A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK

1. Download high-res image (222KB)
2. Download full-size image

     

Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites

Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria.     

Varicella pneumonia in the previously healthy adult

Varicella (chickenpox) is a contagious, self-limited, usually benign disease common in childhood but uncommon in adulthood. Pneumonia is the most frequent complication of the disease in adults. We retrospectively review 7 cases of varicella pneumonia in previously healthy adults diagnosed in our hospital between 1992 and 1996. All of them were treated with intravenous acyclovir with good therapeutic response save for a patient who developed respiratory insufficiency and died 8 days after his admission. Smoking was the only risk factor detected. Clinical features of our patients are described and the need of an early diagnosis and treatment of varicella pneumonia is emphasized.     

A novel 2-pyrone derivative,BHP, impedes oncogenic KRAS-driven malignant progression in breast cancer

Elevated KRAS expression has been frequently associated with cancer progression including breast cancer; however, therapeutic approaches targeting KRAS have been widely unsuccessful and KRAS mutant cancers remain unsolved problem in cancer therapy. In this study, we found that a new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP) can block KRAS-driven breast cancer progression. Importantly, treatment with BHP effectively suppressed the migratory and invasive properties along with epithelial–mesenchymal transition (EMT) in MDA-MB231 breast cancer cells that carry oncogenic KRAS and mesenchymal malignant phenotypes. In parallel, BHP also sensitized the cells to anticancer treatment. Consistently, forced-expression of oncogenic KRAS bestowed the migratory and invasive properties, mesenchymal transition and resistance to anticancer treatment into normal human mammalian breast cells MCF10A and relatively non-malignant MCF7 and SK-BR3 breast cancer cells; however, treatment with BHP blocked those KRAS-induced malignant phenotypes. Notably, BHP interfered the interaction of KRAS with Raf-1 in concentration-dependent manner, thereby blocking the downstream effectors of KRAS signaling that is PI3K/AKT and ERK. Taken together, our findings indicate that the BHP, an α-pyrone derivative, suppresses malignant breast cancer progression by targeting of oncogenic KRAS signaling pathways.     

Acute complicated pyelonephritis: contrast-enhanced ultrasound

Imaging is required if complication is suspected in acute pyelonephritis to assess the nature and extent of the lesions, and to detect underlying causes. The current imaging modality of choice in clinical practice is computed tomography. Because of associated radiation and potential nephrotoxicity, CEUS is an alternative that has been proven to be equally accurate in the detection of acute pyelonephritis renal lesions. The aims of this study of 48 patients are to describe in detail the CEUS findings in acute pyelonephritis, and to determine if abscess and focal pyelonephritis may be distinguished. Very characteristic morphologic and temporal patterns of enhancement are described. These allow differentiation of focal pyelonephritis from renal abscess, and detection of tiny suppurative foci within focal pyelonephritis. The detection of abscesses is important because follow-up in 25 patients revealed a longer clinical course. Typical pyelonephritis CEUS features permit distinction from other renal lesions. As a whole, CEUS is an excellent tool in the work-up of complicated acute pyelonephritis, so it may be considered as the imaging technique of choice in the evaluation and follow-up of these patients who frequently are very young, so as to minimise radiation exposure.     

Susceptibility to Plasmodium yoelii Preerythrocytic Infection in BALB/c Substrains Is Determined at the Point of Hepatocyte Invasion

After transmission by Anopheles mosquitoes, Plasmodium sporozoites travel to the liver, infect hepatocytes, and rapidly develop as intrahepatocytic liver stages (LS). Rodent models of malaria exhibit large differences in the magnitude of liver infection, both between parasite species and between strains of mice. This has been mainly attributed to differences in innate immune responses and parasite infectivity. Here, we report that BALB/cByJ mice are more susceptible to Plasmodium yoelii preerythrocytic infection than BALB/cJ mice. This difference occurs at the level of early hepatocyte infection, but expression levels of reported host factors that are involved in infection do not correlate with susceptibility. Interestingly, BALB/cByJ hepatocytes are more frequently polyploid; thus, their susceptibility converges on the previously observed preference of sporozoites to infect polyploid hepatocytes. Gene expression analysis demonstrates hepatocyte-specific differences in mRNA abundance for numerous genes between BALB/cByJ and BALB/cJ mice, some of which encode hepatocyte surface molecules. These data suggest that a yet-unknown receptor for sporozoite infection, present at elevated levels on BALB/cByJ hepatocytes and also polyploid hepatocytes, might facilitate Plasmodium liver infection.     

Efficacy of hepatocellular carcinoma locoregional therapies on patients waiting for liver transplantation

The aim of this study was to evaluate the efficacy of different locoregional therapies in patients with HCC on the waiting list for liver transplantation. From October 2001 to July 2003, 13 patients, all men, with HCC diagnosed by cytology, were transplanted at our center. Locoregional therapies were percutaneous ethanol injection (PEI), transcatheter hepatic arterial chemoembolization (TACE), and radiofrequency microwave ablation (RFA). PEI was employed in seven patients, TACE in five (one of them associated with PEI) and RFA in one. Efficacy was evaluated by determining the percentage of tumoral necrosis in the liver explant. Five tumors were T4, four T3, three T2, and one T1. Ten were well differentiated, two moderately differentiated, and one undifferentiated. One patient died due to primary graft malfunction. After a median posttransplant follow-up of 15 months, 12 patients are alive with no sign of tumor recurrence. Most patients with solitary nodules <4 cm who received PEI had 90% to 100% tumor necrosis. Larger tumors had 25% to 30% necrosis. TACE was employed in six patients with large and/or multiple tumors, obtaining 20% to 50% tumor necrosis. RFA was employed in one case obtaining 85% necrosis (tumor of 4 cm). No serious complications occurred with any technique. According to our experience, PEI and RFA are effective locoregional therapies to treat hepatocellular carcinomas of <4 cm in patients on the waiting list. For larger tumors, their association with other techniques, such as TACE, seems adequate.     

Treatment of Angina and Microvascular Coronary Dysfunction

Microvascular coronary dysfunction (MCD) is an increasingly recognized cause of cardiac ischemia and angina that is diagnosed more commonly in women. Patients with MCD present with the triad of persistent chest pain, ischemic changes on stress testing, and no obstructive coronary artery disease on cardiac catheterization. Data from the National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation (WISE) study show that the diagnosis of MCD is not benign, with a 2.5% annual risk of adverse cardiac events including myocardial infarction, stroke, congestive heart failure, and death. The gold standard diagnostic test for MCD is the invasive coronary reactivity test (CRT), which uses acetylcholine, adenosine, and nitroglycerin to test endothelial-dependent and -independent microvascular and macrovascular coronary function. The CRT allows for diagnostic and treatment options as well as further risk stratification of patients for future cardiovascular events. Treatment of angina and MCD should be aimed at ischemia disease management to reduce the risk of adverse cardiac events, ameliorate symptoms to improve quality of life, and decrease morbidity from unnecessary and repeated cardiac catheterization in patients with open coronary arteries. A comprehensive treatment approach aimed at risk factor management, including lifestyle counseling regarding smoking cessation, nutrition, and physical activity, should be initiated. Current pharmacotherapy for MCD may include treatment of microvascular endothelial dysfunction (with statins, angiotensin-converting enzyme inhibitors, or low-dose aspirin), as well as treatment for angina and myocardial ischemia (with β-blockers, calcium channel blockers, nitrates, or ranolazine). Additional symptom management techniques may include tricyclic medication, enhanced external counterpulsation, hypnosis, and spinal cord stimulation. Although our current therapies are effective in treating angina and MCD, large randomized outcome trials are needed to optimize strategies to improve morbidity and mortality.