Kevin Kolahi

AbbVie | ABBVIE · Precision Medicine

The concept of the early life developmental origins of health and disease (DOHaD) in adults has stimulated a new approach to understanding disease trajectories, with major public health implications. Indeed, the principle of the 'lifecourse of disease' now influences health policies internationally. Environmental influences during pregnancy and ear...

Somatic copy number gains are pervasive in many cancer types, yet their roles in oncogenesis are often poorly explored. This lack of understanding is in part due to broad extensions of copy gains across cancer genomes spanning large chromosomal regions, obscuring causal driver loci. Here we employed a multi-tissue pan-organoid modeling approach to...

Mutations in ARID1A, encoding a subunit of the BAF chromatin remodeling complex, rank amongst the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward human genetic model systems. Here, CRISPR/Cas9 knockout of ARID1A in primary TP53-/- human...

The degree that maternal glycemia affects placental metabolism of trophoblast cell types [cytotrophoblast (CTB) and syncytiotrophoblast (SCT)] in pregnant persons with gestational diabetes mellitus (GDM) is unknown. We tested the hypotheses that (a) hyperglycemia suppresses the metabolic rates of CTB and SCT; and (b) low placental metabolic activit...

Mutations in ARID1A rank among the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward genetic models. Here, CRISPR/Cas9-mediated ARID1A knockout (KO) in primary TP53−/− human gastric organoids induced morphologic dysplasia, tumorigenicity,...

Tenosynovial giant cell tumors (TGCTs) are benign neoplasms that arise from the synovium of tendon sheaths, bursae, and joints. We report a rare presentation of TGCT involving the suboccipital spine.

Two recent papers in Cell Stem Cell and Nature Medicine ( Yao et al. [2019] • Yao Y. • Xu X. • Yang L. • Zhu J. • Wan J. • Shen L. • Xia F. • Fu G. • Deng Y. • Pan M. • et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell. 2019; 26 : 17-26 • Google Scholar and Ganesh et al. [2019]...

Background & aims: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have demonstrated similar efficacy in removal of neoplastic esophageal lesions. However, significant controversy exists over the preferred resection technique. Our primary aim was to compare the pathologic specimens produced via EMR and ESD and seconda...

Introduction: The placenta employs an efficient and selective fatty acid transport system to supply lipids for fetal development. Disruptions in placental fatty acid transport lead to restricted fetal growth along with cardiovascular and neurologic deficits. Nevertheless, little is known about the molecular mechanisms involved in human placental f...

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the me...

The syncytiotrophoblast (SCT) at the maternal-fetal interface has been presumed to be the primary driver of placental metabolism, and the underlying progenitor cytotrophoblast cells (CTB) an insignificant contributor to placental metabolic activity. However, we now show that the metabolic rate of CTB is much greater than the SCT. The oxygen consump...

The placenta is a key organ in programming the fetus for later disease. This review outlines eight of many structural and physiological features of the placenta which are associated with adult onset chronic disease. 1) Placental efficiency relates the placental mass to the fetal mass. Ratios at the extremes are related to cardiovascular disease ris...

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At the 2015 IFPA annual meeting there were 12 themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology and collectively covered areas of obesity and the placenta, stem...

While the human placenta must provide selected long-chain fatty acids to support the developing fetal brain, little is known about the mechanisms underlying the transport process. We tracked the movement of the fluorescently labeled long-chain fatty acid analogue, BODIPY-C12, across the cell layers of living explants of human term placenta. Althoug...

Syncytialized cytotrophoblast contain few detectable BODIPY-C12 LDs. Cytotrophoblast cells cultured for 72hr were incubated with 2uM BODIPY-C12 for 30 mins, fixed, and immunolabeled with desmoplakin (1:200, ab16434, Abcam) as described in the methods section. Nuclei are stained with Hoechst dye. Imaging was performed using a Zeiss 880 LSM Confocal...

Time lapse confocal movie of human term placental explant over 30 minutes. BODIPY-C12 (green) is incorporated into cytotrophoblast lipid droplets (LipidTOX Far Red, red), but very little in syncytiotrophoblast. Time (min:sec). Dashed line represents the syncytiotrophoblast-cytotrophoblast interface. Magnification: 600X, Scale Bar: 5μm. (AVI)

Time lapse confocal movie of human term placental explant over 30 minutes over a larger field of view. This video illustrates a larger field of view and scans through the villus depth (0.2μm min-1). Similar to Movie S1, (BODIPY-C12 (green) is incorporated into cytotrophoblast lipid droplets (LD, LipidTOX Far Red, red), but very little in syncytiotr...

The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases like diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertil...

It is becoming increasingly clear that cells are remarkably sensitive to the biophysical cues of their microenvironment and that these cues play a significant role in influencing their behaviors. In this study, we investigated whether the early pre-implantation embryo is sensitive to mechanical cues, i.e. the elasticity of the culture environment....

Distribution of forces in the preimplantation embryo. (A) FZ-EX and FB-Z represent net forces on the zona and on the blastomeres. FZ-EX is defined as the net force operating on the ZP because of the extra-embryonic environment; FB-Z indicates the net force acting on the blastomeres and caused by the ZP. While both FB-Z and FZ-EX are dependent upon...

Method used to create wells for culturing embryos on collagen. PDMS (10∶1) was first layered onto a polystyrene dish to create a uniform, flat gel. After the first layer was cured, a second layer of PDMS, also pre-cured and pre-cut with holes, was laid on top of it. The two layers were then permanently bonded by exposing them into a reactive ion et...

Gene expression in in vivo embryos or embryos cultured on collagen or polystyrene. A. Gene expression changes of selected genes assessed by real time RT PCR: cycd (proliferation), cdx2, Eomes (trophectoderm lineage commitment) and ankrd1, ctgf (mechanotransduction). To facilitate comparisons expression in the FB was normalized to 1. Embryos culture...

Effect of Culture Environment on Preimplantation Embryo Development. Tabulated distribution of embryo development after in vitro culture for 96 hours in substrates of different stiffness. (DOCX)

More than 4.5 million children have been conceived by in vitro fertilization (IVF). Interestingly, singleton IVF offspring born at term have an increased incidence of low birth weight. The mechanism responsible for the lower birth weight is unknown, but alterations in placental function are possible. Hence, the goal of our study was to examine plac...

In nearly all aspects of biology, forces are a relevant regulator of life's form and function. More recently, science has established that cells are exquisitely sensitive to forces of varying magnitudes and time scales, and they convert mechanical stimuli into a chemical response. This phenomenon, termed mechanotransduction, is an integral part of...

Filamins are actin binding proteins that contribute to cytoskeletal integrity and biochemical scaffolds during mechanochemical signal transductions. Structurally, human filamins are dimers composed of an actin-binding domain with 24 immunoglobulin (Ig)-like repeats. In this study, we focus on the recently solved high-resolution crystal structure of...

The process of epithelial morphogenesis is ubiquitous in animal development, but much remains to be learned about the mechanisms that shape epithelial tissues. The follicle cell (FC) epithelium encapsulating the growing germline of Drosophila is an excellent system to study fundamental elements of epithelial development. During stages 8 to 10 of oo...

Rearrangement of the actin cytoskeleton is integral to cell shape and function. Actin-binding proteins, e.g., filamin, can naturally contribute to the mechanics and function of the actin cytoskeleton. The molecular mechanical bases for filamin's function in actin cytoskeletal reorganization are examined here using molecular dynamics simulations. Si...