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"Cohen, David"
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Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.
Journal Article
Mathematical Modelling of Molecular Pathways Enabling Tumour Cell Invasion and Migration
Understanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-β-dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.
Journal Article
From Medical Exceptions to Reproductive Freedom
Since the Supreme Court overruled Roe v. Wade in 2022, there has been a significant focus on pregnancy complications. This focus has created some risks. Highlighting medically indicated abortion stories could stigmatize the vast majority of abortion seekers who lack medical reasons for abortion and result in narrow remedies that do nothing to undermine abortion bans. This Article presents a way to convert these risks into an opportunity: to use pregnancy complications as a wedge to challenge abortion bans more generally and make abortion more accessible for everyone. We present a long-term strategy to dismantle abortion bans, using several legal theories surrounding pregnancy complications to show that abortion bans are inherently vague, religiously discriminatory, and arbitrary. We then zoom out and show that pregnancy complication cases reveal that Dobbs itself is unworkable and must be overturned. Though the current Supreme Court is unlikely to adopt the theories we describe, there is already evidence that state and lower federal courts are open to them. Moreover, legal losses have the potential to sway public attitudes by revealing how all abortions are health-saving.
Journal Article
Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement
Intermediate-risk patients with aortic stenosis were randomly assigned to undergo either transcatheter or surgical aortic-valve replacement. At 5 years, there was no significant difference between the two groups in the incidence of death or disabling stroke. The incidence of aortic regurgitation was higher with transcatheter AVR.
Journal Article
Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis
Patients with proximal deep-vein thrombosis were assigned to undergo anticoagulation either alone or combined with pharmacomechanical thrombolysis. After 6 to 24 months, there was no significant between-group difference in the incidence of the post-thrombotic syndrome.
Journal Article