Population declines of tuna and relatives depend on their speed of life.

Larger-bodied species in a wide range of taxonomic groups including mammals, fishes and birds tend to decline more steeply and are at greater risk of extinction. Yet, the diversity in life histories is governed not only by body size, but also by time-related traits. A key question is whether this size-dependency of vulnerability also holds, not just locally, but globally across a wider range of environments. We test the relative importance of size- and time-related life-history traits and fishing mortality in determining population declines and current exploitation status in tunas and their relatives. We use high-quality datasets of half a century of population trajectories combined with population-level fishing mortalities and life-history traits. Time-related traits (e.g. growth rate), rather than size-related traits (e.g. maximum size), better explain the extent and rate of declines and current exploitation status across tuna assemblages, after controlling for fishing mortality. Consequently, there is strong geographical patterning in population declines, such that populations with slower life histories (found at higher cooler latitudes) have declined most and more steeply and have a higher probability of being overfished than populations with faster life histories (found at tropical latitudes). Hence, the strong, temperature-driven, latitudinal gradients in life-history traits may underlie the global patterning of population declines, fisheries collapses and local extinctions.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation.

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.

Correlation of GREB1 mRNA with protein expression in breast cancer: validation of a novel GREB1 monoclonal antibody.

Studies of gene regulated by estrogen in breast cancer 1 (GREB1) have focused on mRNA levels with limited evidence about GREB1 protein expression in normal and breast cancer cells. A monoclonal antibody that recognizes GREB1 protein in breast tissues could be applied to correlate protein expression with established mRNA expression data. A hybridoma expressing a murine monoclonal antibody targeting a 119 amino acid peptide specific to human GREB1 was generated. The novel monoclonal GREB1 antibody (GREB1ab) was validated for use in Western blotting as well as immunohistochemical (IHC) applications. GREB1ab detects a 216 kDa protein corresponding to GREB1 in estrogen receptor alpha (ERalpha+) breast cancer cells as well as ERalpha- breast cancer cells transduced with a GREB1 expression vector. GREB1ab specificity was verified using an ERalpha antagonist to prevent GREB1 induction as well as a silencing siRNA targeting GREB1 mRNA. GREB1ab was further validated for detection of GREB1 by IHC in breast cancer cell lines and breast tissue microarrays (TMA). ERalpha+ cell lines were observed to express GREB1 while ERalpha- cell lines did not express detectable levels of the protein. Using breast cancer tissue whole sections, IHC with the GREB1ab identified protein expression in ERalpha+ breast cancer tissue as well as normal breast tissue, with little GREB1 expression in ERalpha- breast cancer tissue. Furthermore, these data indicate that GREB1 mRNA expression correlates well with protein expression. The novel monoclonal GREB1ab is specific for GREB1 protein. This antibody will serve as a tool for investigations focused on the expression, distribution, and function of GREB1 in normal breast and breast cancer tissues.

Breast specimen orientation.

Lumpectomy specimens are commonly divided into six sides: superficial, deep, superior, inferior, medial, and lateral. Orienting stitches are placed on the specimen during surgery to allow reorientation by pathology. Despite those efforts, specimen disorientation may occur. The aim of this study was to assess the correlation in orientation between surgeons and pathologists. Lumpectomy specimens were routinely oriented. An additional Prolene suture was randomly placed by the surgeon on one side to be localized by pathology. The results were recorded and the disorientation rate calculated. Specimen size and presence of skin and/or muscle were also recorded. There were 122 lumpectomy specimens prospectively entered. Average specimen volume was 95.5 cm(3). Twenty-four specimens had segments of skin or muscle. The additional sutures were evenly divided between the six sides. The overall disorientation rate was 31.1% (95% confidence interval, 23.1-40.2).The side-specific disorientation rates were 43%, 40%, 35%, 29%, 28%, and 14% for the deep, superficial, lateral, medial, superior, and inferior surfaces, respectively (no statistical difference). Presence of skin or muscle on the specimen did not contribute to better orientation. Specimen volumes, however, were highly associated with orientation. Specimens of <20 cm(3) had a disorientation rate of 78%, while larger specimen had a disorientation rate of 20% (p < .001). Specimen orientation with stitches placed on two surfaces is associated with a high disorientation rate. Better orientation techniques are necessary to minimize the specimen disorientation.

Snail silencing effectively suppresses tumour growth and invasiveness.

The transcription factor Snail has been recently proposed as an important mediator of tumour invasion because of its role in downregulation of E-cadherin and induction of epithelial-mesenchymal transitions (EMT). This behaviour has led to the consideration of Snail as a potential therapeutic target to block tumour progression. In this report, we provide evidence for this hypothesis. We show that silencing of Snail by stable RNA interference in MDCK-Snail cells induces a complete mesenchymal to epithelial transition (MET), associated to the upregulation of E-cadherin, downregulation of mesenchymal markers and inhibition of invasion. More importantly, stable interference of endogenous Snail in two independent carcinoma cell lines leads to a dramatic reduction of in vivo tumour growth, accompanied by increased tumour differentiation and a significant decrease in the expression of MMP-9 and angiogenic markers and invasiveness. These results indicate that use of RNA interference can be an effective tool for blocking Snail function, opening the way for its application in new antiinvasive therapies.

First Report of Pea enation mosaic virus Infecting Pea and Broad Bean in Spain.

During the spring of 2007, pea plants (Pisum sativum L.) (cvs. Utrillo and Floreta) showing virus-like symptoms were observed in several commercial fields in the southern and eastern regions of Catalonia, Spain. Incidence of symptomatic plants ranged from 5 to 15% and was distributed in both small and large patches. Infected plants exhibited yellow mosaic leaf symptoms that later became translucent. Leaves gradually curled and in some cases developed enations near the veins on the abaxial surface. Plants were "bushy" and had shortened internodes. Infection prior to pod formation resulted in pods that were distorted and stunted (1). The infected leaves and pods were tested by indirect-ELISA with a potyvirus-specific antibody (Agdia, Elkhart, IN) and double-antibody sandwich (DAS)-ELISA with antibodies specific to Pea enation mosaic virus (PEMV), Broad bean wilt virus 1 (BBWV-1), Beet western yellow virus (BWYV), Bean yellow mosaic virus (BYMV), Alfalfa mosaic virus (AMV), and Tomato spotted wilt virus (TSWV) (Loewe Biochemica GmbH, Sauerlach, Germany). PEMV was detected in all 24 symptomatic samples that were collected from 10 locations between March 2007 and March 2008. Thirteen of these samples also tested positive for BWYV, but no differences in symptom expression were observed in plants infected with both viruses or PEMV alone. PEMV was also identified in seven broad bean plants (Vicia faba L.) from three additional locations. These plants expressed interveinal yellow mosaic on leaves and deformed pods. The genomic sequence of PEMV-1 (GenBank Accession No. L04573) was used to design primers to amplify a 451-nt segment of the polymerase gene by reverse transcription (RT)-PCR; PEMV-D (5'-TGACCATGAGTCCACTGAGG-3'), PEMV-R (5'-AGTATCTTCCAACAACCACAT-3'). One ELISA-positive sample was analyzed and the expected size amplicon was generated. Direct sequencing (GenBank Accession No. EU652339) revealed that PEMV-1 and our pea isolate have nucleotide sequence identities of 95%. To our knowledge, this is the first report of PEMV in Spain, which might cause important economical losses since PEMV is an important viral disease of pea and other legumes worldwide. Reference: (1) J. S. Skaf and G. A. Zoeten. No. 372 (No. 257 revised) in: Description of Plant Viruses. AAB, Kew, Surrey, England, 2000.

An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia.

Leukemias harboring the ETV6-ABL1 fusion represent a rare subset of hematological malignancies with unfavorable outcomes. The constitutively active chimeric Etv6-Abl1 tyrosine kinase can be specifically inhibited by tyrosine kinase inhibitors (TKIs). Although TKIs represent an important therapeutic tool, so far, the mechanism underlying the potential TKI resistance in ETV6-ABL1-positive malignancies has not been studied in detail. To address this issue, we established a TKI-resistant ETV6-ABL1-positive leukemic cell line through long-term exposure to imatinib. ETV6-ABL1-dependent mechanisms (including fusion gene/protein mutation, amplification, enhanced expression or phosphorylation) and increased TKI efflux were excluded as potential causes of resistance. We showed that TKI effectively inhibited the Etv6-Abl1 kinase activity in resistant cells, and using short hairpin RNA (shRNA)-mediated silencing, we confirmed that the resistant cells became independent from the ETV6-ABL1 oncogene. Through analysis of the genomic and proteomic profiles of resistant cells, we identified an acquired mutation in the GNB1 gene, K89M, as the most likely cause of the resistance. We showed that cells harboring mutated GNB1 were capable of restoring signaling through the phosphoinositide-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, whose activation is inhibited by TKI. This alternative GNB1K89M-mediated pro-survival signaling rendered ETV6-ABL1-positive leukemic cells resistant to TKI therapy. The mechanism of TKI resistance is independent of the targeted chimeric kinase and thus is potentially relevant not only to ETV6-ABL1-positive leukemias but also to a wider spectrum of malignancies treated by kinase inhibitors.

Past and current trends in soy supplementation: a bibliographic study.

The aim was to determine in what areas the therapeutic application of soy predominates in clinical trials and to assess the emerging fields of its use by means of an analysis of bibliographic resources. A search was performed in the MEDLINE database up to 31 december 2004, limited to the Title/Abstract field, and Clinical Trials as the type of publication. The abstracts from the publications selected (n=86) were reviewed and different variables were assessed. A total of 3280 subjects were included: 15% men and 59% women (71% postmenopausal). The studies were performed basically in healthy individuals (71%). Twenty five percent of the studies investigated plasma levels of different metabolites and 21% determined hormone or lipid profiles. After the year 2000 a new population focus was detected, with the publication of two studies in elite gymnasts and judoists, with positive results. The present observations indicate that soy supplementation in the competitive sports elite may be an emerging application.

Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells.

l-asparaginase (ASNase), a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), hydrolyzes plasma asparagine and glutamine and thereby disturbs metabolic homeostasis of leukemic cells. The efficacy of such therapeutic strategy will depend on the capacity of cancer cells to adapt to the metabolic challenge, which could relate to the activation of compensatory metabolic routes. Therefore, we studied the impact of ASNase on the main metabolic pathways in leukemic cells. Treating leukemic cells with ASNase increased fatty-acid oxidation (FAO) and cell respiration and inhibited glycolysis. FAO, together with the decrease in protein translation and pyrimidine synthesis, was positively regulated through inhibition of the RagB-mTORC1 pathway, whereas the effect on glycolysis was RagB-mTORC1 independent. As FAO has been suggested to have a pro-survival function in leukemic cells, we tested its contribution to cell survival following ASNase treatment. Pharmacological inhibition of FAO significantly increased the sensitivity of ALL cells to ASNase. Moreover, constitutive activation of the mammalian target of rapamycin pathway increased apoptosis in leukemic cells treated with ASNase, but did not increase FAO. Our study uncovers a novel therapeutic option based on the combination of ASNase and FAO inhibitors.

A Lotus japonicus nodulation system based on heterologous expression of the fucosyl transferase NodZ and the acetyl transferase NoIL in Rhizobium leguminosarum.

Heterologous expression of NodZ and NolL proteins in Rhizobium leguminosarum bv. viciae led to the production of acetyl fucosylated lipo-chitin oligosaccharides (LCOs), indicating that the NolL protein obtained from Mesorhizobium loti functions as an acetyl transferase. We show that the NolL-dependent acetylation is specific for the fucosyl penta-N-acetylglucosamine species. In addition, the NolL protein caused elevated production of LCOs. Efficient nodulation of Lotus japonicus by the NodZ/NolL-producing strain was demonstrated. Nodulation efficiency was further improved by the addition of the ethylene inhibitor L-alpha-(2-aminoethoxyvinyl) glycine (AVG).

Cytologic characteristics of meningeal carcinomatosis: increased diagnostic accuracy using carcinoembryonic antigen and epithelial membrane antigen immunocytochemistry.

BACKGROUND AND OBJECTIVES: Traditionally, the diagnosis of meningeal carcinomatosis has been based on clinical suspicion and confirmed by cytologic study of cerebrospinal fluid. However, routine cytologic study may fail to detect malignant cells in a relatively large number of cases. We used immunocytochemistry in an attempt to increase the sensitivity of cytologic detection of malignant neoplasms in cerebrospinal fluid. MATERIALS AND METHODS: Thirty-eight consecutive cerebrospinal fluid specimens from patients with clinically suspected meningeal carcinomatosis were selected for this study. Immunocytochemistry for carcinoembryonic antigen and epithelial membrane antigen were used on the archival Papanicolaou-stained cerebrospinal fluid preparations. RESULTS: Of the 23 specimens from patients with proven meningeal carcinomatosis, 13 were correctly diagnosed using cytomorphologic criteria alone. The diagnosis of malignant neoplasm in 8 cytologically suspicious and 1 cytologically negative specimen was confirmed using immunocytochemistry. All cases that were negative on follow-up were also negative cytologically and immunocytochemically. CONCLUSIONS: We conclude that in using common antibodies, such as carcinoembryonic antigen and epithelial membrane antigen, the sensitivity of the cytologic diagnosis of meningeal carcinomatosis increases, and that previously Papanicolaou-stained preparations are suitable for immunocytochemical studies.

Short report: Schistosoma mansoni miracidia are killed by the defense system of an Argentine strain of Biomphalaria straminea.

Biomphalaria straminea snails from Argentina fail to shed cercariae even if exposed to high doses of Schistosoma mansoni EC miracidia. Alternative explanations for this failure are that miracidia are unable to penetrate the snail's epithelium or that the miracidia are killed by the snail's defense system. To discriminate between these 2 possibilities, B. straminea snails were individually exposed to increasing doses of miracidia. Susceptible B. glabrata were used as controls. Exposed snails were fixed 12 hr after exposure, and histological sections of the whole specimens were examined. Miracidia were seen to penetrate the epithelium of B. straminea and B. glabrata at similar rates (14.7%), independent of the exposure level. Regardless of the miracidial dose, 94% of the penetrating miracidia appeared encapsulated by the B. straminea defense system, whereas in B. glabrata, only 42% of the miracidia underwent encapsulation. These results show that resistance of B. straminea to S. mansoni EC strain is due to an efficient defense system that destroys miracidia once they have penetrated.

Invasion of human embryo by Enterobius vermicularis.

Two Enterobius vermicularis organisms invading a macerated embryo 2 cm in length were found in the tissue from an endometrial curettage performed for missed abortion in a pregnant woman. Ova from the helminths were recovered from the vagina and endometrium of the patient. This most unusual case provides further evidence for the invading capacity of E vermicularis.

Prognostic factors in follicular carcinoma of the thyroid.

Although there are numerous publications on the nomenclature, morphological diagnostic criteria, and prognostic factors of follicular carcinoma of the thyroid, these issues remain controversial. We present the findings of a retrospective and comparative study of 82 patients who underwent thyroid surgery for thyroid neoplasms. Of these patients, 58 had follicular carcinoma, 12 had atypical adenoma, and the remaining 12 patients had adenoma with partial capsular invasion in the surgical specimen. The goal of the study was to determine diagnostic criteria and prognostic factors in follicular carcinoma. Our results showed that encapsulated thyroid follicular neoplasms should be considered malignant when they demonstrate total capsular invasion and/or vascular invasion. Statistical analysis of the cases of follicular carcinoma showed that higher morbidity rates were seen in the patients with metastasis at the time of diagnosis, with extensively invasive tumors, with age older than 35 years, and with tumors with simultaneous vascular and capsular invasion. The accumulated survival rate over 5 years based on mortality was 91%, and based on morbidity it was 71% (84% for patients with encapsulated tumors and 56% for patients with extensively invasive tumors). In the univariate survival study based on morbidity, we found a relationship with the following parameters: metastasis at the time of diagnosis, grade of local invasion, presence of capsular and vascular invasion, cellular atypia, histologic pattern (insular vs others), presence of thyroid nodule, and age of the patient at the time of diagnosis. In the multivariate survival study based on morbidity, the factors that showed prognostic value were metastasis at the time of diagnosis, grade of local invasion, and age of the patient at the time of diagnosis.

Hemangioma calcificans--a benign epileptogenic lesion.

Hemangioma calcificans is a rare condition that may be regarded as a calcified cerebral cavernous angioma. The clinical presentation is usually that of epilepsy in an adult. A calcified nodule is visible on radiographs of the skull or computed tomographic (CT) scans. Angiography does not demonstrate vascularity. It is usually a solitary subcortical lesion that is surgically removable. Because of the favorable results from treatment of this lesion, this report reviews the clinical and radiological features described in the literature and includes an additional case.

Retrospective c-erbB-2 immunostaining in aspiration cytology of breast cancer.

Fifty fine-needle aspiration cytologies of breast that were diagnosed as carcinomas were retrieved from the files and retrospectively evaluated for the expression of c-erbB-2 oncoprotein using standard immunocytochemical methods. Corresponding histologic sections of all tumors were similarly studied. Seventeen fine-needle aspirates (34%) reacted positively for the presence of c-erbB-2 oncoprotein. All but one (32%) of the corresponding tissue sections were also positive for c-erbB-2 by immunohistochemistry. All positive cases were infiltrative ductal carcinomas with a preponderance of the comedo type. Positive reactions were localized in the cytoplasmic membrane of tumor cells. The staining was either present in all cells throughout a tumor, or it was completely absent. We conclude that immunocytochemistry for c-erbB-2 oncoprotein can be performed on fine-needle aspiration cytology samples that are previously fixed and stained with the Papanicolaou technique. Furthermore, the sensitivity of immunostaining results are comparable to that obtained in histologic sections.

The value of fine-needle aspiration cytology in the diagnosis of inflammatory pancreatic masses.

In order to determine the accuracy of fine-needle aspiration cytology (FNAC) in the diagnosis of inflammatory pancreatic masses (pseudocyst and abscess), we reviewed 91 FNAC specimens performed during 1985-1989 at the University of Miami/Jackson Memorial Medical Center. All specimens were collected under computed tomographic guidance. A sensitivity of 100% and a specificity of 98% were recorded in the diagnosis of inflammatory pancreatic masses. The sensitivity and specificity of the method in the diagnosis of malignant neoplasms were 79.5% and 100%, respectively. We conclude that fine-needle aspiration cytology of pancreas is not only an important diagnostic tool in patients with pancreatic cancer, but can also be used to diagnose inflammatory masses of the pancreas. In fact, aspiration of such masses may not only be diagnostic, but also therapeutic in some patients.

[Results of a combination of platinum-vindesin-ametycin-bleomycin (CEMB) in the treatment of stage IV non-small-cell lung cancers]. / Résultats de l'association platine-vindésine-amétycine-bléomycine (CEMB) dans les cancers du poumon non à petites cellules de stade IV.

From July 1987 to July 1988, 35 patients with non small cell lung cancer, stage IV, were included in a phase II trial (GLOT NPC 87/01). The treatment was as follows: cisplatin 50 mg/m2 day 1, vindesin 3 mg/m2 day 1, mitomycin 6 mg/m2 day 2, and bleomycin 15 mg/day, day 1 + 2 by continuous infusion. The evaluation for response was assessed after three courses of chemotherapy. The results were poor: an objective response was observed in three patients: three partial responses and no complete response. Because of tumor progression (18 patients) or toxicity (three patients), 21 patients did not complete the three cycles of chemotherapy. The median survival rate was 100 days. Toxicity was mild: grade III neutropenia occurred in one patient, grade IV thrombocytopenia was also observed in one patient. We conclude that this treatment has only a poor efficacy in stage IV non small cell lung cancer.