MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.     

Predicting a human gut microbiota's response to diet in gnotobiotic mice

The interrelationships between our diets and the structure and operations of our gut microbial communities are poorly understood. A model community of 10 sequenced human gut bacteria was introduced into gnotobiotic mice, and changes in species abundance and microbial gene expression were measured in response to randomized perturbations of four defined ingredients in the host diet. From the responses, we developed a statistical model that predicted over 60% of the variation in species abundance evoked by diet perturbations, and we were able to identify which factors in the diet best explained changes seen for each community member. The approach is generally applicable, as shown by a follow-up study involving diets containing various mixtures of pureed human baby foods.     

Higher-tier assessment of the potential for groundwater issues due to the use of 1,3-D soil fumigant; evaluation of the active ingredient, metabolites and potentially related chlorinated compounds

BACKGROUND: 1,3‐Dichloropropene (1,3‐D, CAS No. 542‐75‐6) is a broad‐spectrum soil fumigant used to control numerous species of soilborne plant‐parasitic nematodes. 1,3‐D consists of two isomers, (Z)‐ and (E)‐1,3‐D. There are a number of low‐level chlorinated compounds that could potentially be produced as a part of the 1,3‐D manufacturing process. 1,3‐D and its metabolites, as well as potentially related chlorinated compounds, represent potential groundwater contaminants. RESULTS: This study has investigated the hydrolytic stability, under biotic and abiotic conditions in the laboratory, of an extensive representative list of 1,3‐D and potentially related chlorinated compounds in order to predict their environmental fate. All of these compounds showed intrinsic hydrolytic instability under both abiotic and biotic test conditions. Furthermore, a monitoring programme was carried out. Twenty‐five wells were monitored in five Italian regions characterised by historical and existing use of 1,3‐D. The parent compound, its two major metabolites and potentially related chlorinated compounds were not detected in the well water at > 0.1 µg L^?1 at any sampling location. CONCLUSION: The soil fumigant (E,Z)‐1,3‐D, its metabolites and potentially related chlorinated compounds constitute a low risk to groundwater. Copyright © 2011 Society of Chemical Industry     

Treatment of experimental ureteral strictures by endourological ureterotomy and implantation of stents in the porcine animal model

The objective of this study is to evaluate the dilation of the ureter using endoureterotomy and an expanding-sheath double pigtail ureteral stent in the treatment of experimentally induced ureteral strictures in the porcine animal model. This is a new treatment in the ureteral strictures resolution in Veterinary Urology, although it is not a common affection, it usually appears as a consequence of ureteritis and in the iatrogenic female genital surgery. The experimental study is design in three phases: induction of experimental stricture, diagnosis and treatment of the stricture and follow-up. We have used 10 healthy Large White female pigs. The internal ureteral diameter was measured prior to laparoscopic ligature stricture induction using retrograde ureteropyelography (RUPG). Experimental stricture was diagnosed 4 weeks after intervention, using RUPG and ultrasound, and treated by endoureterotomy and subsequent placement of a double pigtail ureteral stent, which was removed 6 weeks later. The study finished 4 weeks later with measurement of ureteral diameters using RPUG and ultrasound evaluation. Except in one case, all ureters displayed permanent dilation of the strictured area for 10 weeks after treatment (6 weeks with ureteral stent and 4 more weeks without stent). Finally, this technique proved to be effective in cases of short-length and short-living ureteral strictures, and represents a viable alternative to conventional surgery in animals.     

Effect of extradurally administered morphine on postoperative analgesia in dogs undergoing surgery for thoracolumbar intervertebral disk extrusion

Objective-To investigate the effect of intraoperative extradural morphine administration on postoperative analgesia in dogs undergoing thoracolumbar spinal surgery to treat disk extrusion. Design-Prospective clinical trial. Animals-26 client-owned dogs undergoing thoracolumbar spinal surgery. Procedures-Animals were randomly allocated to receive morphine (0.1 mg/kg [0.045 mg/lb], extradurally) or no treatment (control group). Following preanesthetic medication with methadone (0.25 mg/kg [0.11 mg/lb], IM), anesthesia was induced with propofol and maintained with isoflurane or sevoflurane in oxygen. Lidocaine and fentanyl were administered during surgery in both groups at fixed rates. In the morphine administration group, morphine was splashed over the dura mater immediately prior to wound closure. Postoperative analgesia was assessed for 48 hours by assessors unaware of group allocation, and methadone was administered as rescue analgesic. Demographic characteristics, urinary output, days of hospitalization, and perioperative use of analgesics were compared via a Mann-Whitney U test. Results-Demographic data were similar between groups. In the morphine administration group, 2 of 13 dogs required postoperative methadone, and in the control group, methadone was administered to 11 of 13 dogs. The total number of doses of methadone administered in the 48 hours after surgery was 28 in the control group and 3 in the morphine administration group. No adverse effects were recorded in any group. Conclusions and Clinical Relevance-Intraoperative extradural morphine administration was effective in reducing postoperative analgesic requirement. Dogs undergoing thoracolumbar spinal surgery benefited from topical administration of preservative-free morphine administered directly on the dura mater as part of analgesic management.     

COMPUTED TOMOGRAPHIC CHARACTERISTICS OF PRESUMED NORMAL CANINE ABDOMINAL LYMPH NODES

Though identification of lymph nodes is essential in staging cancer patients, little has been reported about the CT features of canine abdominal lymph nodes. The purpose of this retrospective study was to describe the visibility, location, and characteristics of abdominal lymph nodes in abdominal CT studies of dogs considered unlikely to have lymphadenopathy. The relationship between the number of identified lymph nodes and intraabdominal fat ranking, body weight, and slice thickness was also investigated. A total of 19 dogs were included. At least two jejunal lymph nodes and both left and right medial iliac lymph nodes were identified in all dogs. Colic lymph nodes were not identified in any of the dogs. Visualization of all other lymph nodes varied. There were significantly more lymph nodes visible in dogs with more intraabdominal fat (P < 0.0001). No correlation between the number of identified lymph nodes and body weight (P = 0.64) or slice thickness (P = 0.76) was found. Though most of all identified lymph nodes had an elongated shape, a rounded shape was most common in splenic, pancreaticoduodenal, renal, ileocolic and caudal mesenteric lymph nodes. Most lymph nodes had a homogeneous structure before and following the intravenous administration of contrast medium. Some lymph nodes had a slightly irregular structure or were relatively more hyper attenuating in the periphery than centrally before and/or after contrast administration. Mean attenuation before contrast was 37 Hounsfield Units (HU) (range 20–52 HU), and 109 HU after contrast (range 36–223 HU). Findings indicated that the CT visibility, characteristics of different abdominal lymph nodes may be variable in dogs.     

Phenolic composition in grape (Vitis vinifera L. cv. Malbec) ripened with different solar UV-B radiation levels by capillary zone electrophoresis

The responses of Vitis vinifera L. cv. Malbec to different solar ultraviolet-B radiation (UV-B) levels were assessed in two contrasting situations, under sunlight with full UV-B (+UV-B) and filtered UV-B (-UV-B), in three different locations at 500, 1000, and 1500 m above sea level (asl). To evaluate the effects of radiation, a simple, accurate, and rapid method for the separation and simultaneous determination of representative phenolic compounds in grape berry skins by capillary zone electrophoresis was developed. Separation was carried out in less than 20 min with 20 mM sodium tetraborate buffer containing 30% methanol, pH 9.00. The procedure is fast and reliable, and extracted grape berry skins can be directly analyzed without prior sample cleanup procedure. Berry skins from the +UV-B treatment at 1500 m asl showed the highest levels of total polyphenols anthocyanins, and resveratrol, compared with the -UV-B treatment at this altitude.     

Targeted metabolite analysis and antioxidant potential of Rumex induratus

Targeted metabolite analysis of aqueous extract of Rumex induratus leaves, in terms of phenolic compounds and organic acids, and the study of its antioxidant activity against the DPPH(*) radical, a reactive oxygen species, hypochlorous acid, and a reactive nitrogen species, nitric oxide ((*)NO), were performed. The samples were collected in several locations, spontaneously occurring or from greenhouse culture, at different stages of development and seasons. The phenolic composition was achieved by high-performance liquid chromatography (HPLC)-diode array detection, and four hydroxycinnamic acid derivatives and 10 flavonoid glycosides (C- and O-heterosides) were determined. Organic acids composition was established by HPLC-UV, revealing five compounds. The total amount of phenolic compounds and organic acids were affected by growing conditions and developmental phase. The aqueous extract exhibited a dose-related activity against all tested reactive species.     

New phenolic compounds and antioxidant potential of Catharanthus roseus

Screening of the phenolic compounds from seeds, stems, leaves and petals of Catharanthus roseus (L.) G. Don (cv. Little Bright Eye) was achieved by HPLC-DAD-ESI-MS/MS. This is the first detailed study of noncolored phenolics in C. roseus, which allowed the characterization of three caffeoylquinic acids and fifteen flavonol glycosides (di- and trisaccharides of kaempferol, quercetin and isorhamnetin). Fifteen compounds are reported for the first time in this species. The scavenging ability of the different plant matrices was assessed against DPPH(*) radical and against reactive oxygen (superoxide radical) and a reactive nitrogen (nitric oxide) species. A concentration-dependent protective effect was observed for seeds and tissues, with petals shown to be the most active.     

Magnetic resonance imaging appearance of the brain and cervical spinal cord in an edema disease affected pig

A 7‐week‐old male pig was presented with signs of a central nervous system disorder. An MRI of the head and cervical spine was performed immediately after euthanasia. The MRI revealed multifocal bilaterally symmetric T2‐weighted hyperintense lesions in the brain and spinal cord, likely due to a toxic metabolic process. Histopathological examination supported the MRI findings and confirmed the diagnosis of edema disease due to Shiga‐like toxin produced by Escherichia coli. This is the first case published of the MRI findings in an edema disease affected pig.