We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

The bacterial pathogen Xanthomonas campestris pv. vesicatoria (Xcv) uses a type III secretion system (TTSS) to translocate effector proteins into host plant cells. The TTSS is required for Xcv colonization, yet the identity of many proteins translocated through this apparatus is not known. We used a genetic screen to functionally identify Xcv TTSS effectors. A transposon 5 (Tn5)-based transposon construct including the coding sequence for the Xcv AvrBs2 effector devoid of its TTSS signal was randomly inserted into the Xcv genome. Insertion of the avrBs2 reporter gene into Xcv genes coding for proteins containing a functional TTSS signal peptide resulted in the creation of chimeric TTSS effector::AvrBs2 fusion proteins. Xcv strains containing these fusions translocated the AvrBs2 reporter in a TTSS-dependent manner into resistant BS2 pepper cells during infection, activating the avrBs2-dependent hypersensitive response (HR). We isolated seven chimeric fusion proteins and designated the identified TTSS effectors as Xanthomonas outer proteins (Xops). Translocation of each Xop was confirmed by using the calmodulin-dependent adenylate cydase reporter assay. Three xop genes are Xanthomonas spp.-specific, whereas homologs for the rest are found in other phytopathogenic bacteria. XopF1 and XopF2 define an effector gene family in Xcv. XopN contains a eukaryotic protein fold repeat and is required for full Xcv pathogenicity in pepper and tomato. The translocated effectors identified in this work expand our knowledge of the diversity of proteins that Xcv uses to manipulate its hosts.bacterial plant pathogenesis ͉ virulence proteins

Twenty‐nine patients had simultaneous malignant epithelial neoplasms of the uterine corpus and ovary. Three groups were defined on the basis of tumor histology: Group A: those with endometrioid carcinoma in both the uterus and ovary; Group B: those with special variants of corpus carcinoma (papillary, clear cell, mucinous) and identical neoplasms in the ovary; and Group C: those whose uterine and ovarian carcinomas were of dissimilar histologic types. Sixteen women had endometrioid carcinoma in both sites. The median age at diagnosis, 41 years, was younger than is usual for corpus or ovarian cancer. For all 16 patients, the grade of the ovarian endometrioid carcinoma was similar to that of the endometrioid carcinoma of the uterine corpus. Seven patients had bilateral ovarian neoplasms. Only one patient had myometrial invasion by the corpus carcinoma. No patient with simultaneous ovarian and uterine endometrioid carcinoma, regardless of grade, has died of cancer although one vaginal relapse was treated successfully. This excellent survival of patients with simultaneous endometrioid carcinomas is better than would be expected for either Stage III adenocarcinoma of the endometrium or Stage II ovarian carcinoma. These simultaneously occurring endometrioid neoplasms of ovary and endometrium are considered to be separate primary tumors. The morphologic reasons for this view and therapeutic implications are discussed. In contrast to the patients with endometrioid carcinoma, the eleven patients with other histologic types of carcinoma in the ovary and corpus were older (median age, 61 years) and more often post‐menopausal (90%). These neoplasms were more aggressive, with frequent deep myometrial involvement (63%), tubal involvement (27%), and extension to other pelvic tissues (36%) at the time of initial diagnosis. Six of these 11 patients succumbed to their cancer despite surgical therapy and radiation. The distribution of tumor in some of these patients with nonendometrioid types of carcinoma is suggestive of a single primary with metastases. The therapeutic implications of these findings are discussed. Cancer 50:163–170, 1982.

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Altered abundance of phosphatidyl inositides (PIs) is a feature of cancer. Various PIs mark the identity of diverse membranes in normal and malignant cells. Phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2) resides predominantly in the plasma membrane, where it regulates cellular processes by recruiting, activating, or inhibiting proteins at the plasma membrane. We find that PTPRN2 and PLCβ1 enzymatically reduce plasma membrane PI(4,5)P2 levels in metastatic breast cancer cells through two independent mechanisms. These genes are upregulated in highly metastatic breast cancer cells, and their increased expression associates with human metastatic relapse. Reduction in plasma membrane PI(4,5)P2 abundance by these enzymes releases the PI(4,5)P2‐binding protein cofilin from its inactive membrane‐associated state into the cytoplasm where it mediates actin turnover dynamics, thereby enhancing cellular migration and metastatic capacity. Our findings reveal an enzymatic network that regulates metastatic cell migration through lipid‐dependent sequestration of an actin‐remodeling factor.

Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumor-forming capacity, we have derived sub-populations that generate tumors more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched (TE) sub-populations displayed increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic sub-populations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, while LAMA4 enhances clonal expansion upon substratum-detachment in vitro, tumor re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. LAMA4’s promotion of cancer cell proliferation and tumor re-initiation requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, while tumoral LAMA4 over-expression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumor re-initiation and identify a key molecular determinant of these processes.

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A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P < 0.01). In contrast, the fractional clearance of dextrans of radius >50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated gomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three-to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis ofglomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude (a) that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and (b) that subepithelial immune deposits do not provide a structural basis for these functional alterations.