Cloning and characterization of a sixth adenylyl cyclase isoform: types V and VI constitute a subgroup within the mammalian adenylyl cyclase family.

A sixth member of the mammalian adenylyl cyclase family has been isolated from a canine cardiac cDNA library. This isoform is more highly homologous to type V than to the other adenylyl cyclase types; sequence similarity is apparent even in the transmembrane regions where the greatest divergence among the types exists. Type VI mRNA expression is most abundant in heart and brain; however, unlike type V, a low level of expression is also observed in a variety of other tissues examined. Type VI adenylyl cyclase can be stimulated by NaF, guanosine 5'-[gamma-thio]triphosphate, and forskolin but not by Ca2+/calmodulin, whereas it is inhibited by adenosine and its analogues. Comparison of both their structural and biochemical properties suggests that types V and VI constitute a distinct subgroup of the mammalian adenylyl cyclase family.     

Breast metastases of prostatic carcinoma: immunohistochemical case study

A breast mass developed in a patient receiving estrogen therapy for prostatic cancer. The prostate tumor was adenocarcinoma of small acinar type, whereas that of the breast was infiltrating medullary adenocarcinoma. Histological features of the two tumors differed and double cancer was suspected by conventional pathological study. However, immunohistochemical staining with prostatic specific antigen and prostatic acid phosphatase was positive in each tumor. These results indicate the breast tumor to be a metastasis from the prostatic cancer.     

SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis.

Fc gammaRIIB is an inhibitory receptor that terminates activation signals initiated by antigen cross-linking of the BCR through the recruitment of SHIP. Fc gammaRIIB can also signal independently of BCR coligation to directly mediate an apoptotic response, requiring only an intact transmembrane domain. Failure to recruit SHIP, either by deletion of SHIP or mutation of Fc gammaRIIB, results in enhanced Fc gammaRIIB-triggered apoptosis. Thus, in the germinal center, where ICs are retained by FDCs, Fc gammaRIIB may be an active determinant in the negative selection of B cells whose BCRs have reduced affinity for antigen as a result of somatic hypermutation. Selection of B cells may represent the sum of opposing signals generated by the interaction of ICs with the BCR and Fc gammaRIIB through pathways modulated by SHIP.     

Relation between blood pressure control, body mass index, and intensity of medical treatment.

A cross-sectional study was performed to assess the rates of blood pressure (BP) control to a systolic goal (< 140 mmHg), to a diastolic goal (< 90 mmHg), and to both in a sample of 226 treated hypertensive patients. We also examined the association between obesity, BP control, intensity of treatment defined as dose score (summed ranks of doses of all antihypertensive drugs taken), and number of drugs. Of the 226 treated patients (mean age, 60 years; 20.4% women), 67.7% were controlled to the systolic goal, 72.1% were controlled to the diastolic goal, and 53.5% were controlled to both. Patients were divided into four groups according to body mass index (BMI): less than 23, A; 23-24.9, B; 25-26.9, C; and 27 or more, D. There were no differences in the rates of BP control to the systolic goal, to the diastolic goal, or to both among the four groups; however, the dose score and number of drugs administered were higher in patients of group D than in those of the other groups. There was a tendency toward a higher intensity of drug treatment in obese patients with either controlled or uncontrolled BP. The dose score and number of drugs correlated positively with BMI. In representative subgroups (n = 62), serum insulin and the homeostasis model assessment value of insulin resistance were higher in the patients in group D than in the other groups. These findings indicate that hypertensive patients managed in a hypertension clinic had satisfactory BP control in 53.5% of cases. A higher intensity of medical treatment is needed to achieve BP control in obese hypertensive patients characterized by insulin resistance.     

Improving immunotherapy by conditionally enhancing MHC class I presentation of tumor antigen-derived Peptide epitopes

Tumors represent an altered self cell type that can be recognized by both the host humoral (B cells, antibodies) and cellular (T cells) adaptive immune systems. Because most known tumor-associated antigens (TAA) recognized by T cells represent overexpressed or aberrantly expressed proteins, which are not mutated and to which tolerance has been developed, the anti-TAA T-cell repertoire available to the cancer patient is of moderate-to-low avidity. Specific vaccinations typically amplify the absolute number of such T cells, but may have little consequence on improving their functional avidity, which may fall below a critical threshold required for effective recognition of tumor cells in situ. This review will discuss methods to improve low-avidity T-cell recognition of cancer cells by manipulating the tumor cells themselves to conditionally express higher levels of TAA-derived peptide epitopes presented in major histocompatibility (MHC) complexes. This may facilitate the design and performance of novel combinational therapies for the effective treatment of a broad range of cancer types.     

Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis

BACKGROUND: Arteriosclerosis obliterans (ASO) is a serious complication in patients with end-stage renal disease (ESRD) caused by diabetic nephropathy. Adsorption of low-density lipoprotein (LDL) has been performed to treat ASO. While efficacy of this treatment has been reported in limb ischemia, the mechanism underlying the benefit remains unclear. We investigated how LDL adsorption affected soluble adhesion molecules; P-selectin, an endothelial and platelet activation marker; inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tissue necrosis factor (TNF)-alpha; and lipids in serum. METHODS: Selective LDL adsorption by dextran sulfate columns (LDL apheresis) was performed weekly for 10 weeks to treat eight hemodialysis patients with ASO, ESRD, and type 2 diabetes mellitus. Serum was sampled before and immediately after apheresis. RESULTS: LDL apheresis was performed safely. After LDL apheresis lipid concentrations were significantly reduced and clinical findings, such as Fontaine's classification and ankle brachial pressure index values, were improved. Pretreatment concentrations of soluble intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1) and also P-selectin were higher in patients than healthy controls. After apheresis these decreased, especially P-selectin. IL-1beta, IL-6, and TNF-alpha concentrations before apheresis were similar to those in controls and were unaffected by treatment. CONCLUSION: Effectiveness of LDL apheresis against ASO may involve decreased endothelial cell and platelet activation.     

R Factor-Mediated Aminoglycoside Antibiotic Resistance in Pseudomonas aeruginosa: a New Aminoglycoside 6′-N-Acetyltransferase

The newly introduced semisynthetic aminoglycoside antibiotics, i.e., 3′,4′-dideoxykanamycin B (DKB), 6′-N-methyl DKB (6′-Me-DKB) and amikacin (AK) have been found to be effective against gram-negative pathogens including Pseudomonas aeruginosa, which are resistant to the known aminoglycoside antibiotics. We have demonstrated in our stock cultures two types of P. aeruginosa strains resistant to DKB, i.e., (DKB^r.AK^r.6′-Me-DKB^s) and (DKB^r.AK^s.6′-Me-DKB^r) (where r = resistant; s = sensitive). Both groups of strains inactivate the drugs by acetylation. The acetylating enzyme was extracted from GN4925(DKB^r.AK^s.6′-Me-DKB^r) and purified by affinity chromatography. Enzymatic studies of the inactivation reaction and chemical studies of the inactivated products indicated that DKB and 6′-Me-DKB were inactivated by acetylation of the 6′-amino group of the drugs. This enzyme acetylates kanamycin A (KM-A), KM-B, DKB, 6′-Me-DKB, 6′-N-methyl kanamycin B, but not KM-C, AK, and gentamicin C₁. The enzyme is named aminoglycoside 6′-N-acetyltransferase 3. Genetic studies of two strains resistant to DKB and 6′-Me-DKB disclosed that the enzyme catalyzing inactivation of both DKB and 6′-Me-DKB was mediated by an R factor, i.e., R_ms167 and R_ms168, capable of conferring resistance to KM, DKB, and 6′-Me-DKB, in addition to resistance to gentamicin, streptomycin, and sulfanilamide, and resistance to tetracycline, chloramphenicol, streptomycin and sulfanilamide respectively.