Traumatic renal artery dissection: from imaging to management.

Injury to the renal artery following blunt trauma is detected increasingly due to widespread and early use of multidetector computed tomography (CT), but optimal treatment remains controversial as no guidelines are available. This review illustrates the spectrum of imaging findings of traumatic renal artery dissection based on our experience, with the aim of understanding the physiopathology of ischaemic damage to the kidney, and the process of choosing the best therapeutic strategy (conservative, endovascular, surgical). Five main patterns of traumatic renal artery dissection are described: avulsion of renal hilum; dissection of the segmental renal branches; preocclusive main renal artery dissection; renal artery stenosis without flow limitation; thrombogenic renal artery intimal tear. In the polytrauma patient, management depends on various factors (haemodynamic status, associated lesions, time of diagnosis) rather than on the degree of renal artery stenosis. Non-operative management (NOM) is the preferred option in case of non-flow-limiting dissection of the renal artery and angio-embolisation is an important adjunct to NOM in cases of active bleeding. Embolisation of the renal artery stump may be the best option in cases of occlusive dissection, as catheter manipulation carries a high risk of vessel rupture. The therapeutic window for kidney revascularisation in cases of flow-limiting dissection of main renal artery may be variable. Endovascular stenting >4 h after trauma should be performed only if residual flow with preserved parenchymal perfusion is detected at angiography. Antiplatelet therapy administration is recommended in cases of stenting, but conditioned by the bleeding risk of the patient.

The effects of visceral obesity and androgens on bone: trenbolone protects against loss of femoral bone mineral density and structural strength in viscerally obese and testosterone-deficient male rats.

SUMMARY: In males, visceral obesity and androgen deficiency often present together and result in harmful effects on bone. Our findings show that both factors are independently associated with adverse effects on femoral bone structure and strength, and trenbolone protects rats from diet-induced visceral obesity and consequently normalises femoral bone structural strength. INTRODUCTION: In light of the rapidly increasing incidence of obesity and osteoporosis globally, and recent conjecture regarding the effects of visceral adiposity and testosterone deficiency on bone health, we investigated the effects of increased visceral adipose tissue (VAT) mass on femoral bone mineral density (BMD), structure and strength in normal weight rats with testosterone deficiency. METHODS: Male Wistar rats (n = 50) were fed either standard rat chow (CTRL, n = 10) or a high-fat/high-sugar diet (HF/HS, n = 40). Following 8 weeks of feeding, rats underwent sham surgery (CTRL, n = 10; HF/HS, n = 10) or orchiectomy (HF/HS + ORX, n = 30). Following a 4-week recovery period, mini-osmotic pumps containing either vehicle (CTRL, n = 10; HF/HS, n = 10; HF/HS + ORX, n = 10), 2.0 mg kg day(-1), testosterone (HF/HS + ORX + TEST, n = 10) or 2.0 mg kg day(-1) trenbolone (HF/HS + ORX + TREN, n = 10) were implanted for 8 weeks of treatment. Dual-energy X-ray absorptiometry and three-point bending tests were used to assess bone mass, structure and strength of femora. RESULTS: Diet-induced visceral obesity resulted in decreased bone mineral area (BMA) and content (BMC) and impaired femoral stiffness and strength. Orchiectomy further impaired BMA, BMC and BMD and reduced energy to failure in viscerally obese animals. Both TEST and TREN treatment restored BMA, BMC, BMD and energy to failure. Only TREN reduced visceral adiposity and improved femoral stiffness and strength. CONCLUSIONS: Findings support a role for both visceral adiposity and testosterone deficiency as independent risk factors for femoral osteoporosis, adverse bone geometry and impaired bone strength in male rats. Trenbolone may be a more effective candidate for androgen replacement therapy than testosterone in viscerally obese testosterone-deficient males.

Myocardial structure, function and ischaemic tolerance in a rodent model of obesity with insulin resistance.

Obesity and its comorbidities (dyslipidaemia, insulin resistance and hypertension) that together constitute the metabolic syndrome are all risk factors for ischaemic heart disease. Although obesity has been reported to be an independent risk factor for congestive heart failure, whether obesity-induced heart failure develops in the absence of increased afterload (induced by hypertension) is not clear. We have previously shown that obesity with insulin resistance decreases myocardial tolerance to ischaemia-reperfusion, but the mechanism for this decreased tolerance remains unclear. We hypothesize that obesity with insulin resistance induces adverse cardiac remodelling and pump dysfunction, as well as adverse changes in myocardial prosurvival reperfusion injury salvage kinase (RISK) pathway signalling to reduce myocardial tolerance to ischaemia-reperfusion. Wistar rats were fed an obesogenic (obese group) or a standard rat chow diet (control group) for 32 weeks. Echocardiography was performed over the 32 weeks before isolated Langendorff-perfused hearts were subjected to 40 min coronary artery ligation followed by reperfusion, and functional recovery (rate-pressure product), infarct size and RISK pathway function were assessed (Western blot analysis). Obesity with insulin resistance increased myocardial lipid accumulation but had no effect on in vivo or ex vivo left ventricular structure/function. Hearts from obese rats had lower reperfusion rate-pressure products (13115 ± 562 beats min(-1) mmHg for obese rats versus 17781 ± 1109 beats min(-1) mmHg for control rats, P < 0.05) and larger infarcts (36.3 ± 5.6% of area at risk in obese rats versus 14.1 ± 2.8% of area at risk in control rats, P < 0.01) compared with control hearts. These changes were associated with reductions in RISK pathway function, with 30-50 and 40-60% reductions in Akt and glycogen synthase kinase 3 beta (GSK-3ß) expression and phosphorylation, respectively, in obese rat hearts compared with control hearts. Total endothelial nitric oxide synthase expression was reduced by 25% in obese rats. We conclude that obesity with insulin resistance had no effect on basal cardiac structure or function but decreased myocardial tolerance to ischaemia-reperfusion. This reduction in ischaemic tolerance was likely to be due to compromised RISK pathway function in obese, insulin-resistant animals.

[Diagnosis of large-vessel vasculitis using [18F]-FDG PET-CT]. / Diagnosi di vasculite dei grandi vasi con (18)F-FDG PET-TC.

PURPOSE: The aim of this retrospective study was to assess the performance of fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography ([(18)F]-FDG PET-CT) for diagnosing large-vessel vasculitis (LVV) for a subset of patients at increased risk of rheumatic/immune diseases, taking into account concurrent immunosuppressive therapy. MATERIALS AND METHODS: The study comprised 64 rheumatological referrals with suspected LVV; half of the patients were on immunosuppressive therapy at the time of examination. The final diagnosis of LVV was established in 31 patients. To evaluate vascular uptake, the nuclear medicine physician employed both a semiquantitative method based on standardised uptake value (SUV) determination and a qualitative method based on a visual score from 0 to 3 on the maximum intensity projection (MIP) reformats. Finally, a joint assessment was carried out between the nuclear medicine physician and the reporting radiologist, in which PET metabolic data were re-evaluated taking into account clinical data and baseline CT scans. McNemar's test was used to compare four types of analysis: semiquantitative (cutoff ≥ 2.4), qualitative with standard cutoff (grade ≥ 2), qualitative with reduced cutoff (grade ≥ 1) and joint. RESULTS: Semiquantitative analysis (sensitivity 74.19%, specificity 78.78%, accuracy 76.56%) and qualitative analysis with standard cutoff (sensitivity 64.51%, specificity 84.84%, accuracy 75.00%) showed no statistical difference for the diagnosis of LVV, whereas qualitative analysis with lower cutoff (sensitivity 93.54%, specificity 75.75%, accuracy 84.37%) proved to be better than the other two. Joint analysis (sensitivity 93.54%, specificity 93.93%, accuracy 93.75%) introduced some corrective elements not present in the qualitative analysis with cutoff ≥ 1 and therefore increased specificity significantly. CONCLUSIONS: Interpretation of PET-CT should be individualised for each patient by taking into account clinical-radiological and metabolic data. To this end, cooperation between the nuclear medicine specialist and the radiologist is essential.

Paragangliomas in an endemic area: from genetics to morphofunctional imaging. A pictorial essay.

The aim of this pictorial essay is to illustrate the morphological [computed tomography (CT) and magnetic resonance imaging (MRI)], vascular (angiography) and functional (nuclear medicine) features of paragangliomas, uncommon lesions of the head and neck region and even more of the thorax, abdomen and pelvis, arising in an endemic area in northern Italy. These hypervascular, well-circumscribed masses usually have innocuous clinical manifestations as slowly enlarging soft-tissue lesions; however, more rarely, they can cause cranial-nerve palsy, particularly lesions arising near the skull base, or symptoms related to their secreting activity. Most paragangliomas are benign and their prognosis is directly related to the location of the tumour: those arising at the carotid body have the best outcome, whereas those located at the skull base have a less favourable prognosis. Angiography is required preoperatively in larger paragangliomas for surgical planning (vascular mapping) and, rarely, for preoperative embolisation. Morphological and functional imaging is also mandatory for surgical and/or radiometabolic treatment planning and follow-up.

Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer.

Platelet-derived growth factor receptor (PDGFR)alpha expression was found in ovarian cancer cells and tumors by microarray hybridization. This led us to test whether ovarian cancers also produce ligands for this receptor, as this would demonstrate that such malignancies support their own growth and spread through autocrine activation. We assayed the expression of ligands for the PDGFR in ovarian tumors, cell lines and peritoneal fluid using RT-PCR, immunohistochemistry (IHC) and ELISA. We detected strong mRNA expression for the PDGFRalpha ligands in most ovarian tumors. Receptor and ligand expressions (PDGFRalpha and PDGF AB) were also detected by IHC in, respectively, 34 and 32 of 47 ovarian tumors. The stainings for PDGFRalpha and PDGF AB were strongly correlated (P-value=0.014), suggesting that an autocrine loop is functional in ovarian cancer. PDGF AA and BB were quantified in peritoneal fluid by ELISA. Both ligands are secreted at higher levels in ovarian cancer ascites specimens (n=54) than in fluid from nonmalignant disorders (n=8). PDGF was detected in media conditioned by ovarian cancer cells. Such conditioned media induced activation of the PDGFR, Akt and MAPK and stimulated cell proliferation. A neutralizing PDGF antibody blocked these effects. Specific PDGFR inhibition by siRNA or a neutralizing antibody to the receptor inhibited PDGF-stimulated receptor activation and cell proliferation, suggesting that receptor targeting has a role in ovarian cancer treatment.

Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-kappaB.

The death domain-containing receptor superfamily and their respective downstream mediators control whether or not cells initiate apoptosis or activate NF-kappaB, events critical for proper immune system function. A screen for upstream activators of NF-kappaB identified a novel serine-threonine kinase capable of activating NF-kappaB and inducing apoptosis. Based upon domain organization and sequence similarity, this novel kinase, named mRIP3 (mouse receptor interacting protein 3), appears to be a new RIP family member. RIP, RIP2, and mRIP3 contain an N-terminal kinase domain that share 30 to 40% homology. In contrast to the C-terminal death domain found in RIP or the C-terminal caspase-recruiting domain found in RIP2, the C-terminal tail of mRIP3 contains neither motif and is unique. Despite this feature, overexpression of the mRIP3 C terminus is sufficient to induce apoptosis, suggesting that mRIP3 uses a novel mechanism to induce death. mRIP3 also induced NF-kappaB activity which was inhibited by overexpression of either dominant-negative NIK or dominant-negative TRAF2. In vitro kinase assays demonstrate that mRIP3 is catalytically active and has autophosphorylation site(s) in the C-terminal domain, but the mRIP3 catalytic activity is not required for mRIP3 induced apoptosis and NF-kappaB activation. Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a tissue-specific regulator of apoptosis and NF-kappaB activity. While the lack of a dominant-negative mutant precludes linking mRIP3 to a known upstream regulator, characterizing the expression pattern and the in vitro functions of mRIP3 provides insight into the mechanism(s) by which cells modulate the balance between survival and death in a cell-type-specific manner.

The down-regulation of alpha-interferon receptors in human lymphoblastoid cells: relation to cellular responsiveness to the antiproliferative action of alpha-interferon.

Human lymphoblastoid cell lines (Daudi, Daudi subclones, Raji and MOLT-4) were compared for sensitivity to the antiproliferative action of alpha-interferon (IFN-alpha) and down-regulation of IFN-alpha receptors. IFN-sensitive and IFN-resistant cell lines have similar numbers (2-4000/cell) of high affinity (20-75 pM) IFN-alpha receptors. Treatment of IFN-sensitive cells with low concentrations (3-10 pM) of IFN-alpha results in low receptor occupancy and nearly complete (greater than 95%) down-regulation of cell surface IFN-alpha receptors within 5 h. Treatment of resistant cells with higher IFN concentrations (30 pM) only results in partial (approximately 60%) receptor down-regulation that is directly related to receptor occupancy. Receptor-receptor interactions, induced by IFN-alpha binding, may account for the enhanced down-regulation of IFN-alpha receptors in IFN-sensitive cells. Such interactions apparently do not occur in IFN-resistant lymphoblastoid cell lines.

Mediation of anorexia by human recombinant tumor necrosis factor through a peripheral action in the rat.

Human recombinant tumor necrosis factor (TNF) produces significant anorexia in the rat which persists for up to 24 h after a single dose (5 micrograms/325 g rat). Dose-response studies indicate similar potencies for TNF following central or peripheral administration. Brain 125I-TNF levels were more than 100-fold greater after intracerebroventricular than i.v. injection, whereas blood levels of radioactivity were quite similar following both routes of administration. Gel filtration chromatography and precipitation by trichloroacetic acid showed that the radioactive label which exited the central nervous system was associated with intact TNF. The rapid effusion of 125I-TNF from the central nervous system resulted in detection of similar levels of the cytokine in a number of important target tissues (skin, muscle, fat) relative to that detected after peripheral administration. After i.v. or intracerebroventricular administration, blood levels of TNF declined rapidly to nearly undetectable levels over 4 h. However, the anorexia induced by TNF was sustained, and feeding remained depressed between 6 and 24 h postadministration. These observations suggest that TNF produces its anorectic effects at peripheral sites, possibly through mediators.

Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing.

Homology PCR has been used to identify receptor tyrosine kinases (RTKs) expressed during activation of rat hepatic stellate cells, the key fibrogenic mesenchymal element in the liver. Partial cDNAs encoding several RTKs were cloned from stellate cells activated in vivo, including those of Flt-1, Flk-1, c-met, PDGFR, and Tyro10/DDR2. RNAse protection from cells activated in vivo demonstrated biphasic induction of flt-1 and flk-1 mRNAs, receptors for vascular endothelial growth factor (VEGF). Culture-activation of stellate cells was associated with increased [125I]VEGF binding and Flt-1 and Flk-1 receptor protein. Induction of VEGF binding sites correlated with an 2.5-fold increase in DNA synthesis in response to VEGF, but only if cells were activated by growth on collagen 1, whereas cells maintained in a quiescent state on a basement membrane-like substratum (EHS matrix) were nonproliferative. In both stellate and endothelial cells VEGF-induced mitogenesis was augmented by co-incubation with basic fibroblast growth factor (bFGF), a cytokine with known synergy with VEGF. These findings suggest that the cellular targets of VEGF in liver may not be confined to sinusoidal endothelial cells, and that VEGF responses reflect combined effects on both hepatic stellate cells and sinusoidal endothelium.

Consequences of 125I-labeled insulin degradation by hepatocytes on the interpretation of receptor binding studies.

The association of 125I-labeled insulin with hepatocytes was assayed by filtration or microcentrifugation. Assay by centrifugation resulted in a greater amount of retained radioactive label throughout the course of association of 125I-labeled insulin with hepatocytes. Similarly, saturation experiments assayed by microcentrifugation suggested greater binding than filtration. During dissociation, cells isolated by centrifugation release a greater amount of rapid-dissociating radioactive label. Control experiments of [3H]-inulin exclusion with cell pellets, which were isolated during microcentrifugation, demonstrated that the difference between the methods was not due to extracellular trapping of radioactivity. Therefore, the data suggested that there was more low-affinity retention when binding was assayed by centrifugation than filtration. The integrity of the 125I-labeled insulin extracted from hepatocytes was determined by column chromatography. A substantially greater proportion of the extracted radioactivity was fragments of 125I-labeled insulin in cells isolated by centrifugation. It is suggested that the extensive washing of the cells during filtration removes more fragments than does centrifugation. During dissociation, the low-affinity component of radioactivity, which was observed in the centrifugal assay, resulted from the transient retention of insulin fragments. The extensive degradation of insulin, which was assayed by either method, and the differences observed between these methods, should be considered in the interpretation of binding experiments with cells.

The effects of bioregulators upon amino acid transport and protein synthesis in isolated rat hepatocytes.

Isolated rat hepatocytes prepared by an enzyme perfusion technique possess a functional amino acid transport system and retain the capacity to synthesize protein. Amino acid transport was studied using the non-metabolizable amino acid analog alpha-aminoisobutyric acid. The transport process was time, temperature and concentration dependent. Similarly, leucine incorporation into protein was time and temperature dependent being optimal at 3m degrees C. Amino acid, fetal calf serum, growth hormone and glucose all produced small, reproducible increases in protein synthesis rates. Bovine serum albumin diminished the uptake of alpha-aminoisobutyric acid and leucine incorporation into protein. The amino acid content on either side of the cell membrane was found to affect transport into or out of the cellular compartment (transconcentration effects). High cell concentrations decreased transport and protein synthesis as a result of isotopic dilution of labelled amino acids with those released by the hepatocytes. This was consistent with the capacity of naturally occurring amino aicds to compete with alpha-aminoisobutyric acid for uptake into the hepatocyte. In order to define more precisely the effects of bioregulators on transport and protein synthesis it will be necessary to define and subfractionate cellular compartments and proteins which are the specific targets of cellular regulation.

Binding and degradation of 125I-labeled insulin by a clonal line of rat pituitary tumor cells.

Receptor sites for insulin on GH3 cells were characterized. Uptake of 125I-labeled insulin by the cells was dependent upon time and temperature, with apparent steady-states reached by 120, 20 and 10 min at 4, 23 and 37 degrees C, respectively. The binding sites were sensitive to trypsin, suggesting that the receptors contain protein. Insulin competed with 125I-labeled insulin for binding sites, with half-maximal competition observed at 5 nM insulin. Neither adrenocorticotropic hormone nor growth hormone competed for 125I-labeled insulin binding sites. 125I-labeled insulin binding was reversible, and saturable with respect to hormone concentration. 125I-labeled insulin was degraded at both 4 and 37 degrees C by GH3 cells, but not by medium conditioned by these cells. After a 5 min incubation at 37 degrees C, products of 125I-labeled insulin degradation could be recovered from the cells but were not detected extracellularly. Extending the time of incubation resulted in the recovery of fragments of 125I-labeled insulin from both cells and the medium. Native insulin inhibited most of the degradation of 125I-labeled insulin suggesting that degradation resulted, in part, from a saturable process. At steady-state, degradation products of 125I-labeled insulin, as well as intact hormone, were recovered from GH3 cells. After 30 min incubation at 37 degrees C, 80% of the cell-bound radioactivity was not extractable from GH3, cells with acetic acid.

Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor.

Vascular endothelial cell growth factor (VEGF) is a ligand for the tyrosine kinase receptor Flk-1/KDR and Flt1 and is considered to be an endothelial cell specific mitogen that plays an important role in angiogenesis. Since Flk-1 mRNA has been detected in primitive and more mature hematopoietic cells, recombinant human VEGF was evaluated for its influence on hematopoiesis, which was assayed as in vitro colony formation by myeloid progenitor cells from human bone marrow. VEGF enhanced colony formation by mature subsets of granulocyte-macrophage and erythroid progenitor cells that had been stimulated with a colony stimulating factor. In contrast, VEGF inhibited colony formation by more immature subsets of granulocyte-macrophage, erythroid and multipotential progenitor cells synergistically stimulated to proliferate with a colony stimulating factor and either steel factor or the ligand for the Flt-3 receptor tyrosine kinase. VEGF produced effects similar to those given above on purified CD34 progenitor cells from bone marrow and VEGF effects were neutralized by VEGF antibodies. However, when assessed for effects on single sorted CD34 cells, VEGF only enhanced or suppressed colony formation by granulocyte-macrophage progenitor cells and the amplitude of the response was less than that observed when populations of these cells were tested. In the single cell assays, VEGF had no effect on colony formation by erythroid or multipotential progenitors. These results suggest that the effects of VEGF, which were not species specific, are mediated by both direct and indirect actions on the progenitors and thereby identify new activities for this important factor.

Detection of nodal micrometastases using immunohistochemistry and PCR in melanoma of the arm and trunk.

Sentinel node (SN) mapping and biopsy seems at present the best way to assess the nodal status in cutaneous melanoma without removing the lymphatic chain. The procedure is minimally invasive, safe and low cost, and allows selection of patients who can benefit from elective node dissection. From March 1997 up to July 1999 we examined 112 SNs excised after lymphatic mapping from 95 patients (48 males and 47 females) with stage I cutaneous melanoma affecting the trunk or limbs. Of these, 88 SNs from 74 patients were submitted to polymerase chain reaction (PCR) in order to detect tyrosinase mRNA. A new antibody (anti-tyrosinase, Clone T311, IgG2a type, Lab Vision Corporation) was used to detect nodal micrometastases. The search for micrometastases was histologically positive in 15 SNs and negative in 97. The 88 SNs examined using molecular biology were positive in 40 cases and negative in 48. In 28 only the PCR was positive. The new antibody used to detect micrometastases was shown to be very useful. Cases positive on both conventional histology and PCR were Clark level II or more and were thicker than 0.6 mm. No difference with regard to site or sex was observed. Lymphoedema and hypersensitivity reactions, nor the inability to work, did not occur. Only patients with histologically proven micrometastases underwent elective node dissection. Cases positive only on molecular biology were submitted to close follow-up.

[99mTc pertechnetate scintigraphy and premedication for the search for ectopic gastric mucosa in Meckel's diverticulum]. / Scintigrafia con 99mTc pertecnetato e "premedicazione" per la ricerca di mucosa gastrica ectopica nel diverticolo di Meckel.

BACKGROUND: Meckel's diverticulum (MD) is the most common anomaly of the large intestinal tract (1-3%) and is more frequent in children (62% < 2 years) and in males (66%). It often involves ectopic gastric mucosa which manifests through gastrointestinal bleeding in 50% of cases. 99m-Technetium scintigraphy (99mTcO4) is one of the procedures available for the non-invasive diagnosis of ectopic gastric mucosa. METHODS: Twenty-eight patients (11 females, 17 males), including 16 children and 12 adults, aged 8 months-80 years old, were included in the study. The patients were admitted to hospital for hematochezia and melena (22) associated with abdominal pain (5): 3 patients repeatedly presented occult blood in their stools. Two patients only suffered from abdominal cramps and one only anemia. Patients were studied using plain abdominal radiographs and ultrasound; 10 underwent gastroscopy and colonoscopy; radiological contrast studies were performed in 5 patients. All tests were inconclusive. All the patients were premedicated with oral cimetidine (20 mg/kg in pediatric patients and 300 mg q.i.d. for adults, 48 hours before the test) or with ranitidine i.v. (1 mg/kg, max 50 mg, in 20 minutes, one hour before the test); barium meals and colonoscopy were deferred for 2-3 days after examination. An intravenous injection of 37-180 Mbq of 99mTcO4 was given followed by a dynamic study of the abdomen in anterior projection. Images were acquired for one hour or until the visualisation of abnormal foci of intake: in this case, lateral and oblique images were acquired for a better localisation of the suspicious area. Some patients were administered furosemide i.v. (0.75 mg/kg). All underwent a follow-up period of 12 months. RESULTS: Pertechnetate scintigraphy was positive in 10 cases and the presence of ectopic gastric mucosa was confirmed by surgery. The study was negative in 18 cases: 3 of them were discharged with a diagnosis of Salmonella infection, polyp of the small bowel or ulcer of the large bowel respectively; the other 15 patients did not show symptoms of onset during follow-up. CONCLUSIONS: These results confirm the high diagnostic accuracy of pertechnetate scintigraphy to detect ectopic gastric mucosa if associated with H2-receptor-blocking agent premedication.

Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.

The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.