Citations

Protein kinase C ι (PKCι) has been implicated in Ras signaling, however, a role for PKCι in oncogenic Ras-mediated transformation has not been established. Here, we show that PKCι is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKCι in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCι (kdPKCι) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKCι in Ras-transformed rat intestinal epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12) restores invasiveness and anchorage-independent growth in Ras-transformed rat intestinal epithelial cells expressing kdPKCι. Our data demonstrate that PKCι is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKCι, and Rac1.

Purpose To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Patients and Methods A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n = 66) versus MEC (n = 63) to treat patients with relapsed or refractory AML and high-risk MDS. Results For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P = not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased—35% versus 15% for the remaining patients (P = .018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients’ overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR− patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P = .09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. Conclusion CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

OBJECTIVE: To report a case of vancomycin-induced anaphylaxis (or anaphylactoid reaction) in a patient with a fever of unrecognized noninfectious origin. CASE SUMMARY: An 83-year-old white man, who was a patient of the Veterans Affairs Medical Center, developed a serious anaphylactic (or anaphylactoid) reaction while receiving intravenous vancomycin as empiric therapy for a nosocomial fever of unknown origin. The fever was subsequently proved to have been due to acute polyarticular gout rather than an infection. DISCUSSION: This patient developed respiratory distress and an increased serum troponin concentration, suggestive of a myocardial enzymatic leak as a result of vancomycin therapy. Vancomycin was given before the noninfectious cause of his fever was recognized. CONCLUSIONS: Even with cautious slow infusion, intravenous vancomycin can precipitate life-threatening infusion-related reactions in some patients. Because of this, and to reduce selective pressure for vancomycin resistance, sources of fever that do not require treatment with vancomycin should be diligently investigated prior to the institution of empiric vancomycin therapy in febrile patients, particularly when the past medical history is suggestive of an alternative diagnosis.

AbstractThese cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at‐risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow‐up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

AbstractWe recently reported that chronic lymphocytic leukemia (CLL) cells synthesize and release vascular endothelial growth factor (VEGF) under normoxic and hypoxic conditions. CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2), suggesting that they use VEGF as a survival factor. To assess the mechanism of apoptosis resistance related to VEGF, we determined the impact of VEGF on CLL B cells, and we studied the impact of epigallocatechin-3-gallate (EGCG), a known receptor tyrosine kinase (RTK) inhibitor, on VEGF receptor status and viability of CLL B cells. VEGF165 significantly increased apoptotic resistance of CLL B cells, and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells. EGCG significantly increased apoptosis/cell death in 8 of 10 CLL samples measured by annexin V/propidium iodide (PI) staining. The increase in annexin V/PI staining was accompanied by caspase-3 activation and poly–adenosine diphosphate ribose polymerase (PARP) cleavage at low concentrations of EGCG (3 μg/mL). Moreover, EGCG suppressed the proteins B-cell leukemia/lymphoma-2 protein (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and myeloid cell leukemia-1 (Mcl-1) in CLL B cells. Finally, EGCG (3-25 μg/mL) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely. Thus, these results suggest that VEGF signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death.

ABSTRACT Polycystin‐2 (PC2), encoded by the PKD2 gene, mutated in 10‐15% of autosomal‐dominant polycystic kidney disease (ADPKD) patients, is a Ca 2+ ‐permeable cation channel present in kidney epithelia and other tissues. As PC2 was found expressed in B‐lymphoblastoid cells (LCLs) and Ca 2+ signaling pathways are important regulators of B cell function activities, we investigated whether PC2 plays some role in B‐LCLs. In LCLs, PC2 was found mainly in ER membranes but ~8 times less than in kidney HEK293 cells. The same reductions were found in PKD2 and PKD1 RNA; thus, PKD genes maintained, in LCLs, the same reciprocal proportion as they do in kidney cells. In LCLs obtained from subjects carrying PKD2 mutations (PKD2‐LCLs) and showing reduced PC2 levels, intracellular Ca 2+ concentrations evoked by platelet‐activating factor (PAF), were significantly lower than in non‐PKD‐LCLs. This reduction was also found in PKD1‐ LCLs but without PC2 reductions. Likewise, cell proliferation, which is controlled by Ca 2+ , was reduced in PKD2‐ and PKD1‐LCLs. Moreover, in LCLs with PKD2 nonsense mutations, aminoglycoside antibiotics reduced the PC2 defect by promoting readthrough of stop codons. Therefore, PC2 and PC1 are functionally expressed in LCLs, which provide a model, easily obtainable from ADPKD patients, to study PKD gene expression and function.

ABSTRACTBasidiobolomycosis is a chronic subcutaneous infection of the trunk and limbs due toBasidiobolus ranarum.The disease is well known in tropical areas, although recent cases of gastrointestinal basidiobolomycosis have also been reported in Arizona. We describe a young immunocompetent women who had presented with eosinophilia and lung infiltrates. She subsequently died, and diagnosis of disseminated basidiobolomycosis was made on the basis of histological features at autopsy.