New Faculty Achievements
A number of UT Southwestern Pathology faculty have released new publications, and have accomplished incredible achievements! Please join us in congratulating them for their accomplishments!
Title: Definition of haemostatic effectiveness in interventions used to treat major bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation
PATH Faculty involved: Ravi Sarode, MD.
Journal: Journal of Thrombosis and Haemostasis
In this revision, the working group aims to clarify the proposed definition as well as provide practical guidance and recommendation for a correct application of this standardized definition.
The hemostatic effectiveness is a binary assessment, i.e., effective or ineffective. The treatment outcome is regarded as “effective hemostasis” only when all criteria within the relevant bleeding type are met. Furthermore, for musculoskeletal or intracranial bleeding, an annotation of “excellent clinical outcome” could be gained when all criteria of good effectiveness and the additional predefined clinical outcome are met..
PATH Faculty involved: Wenxin Zheng, M.D.
Journal: Cancer Research
Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.
PATH Faculty involved: Shaheen Khan, Ph.D.
Journal: Cancer Cell
There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.
Title: LIFR-α-dependent Adipocyte Signaling in Obesity Limits Adipose Expansion Contributing to Fatty Liver Disease
PATH Faculty involved: Bret Evers, M.D., Ph.D.
The role of chronic adipose inflammation in diet-induced obesity (DIO) and its sequelae including fatty liver disease remains unclear. Leukemia inhibitory factor (LIF) induces JAK-dependent adipocyte lipolysis and altered adipo/cytokine expression, suppressing in vivo adipose expansion in normal and obese mouse models. To characterize LIF receptor (LIFR-α)-dependent cytokine signaling in DIO, we created an adipocyte-specific LIFR knockout mouse model (Adipoq-Cre;LIFRfl/fl). Differentiated adipocytes derived from this model blocked LIF-induced triacylglycerol lipolysis. Adipoq-Cre;LIFRfl/fl mice on a high fat diet (HFD) displayed reduced adipose STAT3 activation, 50% expansion in adipose, 20% body weight increase, and a 75% reduction in hepatic triacylglycerides compared to controls. To demonstrate that LIFR-α signals adipocytes through STAT3, we also created an Adipoq-Cre;STAT3fl/fl model that showed similar findings when fed a HFD as Adipoq-Cre;LIFRfl/fl mice. These findings establish the importance of obesity-associated LIFR-α/JAK/STAT3 inflammatory signaling in adipocytes blocking further adipose expansion in DIO contributing to ectopic liver triacylglyceride accumulation.