Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE).

BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. RESULTS: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, P = 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade ≥3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34.

Characterization of three PDI-like genes in Physcomitrella patens and construction of knock-out mutants.

Plant genomes typically contain several sequences homologous to protein disulfide isomerase (PDI). PDI was first identified as an abundant enzyme in the endoplasmic reticulum, where it catalyzes the formation, reduction, and isomerization of disulfide bonds during protein folding. PDI-like proteins have also been implicated in a variety of other functions, such as the regulation of cell adhesion, and may act as elicitors of the autoimmune response in mammals. A PDI-like protein (RB60) was recently shown to be imported into chloroplasts in the unicellular green alga Chlamydomonas reinhardtii and a higher plant, Pisum sativum, where it associates with thylakoid membranes. This suggests that the different PDI-like proteins in plant and animals may have diverse biological roles. To begin to elucidate the roles of PDI-like proteins, we have cloned, characterized, and generated knock-out mutants for three PDI-like genes that have high, medium, and low levels of expression, respectively, in the moss Physcomitrella patens. Phylogenetic analysis indicates that the three PDI-like proteins cluster with RB60 and four proteins from Arabidopsis thaliana. They are typified by an N-terminal domain rich in negatively charged residues. The knock-out mutants, which are the first knock-outs available for PDI-like proteins in a multicellular organism, were found to be viable, indicating that the function of each single gene is dispensable, and suggesting that they may be functionally complementary.

The protein disulfide isomerase-like RB60 is partitioned between stroma and thylakoids in Chlamydomonas reinhardtii chloroplasts.

Translation of psbA mRNA in Chlamydomonas reinhardtii chloroplasts is regulated by a redox signal(s). RB60 is a member of a protein complex that binds with high affinity to the 5'-untranslated region of psbA mRNA. RB60 has been suggested to act as a redox-sensor subunit of the protein complex regulating translation of chloroplast psbA mRNA. Surprisingly, cloning of RB60 identified high homology to the endoplasmic reticulum-localized protein disulfide isomerase, including an endoplasmic reticulum-retention signal at its carboxyl terminus. Here we show, by in vitro import studies, that the recombinant RB60 is imported into isolated chloroplasts of C. reinhardtii and pea in a transit peptide-dependent manner. Subfractionation of C. reinhardtii chloroplasts revealed that the native RB60 is partitioned between the stroma and the thylakoids. The nature of association of native RB60, and imported recombinant RB60, with thylakoids is similar and suggests that RB60 is tightly bound to thylakoids. The targeting characteristics of RB60 and the potential implications of the association of RB60 with thylakoids are discussed.

Recombination of engineered defective RNA species produces infective potyvirus in planta.

Recombination occurred between viral genomes when squash plants were cobombarded with mixtures of engineered disabled constructs of a zucchini yellow mosaic potyvirus. Single and double recombinants were detected in the progeny. Genes involved in the recombination process and the mechanisms of recombination were studied in potyviruses for the first time.

Simple hand-held devices for the efficient infection of plants with viral-encoding constructs by particle bombardment.

An efficient method for infection of plants with a cloned potyvirus by particle bombardment has been described (Gal-On et al., 1995). A simplified method is described now whereby a vaccuum chamber and helium propulsive gas are not required to achieve a high efficiency of infection. The new device-the 'HandGun'--is hand-held, and easily constructed from readily available materials. With this technique it is possible to bombard soft plants and seedings that do not survive particle bombardment by other devices. bombardment of C. pepo plants with a full length clone of zucchini yellow mosaic potyvirus results in approximately 100% infection at 100 pg cDNA per plant using air or helium to propel the microprojectiles. The HandGun is 10(5)-fold more efficient than mechanical inoculation. Tungsten and gold were found to be the most efficient materials tested for use as microprojectiles. Crude extracts of plasmids from E. coli were found to be effective, as well as column-purified cDNA. A functional, simple version of the HandGun--'the Blowpipe'--was also constructed, which does not require an electrically controlled valve. Plants can be inoculated with plant viruses from sap with the HandGun.

Particle bombardment drastically increases the infectivity of cloned DNA of zucchini yellow mosaic potyvirus.

An infectious full-length cDNA clone of the RNA genome of the potyvirus zucchini yellow mosaic virus (ZYMV) was constructed under the control of the cauliflower mosaic virus 35S promoter. All squash, cucumber, melon and watermelon plants inoculated with the cloned cDNA of ZYMV by particle bombardment become infected. Bombardment technology is 10(6)-fold more effective than mechanical inoculation. Due to the great increase in efficiency, ineffective constructs now became infective (i.e. cDNA under the control of the 35S promoter without the NOS terminator; with an addition of 127 nucleotides at the 5' end of the viral cDNA; uncapped transcripts), and the infectivity of capped-transcripts was maximized. Inoculation by particle bombardment produced visual symptoms rapidly (3-4 days), allowing the detection of viral coat protein and virions after 2 and 3 days in systemically infected leaves and inoculated cotyledons respectively.

Rectal non-Hodgkin's lymphoma: a clinicopathologic study and review.

A total of 11 patients with lymphomatous involvement of the rectum were seen at Henry Ford Hospital between 1964 and 1987. Eight of these patients had primary rectal lymphoma and three had secondary rectal lymphoma. These patients' clinical presentation and course as well as pathological findings are described and compared with cases previously reported. As identified in ours and others' series, rectal lymphomas are associated with the acquired immunodeficiency syndrome and tend to have a B-cell phenotype.

Hypoglycemia after administration of somatostatin analog (SMS 201-995) in metastatic carcinoid.

SMS 201-995 (Sandoz Pharmaceuticals, East Hanover, NJ) is a synthetic peptide analog of native somatostatin that has been used to relieve symptoms caused by neuroendocrine tumors. Reports have described an insulin suppressive effect of SMS 201-995 that results in elevations of blood glucose. We report a patient with a metastatic small bowel carcinoid and renal failure in whom mild symptomatic hypoglycemia occurred 30 to 60 minutes after SMS 201-995 administration. No increase in insulin or decreases in glucagon, cortisol, or catecholamines were observed during these hypoglycemic episodes. Elevated levels of growth hormone fell gradually following SMS 201-995 administration and did not temporally correspond to the 30- to 60-minute nadir of blood glucose. However, SMS 201-995 levels peaked during this 30- to 60-minute period. As clinical experience with this drug broadens, patients whose glucose control is dependent on counter-regulatory hormones should be monitored for the possibility of hypoglycemia.