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Quantum dot-plasmon waveguide systems are of interest for the active control of plasmon propagation, and consequently, the development of active nanophotonic devices such as nano-sized optical transistors. This paper is concerned with how varying aspect ratio of the waveguide cross-section affects the quantum dot-plasmon coupling. We compare a stripe waveguide with an equivalent nanowire, illustrating that both waveguides have a similar coupling strength to a nearby quantum dot for small waveguide cross-section, thereby indicating that stripe lithographic waveguides have strong potential use in quantum dot-plasmon waveguide systems. We also demonstrate that changing the aspect ratio of both stripe and wire waveguides can increase the spontaneous emission rate of the quantum dot into the plasmon mode, by up to a factor of five. The results of this paper will contribute to the optimisation of quantum dot-plasmon waveguide systems and help pave the way for the development of active nanophotonics devices. [ABSTRACT FROM AUTHOR]

Subacute ruminal acidosis (SARA) increases lipopolysaccharide endotoxin in the rumen, which might translocate into the systemic circulation, triggering a cascade of clinical and immunological alterations. The objective of this study was to characterize the clinical immune and metabolic responses to ruminal-derived lipopolysaccharide in nonlactating cows induced with SARA using 2 challenges, a grain-based SARA challenge (GBSC) or an alfalfa-pellet SARA challenge (APSC). Six dry, nonlactating Holstein cows were used in a 3 x 3 Latin square arrangement of treatments with 4-wk experimental cycles. All cows received the control diet containing 70% forage and 30% mixed concentrates (dry matter basis) for 3 wk. In wk 4, cows received a control diet, GBSC (38% wheat-barley pellets, 32% other mixed concentrate, and 30% forages), or APSC (45% mixed concentrate, 32% alfalfa pellets, and 23% other forages). Total plasma proteins and immunology-related proteins, acute phase proteins, blood cells, serum chemistry, mRNA gene expression of peripheral blood cell surface markers, and selected proinflammatory cytokines were evaluated. Ruminal pH was lower in both groups with induced SARA compared with a control group. Ruminal endotoxins were higher in GBSC; however, plasma endotoxin was not detected in any study group. No significant differences in feed intake, rectal temperature, white blood cell counts, or differentials were found between control and SARA challenge groups; changes in glucose, urea, Ca, and Mg were observed in SARA groups. Total plasma proteins were lower in both SARA groups, and acute phase proteins were higher in GBSC. The expression of CD14, MD2, and TLR4 mRNA in peripheral blood leukocytes was not affected by SARA induction. The induction of SARA as a result of GBSC or APSC challenge was successful; however, LPS was not detected in plasma. Changes in clinical, metabolic, and inflammatory responses were not observed in the SARA-challenged cows, suggesting that, in this study, SARA was not associated with a systemic response to inflammation. [ABSTRACT FROM AUTHOR]

Surplus dairy calves often arrive at veal and dairy-beef rearing facilities with health and blood metabolite level abnormalities, which can affect their welfare and performance, predisposing them to future health challenges. The objective of this randomized controlled trial was to investigate the effects of transport duration and age at the time of transport on blood parameters in surplus dairy calves following 6, 12, or 16 h of continuous road transportation. All surplus calves from 5 commercial dairy farms in Ontario were enrolled and examined daily before transport (n = 175). On the day of transportation, calves were weighed, blood sampled, and randomly assigned to 6, 12, or 16 h of transportation. Blood samples were then collected immediately after transportation, as well as 24, 48, and 72 h thereafter. Serum was analyzed at a provincial diagnostic laboratory for nonesterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA), creatine kinase (CK), cholesterol, and haptoglobin. In addition, blood gas and electrolyte values were also assessed at the time of sample collection. Mixed models with repeated measures were used to assess the effects of transport duration, breed, sex, transfer of passive immunity status, weight before transportation, and age at transportation on blood parameters. Immediately following transportation, NEFA and BHBA were greater for calves transported for 12 h (Δ = 0.22 mmol/L NEFA, 95% CI = 0.15 to 0.30; Δ = 0.04 mmol/L BHBA, 95% CI = 0.02 to 0.06) and 16 h (Δ = 0.35 mmol/L NEFA, 95% CI = 0.27 to 0.42; Δ = 0.10 mmol/L BHBA, 95% CI = 0.08 to 0.11) compared with calves transported for 6 h. Glucose was lower immediately following transportation in calves transported for 16 h compared with 6 h (Δ = -15.54 mg/dL, 95% CI = -21.54 to -9.54). In addition, pH and HCO 3 - were lower in calves transported for 12 (Δ = -0.09 pH, 95% CI = -0.13 to -0.05; Δ = -1.59 mmol/L HCO 3 , 95% CI = -2.95 to -0.95) compared with calves transported for 6 h. Calves transported between 15 and 19 d of age had a higher concentration of cholesterol and CK (Δ = 0.27 mmol/L cholesterol; 37.18 U/L CK) compared with 2- to 6-d-old calves, and calves 12 to 14 d old had greater reduction in HCO - (Δ = -0.92 mmol/L) compared with 2- to 6-d-old calves. These findings show that transporting calves for long distances results in lower glucose concentration and suboptimal energy status, and that this effect varies based on the calf's age.3 - , 95% CI = -2.95 to -0.95) compared with calves transported for 6 h. Calves transported between 15 and 19 d of age had a higher concentration of cholesterol and CK (Δ = 0.27 mmol/L cholesterol; 37.18 U/L CK) compared with 2- to 6-d-old calves, and calves 12 to 14 d old had greater reduction in HCO 3 - (Δ = -0.92 mmol/L) compared with 2- to 6-d-old calves. These findings show that transporting calves for long distances results in lower glucose concentration and suboptimal energy status, and that this effect varies based on the calf's age., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

This study evaluated the impact of a multidisciplinary intervention to reduce and refine antimicrobial drug use for treatment of diarrhoea in dairy calves. The intervention consisted of modification of management practices for disease prevention, health evaluation training of farm staff, implementation of an algorithm directed at antimicrobial therapy for diarrhoeic calves, and monthly farm visits. A combination of retrospective (before intervention period [BP], 1 year) and prospective (immediately after intervention period [AP], 1 year) cohorts were used. Health outcomes measured included incidence of diarrhoea and overall mortality. Antimicrobial treatment rates for diarrhoea and total mass of antimicrobial drugs used at the calf and farm level were also evaluated. Outcomes were assessed using the χ 2 or Fisher's exact test, and odds ratios and 95% confidence intervals (95% CI) were calculated. Records of 2049 and 2251 calves from 10 farms were available in the BP and AP, respectively. Reduced antimicrobial treatment rates occurred on seven farms (P < 0.01), but not on three farms in the AP. A total of 85% (1303/1573) and 18% (310/1698) of diarrhoeic calves were treated with antimicrobial drugs in the BP and AP (P < 0.001), respectively. There were no differences in the incidence of diarrhoea or mortality between periods. In the AP, the use sulfamethazine and trimethoprim decreased on eight farms, one farm discontinued use of lincomycin and spectinomycin, while two farms discontinued use and one reduced use of cephalosporins. This multidisciplinary approach was effective in reducing antimicrobial drug use for calf diarrhoea on dairy farms without negative impacts on calf health., (Copyright © 2021. Published by Elsevier Ltd.)

Rac1 GTPase signaling pathway has a critical role in the regulation of a plethora of cellular functions governing cancer cell behavior. Recently, it has been shown a critical role of Rac1 in the emergence of resistance mechanisms to cancer therapy. This review describes the current knowledge regarding Rac1 pathway deregulation and its association with chemoresistance, radioresistance, resistance to targeted therapies and immune evasion. This supports the idea that interfering Rac1 signaling pathway could be an interesting approach to tackle cancer resistance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: BCoV is identified in both healthy and diarrheic calves, complicating its assessment as a primary pathogen., Objectives: To investigate the detection rates of bovine coronavirus (BCoV) in feces of healthy and diarrheic calves and to describe the usefulness of a pancoronavirus reverse transcriptase (RT) PCR (PanCoV-RT-PCR) assay to identify BCoV in samples of diarrheic calves., Animals: Two hundred and eighty-six calves <21 days. Calves with liquid or semiliquid feces, temperature >39.5°C, and inappetence were considered as cases, and those that had pasty or firm feces and normal physical examination were designated as controls., Methods: Prospective case-control study. A specific BCoV-RT-PCR assay was used to detect BCoV in fecal samples. Association between BCoV and health status was evaluated by exact and random effect logistic regression. Fecal (n = 28) and nasal (n = 8) samples from diarrheic calves were tested for the presence of BCoV by both the PanCoV-RT-PCR and a specific BCoV-RT-PCR assays. A Kappa coefficient test was used to assess the level of agreement of both assays., Results: BCoV was detected in 55% (157/286) of calves; 46% (66/143), and 64% (91/143) of healthy and diarrheic calves, respectively. Diarrheic calves had higher odds of BCoV presence than healthy calves (OR: 2.16, 95% CI: 1.26 to 3.83, P = 0.004). A good agreement between PanCoV-RT-PCR and BCoV-RT-PCR to detect BCoV was identified (κ = 0.68, 95% CI: 0.392 to 0.967; P < 0.001)., Conclusions and Clinical Importance: BCoV was more likely to be detected in diarrheic than healthy calves. The PanCoV-RT-PCR assay can be a useful tool to detect CoV samples from diarrheic calves., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The signalment, clinicopathologic, bacteriological, histopathological, ultrasonographic characteristics, and the treatment and outcomes of adult cattle with cholangiohepatitis are poorly defined., Animals: Thirteen Holstein cows with cholangiohepatitis., Methods: Retrospective study of medical records of cattle admitted to the CHUV and the AVC between 1992 and 2012 and 2000 and 2012, respectively, for cattle older than 3 months of age with a histopathological diagnosis of cholangiohepatitis. Cholangiohepatitis was defined as the presence of portal inflammation surrounding or infiltrating bile ducts, with or without epithelial damage, and extending into the adjacent lobules., Results: At the time of diagnosis of cholangiohepatitis, cows had decreased appetite (n = 7) or were anorectic (n = 6), had fever (n = 5), and had tachycardia (n = 8). Icterus was detected in 5 cows. Yellow discoloration was identified on the skin of the udder (n = 3), conjunctiva (n = 2), and vulva (n = 1). There was leukocytosis (n = 6), neutrophilia (n = 9), and hyperfibrinogenemia (n = 8). Alteration in the serum biochemistry profile included hyperglobulinemia (n = 8), hypoalbuminemia (n = 10), increased activity of GGT (n = 12), AST (n = 8), and ALP (n = 10), and hyperbilirubinemia (n = 10). Histopathological diagnosis included mild, subacute, nonsuppurative cholangiohepatitis (n = 4), mild suppurative cholangiohepatitis (n = 4), mild mixed (neutrophilic and lymphocytic) cholangiohepatitis (n = 3), and moderate, chronic, nonsuppurative cholangiohepatitis (n = 1). Six cows were discharged from the hospital, and 7 were euthanized., Conclusions and Clinical Importance: Cholangiohepatitis is a rare condition in adult cattle. Antemortem diagnosis can be challenging because clinical signs are unspecific., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Neonatal diarrhea accounts for more than 50% of total deaths in dairy calves. Few population-based studies of cattle have investigated how the microbiota is impacted during diarrhea., Objectives: To characterize the fecal microbiota and predict the functional potential of the microbial communities in healthy and diarrheic calves., Methods: Fifteen diarrheic calves between the ages of 1 and 30 days and 15 age-matched healthy control calves were enrolled from 2 dairy farms. The Illumina MiSeq sequencer was used for high-throughput sequencing of the V4 region of the 16S rRNA gene (Illumina, San Diego, CA)., Results: Significant differences in community membership and structure were identified among healthy calves from different farms. Differences in community membership and structure also were identified between healthy and diarrheic calves within each farm. Based on linear discriminant analysis effect size (LEfSe), the genera Bifidobacterium, Megamonas, and a genus of the family Bifidobacteriaceae were associated with health at farm 1, whereas Lachnospiraceae incertae sedis, Dietzia and an unclassified genus of the family Veillonellaceae were significantly associated with health at farm 2. The Phylogenetic Investigation of Communities Reconstruction of Unobserved States (PICRUSt) analysis indicated that diarrheic calves had decreased abundances of genes responsible for metabolism of various vitamins, amino acids, and carbohydrate., Clinical Relevance: The fecal microbiota of healthy dairy calves appeared to be farm specific as were the changes observed during diarrhea. The differences in microbiota structure and membership between healthy and diarrheic calves suggest that dysbiosis can occur in diarrheic calves and it is associated with changes in predictive metagenomic function., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success, development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signaling pathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of the most important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhanced activity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not only showed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but also showed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype. We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylation levels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, we evaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells. 1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreased estrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrine therapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition of Rac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies., (Copyright © 2016. Published by Elsevier Inc.)

Telomeres are the terminal part of the chromosome containing a long repetitive and noncodifying sequence that has as function protecting the chromosomes. In normal cells, telomeres lost part of such repetitive sequence in each mitosis, until telomeres reach a critical point, triggering at that time senescence and cell death. However, in most of tumor cells in each cell division a part of the telomere is lost, however the appearance of an enzyme called telomerase synthetize the segment that just has been lost, therefore conferring to tumor cells the immortality hallmark. Telomerase is significantly overexpressed in 80-95% of all malignant tumors, being present at low levels in few normal cells, mostly stem cells. Due to these characteristics, telomerase has become an attractive target for new and more effective anticancer agents. The capability of inhibiting telomerase in tumor cells should lead to telomere shortening, senescence and apoptosis. In this work, we analyze the different strategies for telomerase inhibition, either in development, preclinical or clinical stages taking into account their strong points and their caveats. We covered strategies such as nucleosides analogs, oligonucleotides, small molecule inhibitors, G-quadruplex stabilizers, immunotherapy, gene therapy, molecules that affect the telomere/ telomerase associated proteins, agents from microbial sources, among others, providing a balanced evaluation of the status of the inhibitors of this powerful target together with an analysis of the challenges ahead.

Background: The quantitative effect of strong electrolytes, unmeasured strong anions (UAs), pCO2, and plasma protein concentrations in determining plasma pH can be demonstrated using the physicochemical approach. Plasma anion gap (AG) and strong ion gap (SIG) are used to assess UAs in different species., Hypotheses: Strong ions are a major factor influencing changes in plasma pH of hospitalized foals. AG and SIG accurately predict severe hyper-L-lactatemia ([L-lac(-)] > 7 mmol/L)., Animals: Seven hundred and ninety three hospitalized foals < 7 days old., Methods: Retrospective study. The relationship between measured pH and physicochemical variables, and the relationship between plasma [L-lac(-)] and AG and SIG, were determined using regression analyses. Optimal AG and SIG cut points to predict hyper-L-lactatemia were identified using an ROC curve analysis., Results: Combined, the measured strong ion difference and SIG accounted for 54-69% of the changes in the measured arterial pH of hospitalized foals. AG and SIG were significantly associated with plasma [L-lac(-)] (P < .0001). The receiver operator characteristics (ROC) AUC of AG and SIG for prediction of severe hyper-L-lactatemia were 0.89 (95%CI, 0.8-0.95; P < .0001) and 0.90 (95%CI, 0.81-0.96; P < .0001), respectively. Severe hyper-L-lactatemia was best predicted by AG > 27 mmol/L (sensitivity 80%, 95%CI, 56-94, specificity 85%, 95%CI, 73-93; P < .0001) and SIG <-15 mmol/L (sensitivity 90%, 95%CI, 68-98; specificity 80%; 95%CI, 68-90; P < .0001)., Conclusion and Clinical Relevance: Altered concentrations of strong ions (Na(+), K(+), Cl(-)) and UAs were the primary cause of acidemia of hospitalized foals. AG and SIG were good predictors of hyper-L-lactatemia and could be used as surrogate tests., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The quantitative effect of strong electrolytes, unmeasured anions (UAs), pCO2 , and plasma protein concentrations in determining plasma pH and bicarbonate (HCO3 (-) ) can be demonstrated using the physicochemical approach. Demeanor of calves with diarrhea is associated with acidemia, dehydration, and hyper-d-lactatemia., Hypothesis: Unmeasured anions are a major factor influencing changes in plasma pH and HCO3 (-) of calves with diarrhea and UAs and strong UAs, estimated by anion gap (AG) and strong ion gap (SIG), respectively, are more strongly associated with alteration of demeanor compared to other acid-base variables., Animals: A total of 264 calves with diarrhea from two data sets (DS1 and DS2)., Methods: Retrospective study. Forward stepwise regression was performed to determine the relationship between measured pH or HCO3 (-) , and physicochemical variables. A two-way ANOVA was performed to investigate the association between acid-base variables and attitude (bright, obtunded, and stuporous), posture (standing, sternal or lateral recumbency), and strength of suckling reflex (strong, weak, or absent)., Results: Increased strong UAs estimated by SIG was the most important contributor to changes in measured pH and HCO3 (-) (DS1: r(2) 66 and 59%, DS2: 39 and 42%, P < .0001). SIG and AG were correlated to deteriorating calf demeanor for all three clinical scoring categories: attitude, posture, and suckle reflex (P < .0001)., Conclusion and Clinical Relevance: Elevated concentrations of strong UAs were the primary cause of acidemia and had an important influence on the demeanor of calves with diarrhea. These findings emphasize the importance of the calculation of UAs when evaluating acid-base abnormalities in calves., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Background: The quantitative effect of strong electrolytes, pCO2 , and plasma protein concentration in determining plasma pH and bicarbonate concentrations can be demonstrated with the physicochemical approach. Plasma anion gap (AG) and strong ion gap (SIG) are used to assess the presence or absence of unmeasured anions., Hypotheses: The physicochemical approach is useful for detection and explanation of acid-base disorders in horses with colitis. AG and SIG accurately predict hyperlactatemia in horses with colitis., Animals: Fifty-four horses with acute colitis and diarrhea., Methods: Retrospective study. Physicochemical variables were calculated for each patient. ROC curves were generated to analyze sensitivity and specificity of AG and SIG for predicting hyperlactatemia., Results: Physicochemical interpretation of acid-base events indicated that strong ion metabolic acidosis was present in 39 (72%) horses. Mixed strong ion acidosis and decreased weak acid (hypoproteinemia) alkalosis was concomitantly present in 17 (30%) patients. The sensitivity and specificity of AG and SIG to predict hyperlactatemia (L-lactate > 5 mEq/L) were 100% (95% CI, 66.4-100; P < .0001) and 84.4% (95% CI, 70.5-93.5 P < .0001). Area under the ROC curve for AG and SIG for predicting hyperlactatemia was 0.95 (95% CI, 0.86-0.99) and 0.93 (95% CI, 0.83-0.99), respectively., Conclusion and Clinical Relevance: These results emphasize the importance of strong ions and proteins in the maintenance of the acid-base equilibria. AG and SIG were considered good predictors of clinically relevant hyperlactatemia., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Metastatic disease is responsible for most of cancer lethality. A main obstacle for therapy of advanced cancers is that the outcome of metastasis depends on a complex interplay between malignant and host cells. The perioperative period represents an underutilized window of opportunity for cancer treatment where tumor-host interactions can be modulated, reducing the risk of local recurrences and distant metastases. Blood-saving agents are attractive compounds to be administered during tumor surgery. Desmopressin (DDAVP) is a safe and convenient hemostatic peptide with proved antimetastastic properties in experimental models and veterinary clinical trials. The compound seems to induce a dual angiostatic and antimetastatic effect, breaking the cooperative function of cancer cells and endothelial cells during residual tumor progression. DDAVP is therefore an interesting lead compound to develop novel synthetic peptide analogs with enhanced antitumor properties.

Tissue factor (TF) is a molecular marker that is up-regulated in cancer cells and aids tumoral dissemination. Our purpose was to develop a nested RT-PCR strategy against TF for detecting blood-borne tumour cells. Our method detected TF expression in a minimum of 1.5 pg total RNA from MCF7 cells. A preliminary study in blood samples from 16 advanced breast carcinoma patients showed that 80% of patients with high TF load progressed and died, while only 18% with low TF load showed the same behaviour. Kaplan-Meier analysis confirmed worse overall survival in patients with high TF load.

Genetic influences, together with epigenetic components and dietary factors, play a fundamental role in the initiation and progression of cancer by causing a number of deregulations. Colorectal cancer (CRC) is a disease influenced by dietary factors, for which established genetic and epigenetic alterations have been identified. Within CRC, there are hereditary syndromes that present mutations in the germ-line hMLH1, and also alterations in the methylation of the promoters. Epigenetics has also been established as a pathway of carcinogenesis. In the present review, we analyzed studies conducted to discern the different pathways leading to established CRC, stressing the importance of identifying factors that may predict CRC at an early stage, since it is mostly a silent disease observed at the clinical level in advanced stages.

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy., (Copyright 2001 Wiley-Liss, Inc.)

Normal cells in culture divide a certain amount of times and undergo a process termed replicative senescence. Telomere loss is thought to control entry into senescence. Activation of telomerase in tumors bypasses cellular senescence and is thus a requirement for tumor progression. We reported previously the preferential incorporation of 3'-azido-2', 3'-dideoxythymidine (AZT) in telomeric sequences of immortalized cells in culture. In this work, we have investigated the effects of chronic in vitro AZT exposure on F3II mouse mammary carcinoma cells. We demonstrate, for the first time, that AZT-treated tumor cells have a reduced tumorigenicity in syngeneic BALB/c mice. Tumor incidence was reduced and survival was prolonged in animals inoculated with AZT-treated cells when comparing with control counterparts. The number and size of spontaneous metastases were also decreased in animals inoculated with AZT-treated cells. In addition, we present evidence of morphological and biochemical signs of senescence, as shown by the staining for senescence associated beta-galactosidase activity, and induction of programmed cell death, as demonstrated by an increase of caspase-3 activity, in tumor cells exposed to AZT. These data indicate that chronic exposure of mammary carcinoma cells to AZT may be sufficient to induce a senescent phenotype and to reduce tumorigenicity.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.