropenem,amikacin combined with fosfomycin were used. Literature retrieval revealed that there were many kinds of antimicrobial therapy options for CRKP infection, but cure rate was not clear. The prevalence of CRKP was more feasible in the intensive care unit(ICU). Reducing irrational use of broad-spectrum antibacterials and unnecessary invasive manipulation were effective strategies for the control of CRKP prevalence and reduction of economic burden on patients.
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PURPOSE OF REVIEW:Atherosclerosis is a complicated cardiovascular disease characterized by unbalanced lipid metabolism and unresolved inflammation that occurred inside of arteries. The transcytosis of LDL across the endothelium and its accumulation in the arterial wall is the initial step of atherosclerosis. Here, we summarize recent research into the understanding of the regulatory mechanisms of endothelial LDL transcytosis and its relevance in the development of atherosclerosis. RECENT FINDINGS:A number of recent studies have revealed the contribution of caveolae, activin-like kinase 1 (ALK1) or scavenger receptor B1 (SR-B1) in endothelial LDL transcytosis and the progression of atherosclerosis. Caveolin-1 (Cav-1), the major protein component in caveolae, is required for the formation of caveolae and caveolae-mediated LDL uptake and transcytosis across the endothelium. SR-B1 and ALK1 directly bind LDL and facilitate the transport of LDL through the endothelial cells. The change in expression of caveolae-associated proteins and SR-B1 regulates endothelial LDL transcytosis and the pathogenesis of atherosclerosis. SUMMARY:Caveolae, ALK1 and SR-B1 are identified as key regulators in the LDL transcytosis across the endothelium. Endothelial LDL transcytosis might be a potential therapeutic approach to limit the initiation of early atherosclerosis and treat the atherosclerotic vascular diseases.