54 research outputs found
Evaluation of Milk Enzymes and Electrolytes, Plasma Metabolites, and Oxidative Status in Twin Cows Milked in an Automatic Milking System or Twice Daily in a Conventional Milking Parlor
The aim of this paper was to evaluate the effects of automatic milking (AM) on milk enzymes and minerals related to mammary epithelial integrity in comparison with twice-daily conventional milking (CM). One cow from each of 6 pairs of twins was assigned to be milked with AM or with CM throughout first lactation. Milk production was recorded and milk samples were collected at 4, 11, 18, 25, 32, and 39 wk of lactation (WOL) to determine fat and protein content, somatic cell count, pH, plasminogen (pl) and plasmin (Pl) activities, Na, K, and Cl. Body condition score was monitored; blood samples were collected to determine energy-related metabolites in the first third of lactation (14 WOL), and plasma oxidative status throughout lactation. Overall mean and standard deviation of milking frequency (MF) in AM were 2.69 and 0.88, respectively. Milk production, fat and protein contents, and somatic cell count did not differ between milking systems. The pl and pl+Pl activities were lesser in AM than in CM. Milk pH was greater in AM than in CM. Milk Na, K, Na/K ratio, and Cl did not differ across the whole lactation. Milk pH had a positive correlation with milk Pl activity (r = 0.41), Na (r = 0.37), and Cl (r = 0.40) concentration, and negative correlation with the log(10) of pl/Pl ratio (r = -0.47). The milk Na/K ratio had a positive correlation (r = 0.55) with milk Pl activity. Milking system (MS) did not seem to affect mammary epithelial permeability. The differences in enzymatic (proteolytic) activity due to the MS, probably related to daily MF, lead one to suppose that the quality of the protein fraction for the cheese-making process was preserved better with AM than with CM, even if differences in pH might negatively interfere. No difference was detected in BCS, and in plasma concentration of triglycerides and nonesterified fatty acids, whereas plasma cholesterol concentration during the first 10 WOL was lesser in AM than CM. Oxidative status, measured by plasma reactive oxygen metabolites and thiol groups, did not differ between MS throughout the whole lactation. These results suggest that early lactation of AM primiparous cows may give rise to crucial situations: for milk production, when a low MF may impair further mammary cell proliferation; for milk quality, if an irregular MF, with prolonged milking intervals, leads to an increased milk pH with increased conversion of pl to Pl
Epidermal Growth Factor Receptor Intron-1 Polymorphism Predicts Gefitinib Outcome in Advanced Non-small Cell Lung Cancer
IntroductionEpidermal growth factor receptor (EGFR) gene intron 1 contains a polymorphic single sequence dinucleotide repeat (CA)n whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)n polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC).MethodsBlood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron 1 gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron 1 polymorphism was also studied.ResultsEGFR intron 1 polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)16 and with a (CA)else genotype, respectively; p = 0.044). Patients with a (CA)16 genotype had a longer survival compared with those with a (CA)else genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)16 allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)16 allele (p = 0.003).ConclusionsThis study supports a potential role of EGFR intron 1 polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC
Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors
Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKIs), but is successful for only a limited amount of time; most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC
Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial
Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics
Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model
We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation.
Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity.
Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge.
The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones
Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study
Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies
The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma
The development of sensitive and non-invasive
‘‘liquid biopsies’’ presents new opportunities for
longitudinal monitoring of tumor dissemination and
clonal evolution. The number of circulating tumor
cells (CTCs) is prognostic in multiple myeloma
(MM), but there is little information on their genetic
features. Here, we have analyzed the genomic landscape
of CTCs from 29 MM patients, including eight
cases with matched/paired bone marrow (BM) tumor
cells. Our results show that 100% of clonal mutations
in patient BM were detected in CTCs and that 99% of
clonal mutations in CTCs were present in BM MM.
These include typical driver mutations in MM such
as in KRAS, NRAS, or BRAF. These data suggest
that BM and CTC samples have similar clonal structures,
as discordances between the two were
restricted to subclonal mutations. Accordingly, our
results pave the way for potentially less invasive
mutation screening of MM patients through characterization
of CTCs
Influence of genic alterations on the response of solid tumors to therapy and secondary prevention
Le sempre più numerose conoscenze a livello epidemiologico, clinico e molecolare
sembrano permettere la caratterizzazione dei diversi istotipi del tumore polmonare non a
a piccole cellule (NSCLC), la previsione delle risposte a specifici trattamenti terapeutici e
l’individuazione di possibili fattori di rischio. In questo studio sono stati valutati specifici
marcatori biologici in differenti tessuti surrogati a quello del tumore polmonare, spesso
disponibile in quantità limitate, per la capacità di discriminare pazienti che potrebbero
rispondere a mirati trattamenti inibitori del gene EGFR frequentemente iperespresso. E’
stato anche validato l’uso di un pannello di più marcatori biologici per la selezione di
sottogruppi di pazienti capaci di rispondere ai trattamenti con inibitori reversibili delle
tirosino-chinasi. In particolare, un gruppo di pazienti non fumatori è stato caratterizzato
per i marcatori molecolari già noti al fine di determinarne la prevalenza in questa
popolazione selezionata e poter identificare nuovi oncogeni implicati nell’eziologia del
tumore.
In conclusione, i risultati ottenuti in questo studio offrono promettenti prospettive per
quanto riguarda l’utilizzo e la ricerca di specifici biomarcatori per l’ottimizzazione di
trattamenti terapeutici e la creazione di mirate strategie diagnostiche e di prevenzione.A better characterization of the different Non Small Cell Lung Cancer (NSCLC)
histotypes and of new possible risk factors, together with the estimation of the response
to specific therapeutic treatments, have been achieved by new epidemiologic, clinical and
molecular knowledge. In this study, we evaluated specific biomarkers in various tissues
different from the tumor one, which is in the most cases available only in a small amount,
to discriminate subsets of patients that could respond in different manner to specific
inihibition treatments of frequently overexpressed EGFR gene. A panel of several
biomarkers was also validated with the aim to select subsets of patients capable to have a
positive response to the treatment based on reversible inhibitors of tyrosine-kinases. In
particular, a group of non smoking patients was characterized for a panel of biomarkers
identified in literature with the aim to determine their prevalence in this selected sample
and identify new oncogenes involved in cancer ethiology.
In conclusion, results obtained in this study give promising information about the
identification and consequently the use of specific biomarkers for the therapeautic
treatment optimization and the development of specific diagnostic and preventive
strategies
Gender Difference in Lymphocyte Aromatase Gene Expression
The aromatase gene is differentially expressed in PBLs from women, men, and prepubertal children, indicating a sexual dimorphism in the enzyme expression and an important role of sex steroids in the modulation of aromatase gene expressio
Aromatase is differentially expressed in peripheral blood leukocytes from children, and adult female and male subjects
Objective: Aromatase. the key enzyme involved in estrogen synthesis, is expressed in a variety of cells and tissues including human peripheral blood leukocytes (PBLs). The present study was designed to evaluate 1:1131, aromatase gene expression in male and female subjects of different age groups. In addition. differences in gene expression during the follicular and luteal phase of the menstrual cycle in women, and before and after testosterone administration in men. were estimated. Design: Aromatase mRNA and protein were measured in PBLs obtained from young (n = 10) and postmenopausal women (n = 10). men (n = 15), and prepubertal children (n = 10). Aromatase mRNA and protein were also measured during the follicular and luteal phases of the menstrual cycle in women. and before and after the intramuscular administration of 250mg testosterone enanthate in men. Methods and Results: Aromatase mRNA measured by real-time PCR in PBLs from women during the follicular phase was significantly higher than during the luteal phase of the menstrual cycle (P < 0.05). In men. PBL aromatase mRNA values increased significantly following testosterone administration (P < 0.05). PBL mRNA aromatase levels in women during the follicular phase and men after testosterone administration were significantly higher (one-way ANOVA: P < 0.05) than in any other group. Children, postmenopausal women, and women during the luteal phase showed the lowest aromatase mRNA expression. The results of the immunoblot analysis confirmed the data obtained by real-time PCR. A positive correlation between PBL aromatase mRNA values and plasma estradiol and estrone levels during the follicular phase of the menstrual cycle was observed in the group of adult women. No other correlations were found. Conclusions: The aromatase gene is differentially expressed in PBLs from women, men, and prepubertal children, indicating a sexual dimorphism in the enzyme expression and an important role of sex steroids in the modulation of aromatase gene expression
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