Citations

Pneumocystis carinii (Pc) causes severe pneumonia in immunocompromised hosts. The binding of Pc trophic forms to alveolar epithelial cells is a central feature of infection, inducing the expression and activation of PcSte20, a gene participating in mating, proliferation, and pseudohyphal growth. In related fungi, Ste20 proteins are generally activated by immediate upstream small G proteins of the Cdc42-like family. PcCdc42 has not been previously described in Pneumocystis . To address the potential role of such a G protein in Pneumocystis , PcCdc42 was cloned from a Pc cDNA library. Using the full-length 576-bp PcCdc42 cDNA sequence, a CHEF blot of genomic DNA yielded a single band, providing evidence that this gene is present as a single copy within the genome. The total length of PcCdc42 cDNA was 576 bp with an estimated molecular mass of ∼38 kDa. BLASTP analysis demonstrated greater than 80% homology with other fungal Cdc42p proteins. Northern analysis indicated equal mRNA expression in both cystic and trophic life forms. Heterologous expression of PcCdc42 in Saccharomyces cerevisiae (Sc) demonstrated that PcCdc42p was able to restore growth in an ScCdc42Δ yeast strain. Additional assays with purified PcCdc42 protein demonstrated GTP binding and intrinsic GTPase activity, which was partially but significantly suppressed by Clostridium difficile toxin B, characteristic of Cdc42 GTPases. Furthermore, PcCdc42 protein was also shown to bind to the downstream PCSte20 kinase partner in the presence (but not the absence) of GTP. These data indicate that Pc possesses a Cdc42 gene expressing an active G protein, which binds the downstream regulatory kinase PcSte20, important in Pc life cycle regulation.

Purpose. Oral mucositis is a serious problem that affects a significant number of hematopoietic cell transplant (HCT) patients. There are many gaps in management, and evidence-based guidelines do not provide consistent recommendations. The purpose of this pilot study was to develop a mucositis oral care protocol for the prevention and management of mucositis in the HCT patient and to evaluate the clinical impact of its implementation. Methods. After receipt of Institutional Review Board approval, all patients admitted to the Hematology—Oncology service for high-dose chemotherapy followed by an autologous or allogeneic HCT were eligible for the study. As part of a change in practice, a new mucositis protocol consisting of a specific oral care regimen was instituted for prevention and treatment of mucositis. Assessment of mucositis began upon admission to the hospital and the patient was evaluated using a mucositis grading scale on a daily basis by the physician and nursing staff. The new mucositis protocol was a part of the HCT service admission orders for each patient. The group of patients treated according to the new mucositis protocol were compared with a retrospective control group consisting of patients who had undergone management of oral mucositis under the previous standard of care. The primary endpoints were to evaluate incidence, severity, and duration of oral mucositis. Secondary endpoints included days requiring narcotics; days of parenteral nutrition, febrile neutropenia, antimicrobial therapy, and length of hospital stay. Results. There were 13 patients enrolled in the control group and 12 patients in the new protocol group. The new protocol resulted in a decreased incidence (100% vs. 75%) and duration (19.2 vs. 8.3 days) of mucositis. Days of maximum grade one and three mucositis were decreased by 56%, and 70%, respectively. Days of maximum grade two mucositis, however increased by 22%. The days of narcotic use were reduced by 19% in the new protocol group (15.8 vs. 12.8 days). All patients in the new protocol group required parenteral nutrition, but days of use were reduced by 41% (17 vs. 10.2 days). The incidence of infection measured by days of febrile neutropenia and antimicrobial therapy were reduced by 35% (10.2 vs. 6.5 days) and 33% (17 vs. 11.4 days). Finally, the overall length of hospital stay was reduced by 7 days (30 vs. 23 days). Conclusion. Implementation of a standardized oral care protocol for mucositis management resulted in a decreased incidence, duration and severity of mucositis, and also reduced the global negative impact of mucositis. Future studies may further evaluate the global impact by adjusting for confounding factors. J Oncol Pharm Practice (2010) 16: 195—204.

ABSTRACT Vesicular stomatitis virus (VSV) has long been regarded as a promising recombinant vaccine platform and oncolytic agent but has not yet been tested in humans because it causes encephalomyelitis in rodents and primates. Recent studies have shown that specific tropisms of several viruses could be eliminated by engineering microRNA target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. We therefore sought to determine whether microRNA targets could be engineered into VSV to ameliorate its neuropathogenicity. Using a panel of recombinant VSVs incorporating microRNA target sequences corresponding to neuron-specific or control microRNAs (in forward and reverse orientations), we tested viral replication kinetics in cell lines treated with microRNA mimics, neurotoxicity after direct intracerebral inoculation in mice, and antitumor efficacy. Compared to picornaviruses and adenoviruses, the engineered VSVs were relatively resistant to microRNA-mediated inhibition, but neurotoxicity could nevertheless be ameliorated significantly using this approach, without compromise to antitumor efficacy. Neurotoxicity was most profoundly reduced in a virus carrying four tandem copies of a neuronal mir125 target sequence inserted in the 3′-untranslated region of the viral polymerase (L) gene.

The costs of health care continue to increase rapidly and steeply in the United States. One area of great expense is that of intensive care units (ICUs). The causes of inflation have not been addressed effectively. ICU resources could become stretched such that they may no longer be available. This paper discusses some of the ethics and concerns behind decision making when providing ICU services in the United States. In particular, the use of electronic records with decision making tools, risk-analysis methods, and documentation of patient wishes for extraordinary care may help with better utilization of resources in the future.

Background— The benefit of primary percutaneous coronary interventions (P-PCI) for patients with ST-elevation myocardial infarction (STEMI) has been well documented. However, controversy still exists as to whether PCI should be expanded to hospitals without coronary artery bypass graft surgery. Methods and Results— Patients who were discharged after PCI for STEMI between January 1, 2003, and December 12, 2006, in P-PCI centers (hospitals with no coronary artery bypass graft surgery, and PCI only for patients with STEMI) were propensity matched with patients in full service centers, and mortality and subsequent revascularization rates were compared. For patients undergoing PCI, there were no differences for in-hospital/30-day mortality (2.3% for P-PCI centers versus 1.9% for full service centers [ P =0.40]), emergency coronary artery bypass graft surgery immediately after PCI (0.06% versus 0.35%, P =0.06), 3-year mortality (7.1% versus 5.9%, P =0.07), or 3-year subsequent revascularization (23.8% versus 21.5%, P =0.52). P-PCI centers had a lower same/next day coronary artery bypass graft rate (0.23% versus 0.69%, P =0.046) and higher repeat target vessel PCI rates (12.1% versus 9.0%, P =0.003). For patients with STEMI who did not undergo PCI, P-PCI centers had higher in-hospital mortality (28.5% versus 22.3%; adjusted odds ratio, 1.38; 95% CI, 1.10 to 1.75). Conclusions— No differences between P-PCI centers and full service centers were found in in-hospital/30-day mortality, the need for emergency surgery, 3-year mortality or subsequent revascularization, but P-PCI centers had higher repeat target vessel PCI rates and higher mortality rates for patients who did not undergo PCI. P-PCI centers should be monitored closely, including the monitoring of patients with STEMI who did not undergo PCI.

Abstract Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)