Martin L Kahn, M.D.

Influence of the hepatic eukaryotic initiation factor 2alpha(eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism
Birkenfeld A.L.; Lee H.-Y.; Majumdar S.; Jurczak M.J.; Camporez J.P.; Jornayvaz F.R.; Frederick D.W.; Guigni B.; Kahn M.; Zhang D.; Weismann D.; Arafat A.M.; Pfeiffer A.F.; Lieske S.; Oyadomari S.; Ron D.; Samuel V.T.; Shulman G.I.
2011 ;286(42):36163-36170, Journal of biological chemistry
Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2alphasignaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2alpha (eIF2alpha-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2alpha-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2alpha. Inhibition of the eIF2alpha-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2alpha inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2alpha. Together, these data imply that the hepatic ER stress eIF2alpha signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2alpha-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2alpha is crucial for proper resolution of insulin-induced ER stress
— id: 139756, year: 2011, vol: 286, page: 36163, stat: Journal Article,

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy
Zhang, W; Winder, T; Ning, Y; Pohl, A; Yang, D; Kahn, M; Lurje, G; Labonte, M J; Wilson, P M; Gordon, M A; Hu-Lieskovan, S; Mauro, D J; Langer, C; Rowinsky, E K; Lenz, H-J
2011 Jan;22(1):104-109, Annals of oncology
Purpose: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy. PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique. RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes. CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials
— id: 144132, year: 2011, vol: 22, page: 104, stat: Journal Article,

Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling
Bertozzi, Cara C; Schmaier, Alec A; Mericko, Patricia; Hess, Paul R; Zou, Zhiying; Chen, Mei; Chen, Chiu-Yu; Xu, Bin; Lu, Min-min; Zhou, Diane; Sebzda, Eric; Santore, Matthew T; Merianos, Demetri J; Stadtfeld, Matthias; Flake, Alan W; Graf, Thomas; Skoda, Radek; Maltzman, Jonathan S; Koretzky, Gary A; Kahn, Mark L
2010 Jul 29;116(4):661-670, Blood
Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK-SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre-mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76-dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development
— id: 149095, year: 2010, vol: 116, page: 661, stat: Journal Article,

Klf2 is an essential regulator of vascular hemodynamic forces in vivo
Lee, John S; Yu, Qing; Shin, Jordan T; Sebzda, Eric; Bertozzi, Cara; Chen, Mei; Mericko, Patti; Stadtfeld, Matthias; Zhou, Diane; Cheng, Lan; Graf, Thomas; MacRae, Calum A; Lepore, John J; Lo, Cecilia W; Kahn, Mark L
2006 Dec;11(6):845-857, Developmental cell
Hemodynamic responses that control blood pressure and the distribution of blood flow to different organs are essential for survival. Shear forces generated by blood flow regulate hemodynamic responses, but the molecular and genetic basis for such regulation is not known. The transcription factor KLF2 is activated by fluid shear stress in cultured endothelial cells, where it regulates a large number of vasoactive endothelial genes. Here, we show that Klf2 expression during development mirrors the rise of fluid shear forces, and that endothelial loss of Klf2 results in lethal embryonic heart failure due to a high-cardiac-output state. Klf2 deficiency does not result in anemia or structural vascular defects, and it can be rescued by administration of phenylephrine, a catecholamine that raises vessel tone. These findings identify Klf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function
— id: 149111, year: 2006, vol: 11, page: 845, stat: Journal Article,

Is it open or is it closed? Thrombosis of a St. Jude's tricuspid valve prosthesis
Mehra, Divya; Tunick, Paul A; Goodkin, Gregory M; Kahn, Martin L; Kronzon, Itzhak
2002 May;19(4):341-342, Echocardiography
A 49-year-old woman with mitral and tricuspid mechanical valve prostheses developed marked weight gain with increasing abdominal girth and facial plethora 4 weeks after anticoagulation was temporarily interrupted for abdominal surgery. Transthoracic and transesophageal echocardiography documented severe tricuspid stenosis and regurgitation. The two discs of the tricuspid prosthesis were immobilized, half open and half closed. The prosthesis was replaced and the patient did well
— id: 32129, year: 2002, vol: 19, page: 341, stat: Journal Article,

Doppler echocardiography and computed tomography in diagnosis of left coronary arteriovenous fistula
Slater, J; Lighty, G W Jr; Winer, H E; Kahn, M L; Kronzon, I; Isom, O W
1984 Dec;4(6):1290-1293, Journal of the American College of Cardiology
A 37 year old man with recurrent episodes of endocarditis was found to have a large left coronary arteriovenous fistula communicating with the right atrium. The origin and termination of the fistula were identified using computed tomography and two-dimensional Doppler echocardiography. Coronary angiography confirmed the diagnosis and the patient underwent a successful operation
— id: 100121, year: 1984, vol: 4, page: 1290, stat: Journal Article,

RESPONSE AND REACTION TO CARDIAC DRUGS
Kahn, ML
1982 ;14(15):52-5?, Emergency medicine
— id: 30308, year: 1982, vol: 14, page: 52, stat: Journal Article,

Frequency-force relationships of mammalian ventricular muscle in vivo and in vitro
Kahn, M L; Kavaler, F; Fisher, V J
1976 Mar;230(3):631-636, American journal of physiology
The change in contractility with increasing heart rate was studied in the left ventricle of dogs and in isolated trabeculae carneae of cats. For some of the studies in situ a transient isovolumic state was created by aortic occlusion. At physiological temperatures the frequency-force relationship is flatter than at room temperature and at the same temperature it is flatter in vivo than in vitro. The frequency-(dF/dt)max relationship is steeper than the frequency-force relationship at both temperatures in vivo and in vitro. The frequency-(dF/dt)max relationship is steeper in vitro than it is in situ, although the discrepancy is less marked than in the case of the frequency-force relationship. It is concluded that 'staircase' plays less of a physiological role in adjustment of contractile state in situ than might be inferred from studies of isolated tissue
— id: 134990, year: 1976, vol: 230, page: 631, stat: Journal Article,