PURPOSE: To identify a dose and schedule of oxaliplatin (OXP) to be safely administered in combination with protracted-infusion (PI) fluorouracil (5-FU) and external-beam radiation therapy (XRT) for patients with primary esophageal carcinoma (EC). PATIENTS AND METHODS: Eligibility included therapeutically naïve EC patients with clinical disease stages II, III, or IV. Initial doses and schedules for cycle 1 consisted of OXP 85 mg/m 2 on days 1, 15, and 29; PI 5-FU 180 mg/m 2 for 24 hours for 35 days; and XRT 1.8 Gy in 28 fractions starting on day 8. At completion of cycle 1, eligible patients could undergo an operation or begin cycle 2 without XRT. Postoperative patients were eligible for cycle 2. Stage IV patients were allowed three cycles in the absence of disease progression. OXP and 5-FU increases were based on dose-limiting toxicity (DLT) encountered in cohorts of three consecutive patients. RESULTS: Thirty-eight eligible patients received therapy: 22 noninvasively staged as IV and 16 noninvasively staged as II and III. Thirty-six patients completed cycle 1, 29 patients started cycle 2, and 24 patients completed cycle 2. The combined-modality therapy was well tolerated, but DLT prevented OXP and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3 and two grade 4 clinical toxicities were noted in eight patients. After cycle 1, 29 patients (81%) had no cancer in the esophageal mucosa. Thirteen patients underwent an operation with intent to resect the esophagus; five patients (38%) exhibited pathologic complete responses. CONCLUSION: OXP 85 mg/m 2 on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC. The role of OXP in multimodality regimens against EC deserves further evaluation.
During the course of a case of primary pulmonary hypertension occurring in a 24 year old man lung tissue became available at heart-lung transplantation in 1986 and from a lung biopsy carried out in 1981. In 1986 the sections showed classic plexogenic pulmonary arteriopathy. In 1981 they revealed migration of myofibroblasts into the intima and lumen of pulmonary arteries and arterioles, the identification of the cells being confirmed by electron microscopy. During the five years that the pulmonary vascular pathology progressed to the formation of plexiform lesions there was an increase in the number of bronchiolar endocrine cells that were immunoreactive to bombesin and calcitonin. This study demonstrates that the classic pathogenesis of primary plexogenic pulmonary arteriopathy originates years earlier as a migration of cells of muscular pedigree from the media into the intima of the pulmonary arteries and arterioles.
This work reports on SiGe HBTs with f/sub T/ of 350 GHz. This is the highest reported f/sub T/ for any Si-based transistor as well as any bipolar transistor. Associated f/sub max/ is 170 GHz, and BV/sub CEO/ and BV/sub CBO/ are measured to be 1.4 V and 5.0 V, respectively. Also achieved was the simultaneous optimization of f/sub T/ and f/sub max/ resulting in 270 GHz and 260 GHz, with BV/sub CEO/ and BV/sub CBO/ of 1.6 V and 5.5 V, respectively. The dependence of device performance on bias condition and device dimension has been investigated. Considerations regarding the extraction of such high f/sub T/ and f/sub max/ values are also discussed.
We give an analogue for complete modular lattices of the result of Goodearl who proved that an arbitrary module M over an arbitrary ring satisfies the ascending chain condition on essential submodules if and only if M/ Soc(M ) is Noetherian, where Soc(M ) denotes the socle of M .Goodearl's Theorem can be extended for certain complete modular lattices to any dual Krull dimension.Let R be a ring with identity and let M be a unital right R-module.Recall that a submodule K of M is essential provided K ∩ L = 0 for every non-zero submodule L of M .The socle Soc(M ) of M is the sum of all simple submodules of M , or 0 if M has no simple submodules.It is well known that Soc(M ) is the intersection of all essential submodules of M (see, for example [5, Prop.9.7]).A well known theorem of Goodearl [6, Prop.3.6] asserts that the module M satisfies the ascending chain condition on essential submodules if and only if the R-module M/ Soc(M ) is Noetherian.There is a dual result.A submodule N of M is superfluous if N +L = M for every proper submodule L of M .The radical Rad(M ) of M is defined to be the intersection of all maximal submodules of M , or M if M has no maximal submodules.It is well known that Rad(M ) is the sum of all superfluous submodules of M (see, for example, [5, Prop.9.13]).In [4] it is proved that Rad(M ) is Artinian if and only if M satisfies the descending chain condition on superfluous submodules.It is natural to ask whether these dual results have dual proofs.In order to investigate this question Alkhazzi [3] looked at the corresponding results in the context of modular lattices, his philosophy being that any proof of the analogue of Goodearl's result for modular lattices gives immediately the dual theorem by passing to the opposite lattice.Alkhazzi was unable to find such a proof.In fact, we suspect that no such proof exists but have
We read with great interest the article by Nahmias et al.1 documenting the potential of naringenin, a grapefruit flavonoid, to reduce hepatitis C virus (HCV) secretion in the Huh-7.5.1 human hepatoma/JFH1 cell model. These findings further document the important advances that are possible with this vastly improved in vitro model of HCV infection. Although the results offer new insight into a promising and novel HCV therapeutic target in the long term, we are struck by the potential short-term impact of this information in the hands of the general public. Since the online release of this manuscript in January 2008, a Google search of the terms "grapefruit" and "hepatitis" in February 2008 provides links to hundreds of Web sites, many of which represent HCV patient forums, nutritional supplement sellers, and internet "blogs". The wide reach and rapid uptake of high-impact scientific journals, such as HEPATOLOGY, among the lay community is truly fascinating. Because of this relatively new and growing phenomenon, we ponder the role of the journal in considering the potential impact of published results within the lay community and how an important scientific finding might be overinterpreted or misused. As mentioned by the authors, several furanocoumarins and flavonoids in grapefruit have been shown to inhibit drug-metabolizing enzymes, including cytochrome P450 (CYP) 3A4 as well as drug transporters such as P-glycoprotein and organic anion transporting polypeptide.2-5 CYP3A4 is responsible for the metabolism of more than 50% of approved drugs, and consumption of grapefruit-containing products has the potential to cause dangerous food–drug interactions with many medications HCV patients may be taking.6 Grapefruit is classified by the U.S. Food and Drug Administration as a moderate inhibitor of CYP3A4, which is defined as any agent that increases the systemic exposure of drugs metabolized through this pathway by two-fold to five-fold.7 Increases of up to 15-fold have been reported.8 Interestingly, there are numerous specifically targeted antiviral therapies for HCV (STAT-C) in various stages of clinical development, with the potential to improve therapeutic outcomes in patients beyond what is currently possible with the combination of peginterferon and ribavirin. At least a number of these orally administered compounds are known to be substrates of CYP3A4 and other drug transporters, and thus systemic exposures may increase significantly if coadministered with grapefruit-containing products. Patients who are coinfected with HCV and human immunodeficiency virus may be at particular risk, because many components of antiretroviral therapy similarly interact with CYP3A4 and drug transporters, resulting in grapefruit being contraindicated with many of these medications. The findings by Nahmias et al. may provide valuable insight toward identification of new targets against HCV. Perhaps in the future, combining one or more of the STAT-C compounds with a compound that inhibits HCV secretion may lead to large improvement in clinical outcomes. Until then, patients infected with HCV who read articles with titles such as "Grapefruit Compound May be the Key to Battling Hepatitis C" may be tempted to supplement their diet with grapefruit, risking potential adverse drug reactions unnecessarily. The patient community needs to understand that the study results were generated using an in vitro model of HCV with the aim of providing scientific information which may be used in the future to develop novel treatments for chronic hepatitis C and be made aware that this study is not suggesting chronic hepatitis C patients begin consuming a grapefruit-rich diet. Peter N. Morcos*, Barbara Brennan*, Patrick F. Smith*, * Department of Clinical Pharmacology, Virology Clinical Research and Experimental Medicine, Hoffmann-La Roche Inc., Nutley, NJ and Palo Alto, CA.
The mechanism of staphylococcal resistance to methicillin is unknown. Peptidoglycan synthesis was studied in a methicillin-resistant and a derived methicillin-sensitive Staphylococcus aureus strain. Although the methicillin minimum inhibitory concentration for growth of the methicillin-resistant strain was 1,600 micrograms/ml, peptidoglycan synthesis by the organism incubated in a wall synthesis solution was inhibited about 90% by 5 micrograms of methicillin per ml. In contrast, high concentrations of methicillin added to actively growing cultures of the methicillin-resistant strain had little effect on growth or peptidoglycan synthesis. Peptidoglycan synthesis in chloramphenicol-treated cultures was more susceptible to methicillin than it was in actively growing cultures of the methicillin-resistant strain. It is proposed that in this strain cell wall thickening peptidoglycan synthesis which predominates in cell wall synthesis solution and chloramphenicol-treated cultures is methicillin sensitive, whereas peptidoglycan synthesis involved in cell division, primarily in the region of the septum, which predominates in actively growing cultures is methicillin resistant. Both cell wall thickening and septal peptidoglycan syntheses are methicillin sensitive in the methicillin-sensitive strain.
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