Demonstration of an efficient, photonic-based astronomical spectrograph on an 8-m telescope.

We demonstrate for the first time an efficient, photonic-based astronomical spectrograph on the 8-m Subaru Telescope. An extreme adaptive optics system is combined with pupil apodiziation optics to efficiently inject light directly into a single-mode fiber, which feeds a compact cross-dispersed spectrograph based on array waveguide grating technology. The instrument currently offers a throughput of 5% from sky-to-detector which we outline could easily be upgraded to ∼ 13% (assuming a coupling efficiency of 50%). The isolated spectrograph throughput from the single-mode fiber to detector was 42% at 1550 nm. The coupling efficiency into the single-mode fiber was limited by the achievable Strehl ratio on a given night. A coupling efficiency of 47% has been achieved with ∼ 60% Strehl ratio on-sky to date. Improvements to the adaptive optics system will enable 90% Strehl ratio and a coupling of up to 67% eventually. This work demonstrates that the unique combination of advanced technologies enables the realization of a compact and highly efficient spectrograph, setting a precedent for future instrument design on very-large and extremely-large telescopes.

Modal noise in an integrated photonic lantern fed diffraction-limited spectrograph.

In an attempt to develop a streamlined astrophotonic instrument, we demonstrate the realization of an all-photonic device capable of both multimode to single mode conversion and spectral dispersion on an 8-m class telescope with efficient coupling. The device was a monolithic photonic spectrograph which combined an integrated photonic lantern and an efficient arrayed waveguide grating device. During on-sky testing, we discovered a previously unreported type of noise that made spectral extraction and calibration extremely difficult. The source of the noise was traced to a wavelength-dependent loss mechanism between the feed fiber's multimode near-field pattern and the modal acceptance profile of the integrated photonic lantern. Extensive modeling of the photonic components replicates the wavelength-dependent loss, and demonstrates an identical effect on the final spectral output. We outline that this could be mitigated by directly injecting into the integrated photonic lantern.

Acquired post-traumatic aortic coarctation presenting as new-onset congestive heart failure: treatment with endovascular repair.

Acquired coarctation of the thoracic aorta is a rare phenomenon in adults. The etiology is often idiopathic, but severe stenosis can develop from prior surgery, blunt thoracic aortic injuries, or severe atherosclerotic/atheroembolic disease. Common symptomatic presentations include refractory upper extremity hypertension and new-onset congestive heart failure. We present the case of a 52-year-old man who developed acquired thoracic aortic coarctation 30 years after a blunt trauma and deceleration injuries to the aorta requiring open surgical aortic repair. He presented with poorly controlled hypertension and new-onset heart failure and was treated surgically with endovascular repair.

'A Friend in the Corner': supporting people at home in the last year of life via telephone and video consultation-an evaluation.

OBJECTIVE: To evaluate 'Gold Line', a 24/7, nurse-led telephone and video-consultation support service for patients thought to be in the last year of life in Bradford, Airedale, Wharfedale and Craven. METHOD: Data on the time and nature of all calls between 1 April 2014 and 30 March 2015 were obtained from the patient Electronic Records. Interviews with 13 participants captured patients and carers perspectives. RESULTS: To date, 3291 patients have been referred to the Gold Line. During the study period, 42% of registered patients had a non-cancer diagnosis and 45.2% of service users were not known to Specialist Palliative Care services. The median time on the caseload was 49 days (range 1-504 days). 4533 telephone calls and 573 video consultations were made involving 1813 individuals. 39% of the 5106 contacts were resolved by the Gold Line team without referral to other services. 69% of calls were made outside normal working hours. Interviews with patients and carers reported experiences of support and reassurance from the Gold Line and the importance of practical advice was emphasised. Current data (year to October 2015) show that 98.5% of calls (4500/4568) resulted in patients remaining in their place of residence. CONCLUSIONS: A nurse led, 24/7 telephone and video consultation service can provide valuable support for patients identified to be in the last year of life and for their carers. The line enabled them to feel supported and remain in their place of residence, hence reducing the pressure for avoidable hospital admissions and use of other services. Providing this service may encourage healthcare professionals to identify more patients approaching the last year of life, widening support offered to this group of patients beyond those known to specialist palliative care services.

New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up.

BACKGROUND: HER2 gene amplification and/or protein overexpression in breast cancer is associated with a poor prognosis and predicts response to anti-HER2 therapy. We examine the natural history of breast cancers in relationship to increased HER2 copy numbers in a large population-based study. PATIENTS AND METHODS: HER2 status was measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in approximately 1,400 breast cancer cases with greater than 15 years of follow-up. Protein expression was evaluated with two different commercially-available antibodies. RESULTS: We looked for subgroups of breast cancer with different clinical outcomes, based on HER2 FISH amplification ratio. The current HER2 ratio cut point for classifying HER2 positive and negative cases is 2.2. However, we found an increased risk of disease-specific death associated with FISH ratios of >1.5. An 'intermediate' group of cases with HER2 ratios between 1.5 and 2.2 was found to have a significantly better outcome than the conventional 'amplified' group (HER2 ratio >2.2) but a significantly worse outcome than groups with FISH ratios less than 1.5. CONCLUSION: Breast cancers with increased HER2 copy numbers (low level HER2 amplification), below the currently accepted positive threshold ratio of 2.2, showed a distinct, intermediate outcome when compared to HER2 unamplified tumors and tumors with HER2 ratios greater than 2.2. These findings suggest that a new cut point to determine HER2 positivity, at a ratio of 1.5 (well below the current recommended cut point of 2.2), should be evaluated.

Fleece rot and dermatophilosis in sheep.

Fleece rot and dermatophilosis reduce health and production of sheep and predispose them to blow fly strike. This paper reviews aetiology, prevalence, pathogenesis, resistance, attempts to develop vaccines and prospects for new control strategies to these important skin diseases. Although the severity of fleece rot is associated with the abundance of Pseudomonas aeruginosa on skin, microbial ecology studies are providing new insights into the contribution of other bacteria to the disease. Wool traits and body conformation traits that predispose sheep to fleece rot and dermatophilosis are heritable and have been used as indirect selection criteria for resistance for many years. Selection against BoLA-DRB3-DQB class II haplotype in cattle can substantially reduce the prevalence of dermatophilosis and holds promise for identification of gene markers for resistance to these bacterial diseases in sheep. Immune responses in skin and systemic antibody responses to bacterial antigens are acquired through natural infection and contribute to resistance; however, prototype antibacterial vaccines have to date failed to provide protection against the diversity of isolates of Dermatophilus congolensis and Pseudomonas species present in the field. Opportunities for future control through breeding for resistance, vaccines and non-vaccine strategies for controlling the microbial ecology of fleece are discussed. In combination, control strategies need to reduce the risk of transmission, minimise exposure of animals to stressors that enhance the risk of infection, and enhance resistance though genetics or vaccines.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase.

We performed genomic subtraction coupled to microarray-based gene expression profiling and identified the PDZ (postsynaptic density-95/Discs large/zona occludens-1)-binding kinase/T-LAK (lymphokine-activated killer T cell) cell originating protein kinase (PBK/TOPK) as a gene highly enriched in neural stem cell cultures. Previous studies have identified PBK/TOPK as a mitogen-activated protein kinase (MAPK) kinase that phosphorylated P38 MAPK but with no known expression or function in the nervous system. First, using a novel, bioinformatics-based approach to assess cross-correlation in large microarray datasets, we generated the hypothesis of a cell-cycle-related role for PBK/TOPK in neural cells. We then demonstrated that both PBK/TOPK and P38 are activated in a cell-cycle-dependent manner in neuronal progenitor cells in vitro, and inhibition of this pathway disrupts progenitor proliferation and self-renewal, a core feature of progenitors. In vivo, PBK/TOPK is expressed in rapidly proliferating cells in the adult subependymal zone (SEZ) and early postnatal cerebellar external granular layer. Using an approach based on transgenically targeted ablation and lineage tracing in mice, we show that PBK/TOPK-positive cells in the SEZ are GFAP negative but arise from GFAP-positive neural stem cells during adult neurogenesis. Furthermore, ablation of the adult stem cell population leads to concomitant loss of PBK/TOPK-positive cells in the SEZ. Together, these studies demonstrate that PBK/TOPK is a marker for transiently amplifying neural progenitors in the SEZ. Additionally, they suggest that PBK/TOPK plays an important role in these progenitors, and further implicates the P38 MAPK pathway in general, as an important regulator of progenitor proliferation and self-renewal.

The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF-alpha induced apoptosis.

The serine proteinase inhibitor (serpin), plasminogen activator inhibitor type 2 (PAI-2), has been reported to inhibit tumor necrosis factor-alpha (TNF) induced apoptosis. In order to begin to understand the molecular basis for this protection, we have investigated the importance of a structural domain within the PAI-2 molecule, the C-D interhelical region, in mediating the protective effect. The C-D interhelical region is a 33 amino acid insertion which is unique among serpins and has been implicated in transglutaminase catalyzed cross-linking of PAI-2 to cell membranes. We have constructed a mutant of PAI-2 wherein 23 amino acids are deleted from the C-D interhelical region generating a structure predicted to be homologous to the closely related, but non-inhibitory serpin, chicken ovalbumin. The PAI-2Delta65/87 deletion mutant retained inhibitory activity against its known serine proteinase target, urokinase-type plasminogen activator (uPA); however expression of this mutant in HeLa cells failed to protect from TNF-induced apoptosis. Analyses of the cellular distribution of PAI-2 showed that intracellular PAI-2, and not secreted or cell-surface PAI-2, was likely responsible for the observed protection from TNF-induced apoptosis. No evidence was found for specific cross-linking of PAI-2 to the plasma membrane in either control or TNF/cycloheximide treated cells. The data demonstrate that the PAI-2 C-D interhelical domain is functionally important in PAI-2 protection from TNF induced apoptosis and suggest a novel function for the C-D interhelical domain in the protective mechanism.

Phase II study of the progesterone antagonist mifepristone in patients with untreated metastatic breast carcinoma: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: Mifepristone (RU486) is a progesterone receptor (PgR) antagonist that has been shown to be active in some preclinical hormone-dependent breast cancer tumor models and to produce a few responses in patients with pretreated metastatic disease in two small trials. This trial was designed to assess the response rate and toxic effects of mifepristone in a favorable group of women with PgR-positive recurrent breast cancer who had received no prior therapy. METHODS: Postmenopausal patients with PgR-positive, bidimensionally measurable disease were eligible provided they had received no other therapy for recurrence. Prior adjuvant hormonal treatment was permitted if a disease-free interval of at least 24 months had been observed. Mifepristone 200 mg was given daily and disease was reassessed every 4 weeks. Standard criteria for tumor response and toxic effects were used. RESULTS: A total of 28 patients were registered in the trial: all were eligible and assessable. Three partial responses were noted for an overall response rate of 10.7% (95% confidence interval [CI], 2% to 28%). Toxic effects were generally mild to moderate and consisted primarily of nausea, lethargy, anorexia, and hot flashes. CONCLUSION: Mifepristone had minimal activity in this optimal group of patients. While there may be reason to conduct some clinical studies with it in combination with antiestrogens on the basis of some preclinical work, our data do not support its use as a single agent in the management of breast cancer.

Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer. PATIENTS AND METHODS: The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence. RESULTS: Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive. CONCLUSION: Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.

Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: The National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-one patients with measurable MBC were studied. Three patients were ineligible and were excluded from analysis. The planned dose of docetaxel was 100 mg/m2 intravenously (i.v.) every 3 weeks. Prior adjuvant chemotherapy was allowed if at least 12 months had elapsed from completion of treatment to recurrence. RESULTS: The most severe toxicity was granulocytopenia. Ten patients (20.8%) were hospitalized for febrile neutropenia. The protocol was amended to a starting dose of 75 mg/m2 for the last 16 patients. Sixty percent of patients experienced hypersensitivity reactions (HSRs). After two protocol amendments, the use of a premedication regimen of oral dexamethasone and i.v. H1 and H2 blockers prevented significant HSRs. Edema developed in 62% of patients and was cumulative, was present in 50% who received greater than 400 mg/m2, and was not improved by premedication regimens. Following an independent radiology review, 22 partial remissions and four complete responses in 47 assessable patients were confirmed (response rate, 55%; 95% confidence interval [CI], 40% to 69%). The response rate for 15 assessable patients registered at 75 mg/m2 was 40% (95% CI, 16% to 67%); for 32 assessable patients registered at 100 mg/m2, the response rate was 63%, (95% CI, 43% to 78%). CONCLUSION: Docetaxel is an active agent in MBC. Its activity as a single agent is comparable to many combination chemotherapy regimens and is not affected by prior adjuvant chemotherapy. Studies are ongoing to improve its therapeutic index and to incorporate docetaxel in combination chemotherapy regimens.

Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8.

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m(2) intravenously (IV) on day 1 and VNB 25 mg/m(2) IV on days 1 and 8 (arm 1) or DOX 70 mg/m(2) IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m(2). After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m(2) on day 1 and VNB 20 mg/m(2) on days 1 and 8 versus DOX 60 mg/m(2) on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P =.4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.

Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Effects of cadmium on Na+ transport in the isolated skin of the toad Pleurodema thaul.

Cadmium ions applied to either (outer or inner) surface of the isolated toad skin dose-dependently increased the short-circuit current (SCC), the potential difference (V) and the active sodium conductance (G(Na)) in the concentration range 0.07-0.50mM. Maximal stimulatory effect was over 30% with an EC(50) of about 0.1mM. The effect of the highest concentration used (0.75mM) decreased considerably, and when it was applied to the inner surface (10 experiments), induced between 30% and 40% inhibition of the electric parameters in four experiments. Pretreatment with amiloride inverted the stimulatory effect of externally applied Cd(2+), suggesting competitive action on the apical Na(+) channel. The effect of noradrenaline (NA) was increased after outer application of Cd(2+) and decreased after inner application of the metal: the latter effect might be due to cadmium inhibition of the activity of Na(+),K(+)-ATPase. On the other hand, pretreatment with amiloride was followed by partial although transient reversal of its effects by serosal Cd(2+), which might be explained by action of cadmium on cytoplasmic lysine residues concerned with Na(+) channel gating. The amiloride test showed that the increment of the electric parameters was due principally to stimulation of the driving potential for Na(+) (V-E(Na(+))) and that inhibition was accompanied by a reduction in the V-E(Na(+)) and by a significant decrease in skin resistance indicating possible disruption of membrane or cell integrity. These data are in favor of the possibility that externally applied Cd(2+) activates toad skin ion transport, partly by increasing apical sodium conductance and also by stimulating the V-E(Na(+)), and that internally applied Cd(2+), with easier access to membrane and cellular constituents, may inhibit the sodium pump.

Structural effects of titanium citrate on the human erythrocyte membrane.

The structural effects of titanium citrate on the human erythrocyte membrane were studied through its interaction with intact erythrocytes and isolated unsealed human erythrocyte membranes (IUM). The studies were carried out by scanning electron microscopy and fluorescence spectroscopy, respectively. Titanium citrate induced shape changes in erythrocytes, which were damaged and ruptured leaving empty and retracted membranes. Fluorescence spectroscopy measurements in IUM indicated a disordering effect at both the polar head group and the acyl chain packing arrangements of the membrane phospholipid bilayer. Titanium citrate also interacted with molecular models of the erythrocyte membrane consisting in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representing classes of phospholipids located in the outer and inner monolayers of the erythrocyte membrane, respectively. X-ray diffraction indicated that titanium citrate induced structural perturbation of the polar head group and of the hydrophobic acyl regions of DMPC, while the effects on DMPE bilayers were negligible. This conclusion is supported by fluorescence spectroscopy measurements on DMPC large unilamellar vesicles. All these findings indicate that the structural perturbations induced by titanium to human erythrocytes can be extended to other cells, thereby affecting their functions.

Preclinical antitumor activity of an antibody against the leukocyte antigen CD48.

We have evaluated the antitumor activity of a murine antibody (IgG2a) against the leukocyte antigen CD48. CD48 is expressed on T and B lymphocytes, monocytes, and a wide range of lymphoid malignancies. To assess the therapeutic potential of an anti-CD48 antibody, we established a reproducible model of human B-cell (Raji) leukemia/lymphoma in C.B17/scid mice, where untreated mice develop hind leg paralysis due to tumor engraftment. Using this model, the murine anti-CD48 antibody HuLy-m3 was shown to mediate a strong in vivo antitumor effect. Long-term survival (>1 year) of scid mice was obtained after treatment with three 200-microg i.v. doses of anti-CD48 antibody on days 0, 2, and 4 after i.v. injection of tumor cells. In contrast, mice treated with an isotype control antibody developed hind leg paralysis after 34 +/- 3 days. A strong antitumor response was still observed when a dose of 20 microg of HuLy-m3 antibody was used. During preclinical investigations, we also examined a number of properties of the CD48 antigen. CD48 is present at high levels on the surface of T and B cells, but most (>95%) CD34-positive cells do not express CD48. Anti-CD48 antibodies are maintained on the surface of antigen-positive cells for extended periods (>24 h). These properties suggest that anti-CD48 antibodies may be useful in the treatment of a number of diseases including lymphoid leukemias and lymphomas.

An amino-terminal truncated progesterone receptor isoform, PRc, enhances progestin-induced transcriptional activity.

Previously we reported the identification of two unique progesterone receptor (PR) messenger RNA transcripts that encode a smaller PR isoform, termed the C-receptor (PRc). These two PR transcripts encode a protein that is N-terminally truncated, so that it lacks the first zinc finger of the DNA binding domain, but still contains a complete hormone binding region with sequences for dimerization and nuclear localization. We also have demonstrated the existence of a 60-kDa progestin-specific binding protein in progestin target cells using a monoclonal antibody directed to the C-terminus of PRs, suggesting that these two novel transcripts generate a truncated form of PR. In this paper, we address the hypothesis that the C-receptor arises from the initiation of translation of a methionine C-terminal to the methionine start sites that generate the larger 94-kDa A and 116-kDa B human PR isoforms. The studies shown here support the postulate that another downstream in-frame methionine within the PR-coding region can serve as a translation initiation site for the generation of a third PR protein. A partial PR complementary DNA, lacking the translation start sites for B- and A-receptors was translated in vitro. The synthetic protein product bound [3H]progestins and unlabeled progestins. The antiprogestin RU486 also competed for this binding. Transfection of this partial PR complementary DNA into PR-negative HeLa cells resulted in progestin-specific binding activity. Because the third PR isoform lacks the first zinc finger of the DNA binding domain, but contains sequences for dimerization, we reasoned that the C-receptor isoform would be transcriptionally in-active and not bind DNA directly. Surprisingly, however, in the presence of A- and/or B-receptors, we found that C-receptors can modulate the transcriptional activity of A- and/or B-receptors using a reporter gene. These studies emphasize that multiple receptor isoforms may have distinct biological properties, and that the truncated C-receptor may play a role in explaining some of the pleiotropic effects of progestins.

Surgical management of haemorrhaging renal angiomyolipoma in pregnancy.

INTRODUCTION: Renal angiomyolipoma (AML) is a benign mesenchymal tumour of the kidney with a tendency of aneurysm formation at risk of rupturing. Due to increased maternal circulation and hormonal influences, rupture risk is greater in pregnancy, often leading to a vascular emergency and premature delivery or termination. PRESENTATION OF CASE: A 24-weeks pregnant woman (45 years old, G6P1) presented with haematuria and flank pain. CT showed AML with acute haemorrhage. The patient became haemodynamically unstable and underwent urgent embolisation and follow-on total radical nephrectomy with the foetus being left in-utero. This involved a multidisciplinary team (urologist, vascular surgeon, interventional radiologist and obstetrician). The procedure was uncomplicated and the pregnancy went to term with a healthy girl delivered at 38 weeks. DISCUSSION: The incidence of AML is 0.13% in the general population. 21 reports of haemorrhaging AML in pregnancy have been published in the last 35 years. Mean gestational age was 29.6 weeks. Eight were treated conservatively to term, one underwent exploratory laparotomy with evacuation of haematoma only, five were embolised, and seven were managed with nephrectomy. Of the nephrectomy subgroup, one was preceded by vaginal delivery and five underwent concurrent caesarean section (one with pre-op embolisation). There were two associated foetal deaths. CONCLUSION: This case demonstrates that with a multidisciplinary approach, it is possible to successfully leave a foetus undelivered whilst performing a radical nephrectomy for a large bleeding AML in a woman carrying a late second trimester pregnancy.