Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model

2008 ◽  
Vol 389 (8) ◽  
Author(s):  
Uta Schurigt ◽  
Lisa Sevenich ◽  
Corinne Vannier ◽  
Mieczyslaw Gajda ◽  
Anne Schwinde ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Control Group ◽  
Breast Cancers ◽  
Cancer Trial ◽  
Tissue Extracts ◽  
Cysteine Cathepsins ◽  
Cysteine Cathepsin ◽  
Effective Inhibition ◽  
Pharmacokinetic Properties

Abstract Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.

scholarly journals Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

2019 ◽  
Author(s):  
Lyndsey S Crump ◽  
Garhett Wyatt ◽  
Taylor R Rutherford ◽  
Jennifer K Richer ◽  
Weston W Porter ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Hormonal Regulation ◽  
Lung Metastases ◽  
Survival Rates ◽  
Poor Response ◽  
Breast Cancers ◽  
Tumor Resistance ◽  
Survival Signaling

ABSTRACTApproximately 70% of all breast cancers are estrogen receptor positive (ER+BC) and endocrine therapy has improved survival for patients with ER+BC. Yet, up to half of these tumors recur within 20 years. Recurrent ER+BCs develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+BC. We found that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+BC. We show that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with anti-estrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drives increased in vitro growth in the presence of estrogen-deprivation, tamoxifen, and fulvestrant. In in vivo studies, we found that SEMA7A confers primary tumor resistance to fulvestrant and, importantly, induced lung metastases. Finally, we identify pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors and propose that targeting with inhibitors of survival signaling such as venetoclax may have efficacy for treating SEMA7A+ tumors.SIGNIFICANCEWe report that SEMA7A predicts for, and likely contributes to, poor response to standard-of-care therapies and suggest that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.

Effective treatment of 4T1 mammary adenocarcinoma by direct tumor injection and continuous systemic infusion of transferrin receptor antisense in mice

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14113-14113
Author(s):  
J. F. Head ◽  
X. Jiang ◽  
K. A. Fort ◽  
V. D. Dye ◽  
R. L. Elliott
Keyword(s):  
Tumor Cells ◽  
Lung Metastases ◽  
Direct Injection ◽  
Post Treatment ◽  
Mammary Adenocarcinoma ◽  
Breast Cancer Cell Lines ◽  
Control Group ◽  
Primary Tumors ◽  
Tumor Growth And Metastasis

14113 Background: Transferrin receptors (TfR) on the cell surface are the major transporters of iron into cells. Tumor cells often have increased expression of TfR, compared to normal cells. TfR antibodies have been shown to inhibit the growth of tumor cells. We previously reported that human TfR antisense inhibited the proliferation of human breast cancer cell lines in vitro. Methods: In the present study, we used antisense oligonucleotides targeted to the mouse TfR gene to treat the 4T1 mammary adenocarcinoma mouse model. The antisense was either directly injected one time into the tumors or continuously infused systemically for 14 days through subcutaneous implantation of Alzet osmotic minipumps. The control group of mice received Hank’s balanced salt solution. Tumor sizes were measured twice a week. Tumor necrosis and metastasis were examined grossly at autopsy and by microscopy. Results: At 4, 7 and 10 days post- treatment, tumor volumes of treated groups, including direct injection and continuous infusion, were significantly smaller than the control group. At 14 days post-treatment, gross and microscopic pathology showed that the continuously systemically treated mice had significantly less lung metastases than the control group (p<0.001 and p<0.01, respectively). Although the group of mice treated with direct injection received an equal total dosage of TfR antisense as the continuously systemic treated mice, direct tumor injection of TfR antisense did not suppress lung metastasis. Primary tumors had varying degrees of necrosis in the treated and control groups, but there was no statistical difference between groups. Summary: TfR antisense effectively inhibited tumor growth and metastasis of 4T1 mammary adenocarcinoma in mice. Furthermore, continuously systemic administration of antisense was more effective than direct tumor injection. No significant financial relationships to disclose.

scholarly journals Processing and Maturation of Cathepsin C Zymogen: A Biochemical and Molecular Modeling Analysis

2019 ◽  
Vol 20 (19) ◽  
pp. 4747 ◽  
Author(s):  
Anne-Sophie Lamort ◽  
Yveline Hamon ◽  
Cezary Czaplewski ◽  
Artur Gieldon ◽  
Seda Seren ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Immune Cell ◽  
Serine Proteinase ◽  
Cathepsin G ◽  
Cathepsin C ◽  
Cysteine Cathepsins ◽  
Modeling Analysis ◽  
Cysteine Cathepsin ◽  
Proteolytic Cleavages

Cysteine cathepsin C (CatC) is a ubiquitously expressed, lysosomal aminopeptidase involved in the activation of zymogens of immune-cell-associated serine proteinases (elastase, cathepsin G, proteinase 3, neutrophil serine proteinase 4, lymphocyte granzymes, and mast cell chymases). CatC is first synthetized as an inactive zymogen containing an intramolecular chain propeptide, the dimeric form of which is processed into the mature tetrameric form by proteolytic cleavages. A molecular modeling analysis of proCatC indicated that its propeptide displayed a similar fold to those of other lysosomal cysteine cathepsins, and could be involved in dimer formation. Our in vitro experiments revealed that human proCatC was processed and activated by CatF, CatK, and CatV in two consecutive steps of maturation, as reported for CatL and CatS previously. The unique positioning of the propeptide domains in the proCatC dimer complex allows this order of cleavages to be understood. The missense mutation Leu172Pro within the propeptide region associated with the Papillon–Lefèvre and Haim–Munk syndrome altered the proform stability as well as the maturation of the recombinant Leu172Pro proform.

In-vitro- und In-vivo-Wirkung von Schilddrüsenhormon auf das Wachstum von Neuroblastomzellen

1990 ◽  
Vol 29 (03) ◽  
pp. 120-124
Author(s):  
R. P. Baum ◽  
E. Rohrbach ◽  
G. Hör ◽  
B. Kornhuber ◽  
E. Busse
Keyword(s):  
Cell Differentiation ◽  
Neuroblastoma Cells ◽  
Control Group ◽  
Initial Value ◽  
Initial Rise ◽  
Biphasic Effect ◽  
Contrast Microscopy ◽  
Morphological Sign

The effect of triiodothyronine (T3) on the differentiation of cultured neuroblastoma (NB) cells was studied after 9 days of treatment with a dose of 10-4 M/106 cells per day. Using phase contrast microscopy, 30-50% of NB cells showed formation of neurites as a morphological sign of cellular differentiation. The initial rise of the mitosis rate was followed by a plateau. Changes in cyclic nucleotide content, in the triphosphates and in the activity of the enzyme ornithine decarboxylase (ODC) were assessed in 2 human and 2 murine cell lines to serve as biochemical parameters of the cell differentiation induced by T3. Whereas the cAMP level increased significantly (3 to 7 fold compared with its initial value), the cGMP value dropped to 30 to 50% of that of the control group. ATP and GTP increased about 200%, the ODC showed a decrease of about 50%. The present studies show a biphasic effect of T3 on neuroblastoma cells: the initial rise of mitotic activity is followed by increased cell differentiation starting from day 4 of the treatment.

Anamnestic factors that shape reproductive health of women with repeated unsuccessful popygamy in vitro fertilization

2016 ◽  
pp. 140-143
Author(s):  
N.V. Cotsabin ◽  
◽  
O.M. Makarchuk ◽  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Polycystic Ovary ◽  
High Risk Group ◽  
Stress Factors ◽  
Control Group ◽  
Fertilization In Vitro ◽  
Infertile Women ◽  
Group I

The proportion of patients with multiple unsuccessful attempts of assisted reproductive technology (ART) is about 30% of all patients treated with the use of ART. Women with history of unsuccessful ART attempts - a special category of patients who require emergency attention and a thorough examination at the stage of preparation for superovulation stimulation,the selection of embryos and endometrium preparation for embryo transfer. The objective: to distinguish high-risk group of unsuccessful attempts based on a detailed analysis of anamnestic and clinical data of infertile women with repeated unsuccessful ART attempts that requires more in-depth study of hormonal features, ovarian reserve and condition of the endometrium. Materials and methods. For better understanding of the problem of repeated unsuccessful ART attempts and сreation of efficient infertility treatment algorithms for these couples we conducted a thorough analysis of anamnestic data of three groups of infertile women (105 patients), which were distributed by age: group I – younger than 35, the II group – from 35 to 40, the III group - over 40 years. These groups of patients were compared with each other and with the control group of healthy women (30 persons). Results. Leading stress factors in the percentage three times prevailed in the group of infertile women and had a direct connection with the fact of procedure «fertilization in vitro» and chronic stressors caused by prolonged infertility. Primary infertility was observed significantly more frequent in patients younger than 35 years (p <0.05), secondary infertility - mostly in the second and third experimental groups (p <0.05). Noteworthy significant percentage of wellknown causes of infertility and idiopathic factor in all groups, and the prevalence of tubal-peritoneal factor in the second and third experimental groups, and endocrine dysfunction in the I experimental group. The most common disorder among this category of woman was polycystic ovary syndrome. Frequency of usual miscarriage among patients of I ana II groups was two times higher than in the third group (p <0.05). Among the experimental groups the leading place belongs urinary tract infection, respiratory tract diseases, pathologies of the cardiovascular system. Data of the stratified analysis show an increase likelihood of repeated unsuccessful ART attempts under the influence of constant chronic stress (odds ratio OR=2.06; 95% CI: 0.95–3.17; p<0.05). Conclusions. Among infertile patients with repeated unsuccessful ART attempts must be separated a high risk group of failures. The identity depends on the duration of infertility, female age and leading combination of factors. Key words: repeated unsuccessful ART attempts, anamnesis, infertility, high risk.

Levels interleukine-4 and interleukin-17 (IL-4, IL-17) of blood in patients with habitual recurrent pregnancy loss, which occurred in a loop in vitro fertilization

2016 ◽  
pp. 137-139
Author(s):  
K.P. Golovatyuk ◽  
Keyword(s):  
In Vitro Fertilization ◽  
Conditioned Medium ◽  
Mononuclear Cells ◽  
Recurrent Miscarriage ◽  
Interleukin 4 ◽  
Control Group ◽  
Interleukin 17 ◽  
Vitro Fertilization ◽  
Blood Mononuclear Cells

The objective: was to investigate the levels of cytokines IL-4 and IL-17 in serum and conditioned medium cultures of blood mononuclear cells (MNC) and evaluation association between their products and miscarriage, which occurred in IVF cycles. Patients and methods. We observed 240 patients with recurrent miscarriage, came in IVF cycles, and 100 apparently healthy fertile women in the control group. The concentrations of IL-4 and IL-17 in serum and conditioned medium of MNC cultures were determined. Results. The levels of IL-4 in the serum and conditioned medium in spontaneous and stimulated mitogen secretion was not significantly different from those in the control group, whereas IL-17 levels were higher than those in the control group serum, in conditioned media of stimulated and non-stimulated MNCs. Conclusion. Disregulation of activity of circulating blood mononuclear cells in women with recurrent miscarriage that followed IVF, is accompanied by increased secretion of IL-17 and almost constant production of IL-4 on the back of high stimulation index of production of these cytokines. Key words: in vitro fertilization, miscarriage, interleukin-4, interleukin-17, serum stimulated and non-stimulated mononuclear blood.

Reverse torque values of abutment screws after dynamic loading: The effects of sealant agents and the taper of conical connections

2020 ◽  
Author(s):  
Arda Ozdiler ◽  
suleyman dayan ◽  
Burc Gencel ◽  
Gulbahar Isık-Ozkol
Keyword(s):  
Dynamic Loading ◽  
Antibacterial Agent ◽  
In Vitro Study ◽  
Control Group ◽  
Silicone Sealant ◽  
Reverse Torque ◽  
The Stability ◽  
Torque Values ◽  
Chlorhexidine Gel

This in vitro study evaluated the influence of taper angles on the internal conical connections of implant systems and of the application of chlorhexidine gel as an antibacterial agent or a polyvinyl siloxane (PVS) sealant on the reverse torque values of abutment screws after dynamic loading. The current study tested four implant systems with different taper angles (5.4°, 12°, 45°, and 60°). Specimens were divided into three groups: control (neither chlorhexidine gel filled nor silicone sealed), 2% chlorhexidine gel-filled or silicone-sealed group, and group subjected to a dynamic load of 50 N at 1 Hz for 500,000 cycles prior to reverse torque measurements. Quantitative positive correlation was observed between the taper angle degree and the percentage of tightening torque loss. However, this correlation was significant only for the 60° connection groups except in the group in which a sealant was applied ( p = 0.013 for the control group, p = 0.007 for the chlorhexidine group). Percentages of decrease in the torque values of the specimens with silicone sealant application were significantly higher compared with both the control and chlorhexidine groups ( p = 0.001, p = 0.002, p = 0.001, and p = 0.002, respectively, according to the increasing taper angles); the percentage of decrease in torque values due to chlorhexidine application was statistically insignificant when compared with the control group. The application of gel-form chlorhexidine as an antibacterial agent does not significantly affect the stability of the implant–abutment connection under dynamic loads. PVS sealants may cause screw loosening under functional loads.

Comparative Study to Evaluate the Surface Detail Reproduction of Dental Stone after Immersion in Various Different Disinfectant Solutions, Under Stereomicroscope 10 X Magnification –An In-Vitro Study

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Rathika Rai ◽  
M. A. Easwaran ◽  
K. T. Dhivya
Keyword(s):  
Sodium Hypochlorite ◽  
In Vitro Study ◽  
Control Group ◽  
Immersion Method ◽  
Significant Difference ◽  
Surface Irregularities ◽  
Disinfectant Solution ◽  
Surface Detail ◽  
Group B

Aim: To evaluate the surface detail reproduction of dental stone this is immersed in different disinfectant solution and studied under stereomicroscope. Methodology: Total number of 30 specimens of dental stone (Type III) were made with measurements of 1.5cm diameter and 1cm height .This samples are divided in to 3 groups group A,B,C. were A is immersed in Distilled water which was taken as control group ;B is immersed in 2% Glutaraldehyde and C is immersed in 5%sodium hypochlorite. Each specimen were immersed in the disinfectant solution for 15 minutes and dried under room temperature for 24 hrs. After 24 hrs each specimens are studied under stereomicroscope for surface details. Result: The results showed no significant difference in the surface irregularities and porosities for a group 1 and group 2 except group 3 which showed significant increase in the porosities, surface irregularities and erosions after disinfection with 5% NaHOCl by immersion method. Conclusion: The surface detail reproduction capacity of die stone was adversely affected when 5% Sodium hypochlorite was used as disinfectant solution when compare d to control group and 2% Glutaraldehyde

Protective Effect of Boswellic Resin Against Memory Loss and Alzheimer’s Induced by Aluminum Tetrachloride and D-Galactose (Experimental study in Mice)

2020 ◽  
Author(s):  
K. Zerrouki ◽  
N. Djebli ◽  
L. Gadouche ◽  
I. Erdogan Orhan ◽  
F. SezerSenol Deniz ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Protective Effect ◽  
Cell Damage ◽  
Memory Loss ◽  
Control Group ◽  
Total Extract ◽  
Swiss Mice ◽  
Octyl Acetate

Nowadays, because of the industrialization, a lot of contaminant were available ; the consequences of this availability are apparition of diseases including neurodegeneration. Neurodegenerative diseases of the human brain comprise a variety of disorders that affect an increasing percentage of the population. This study is based on the effect of the Boswellic resin, which is from a medicinal plant and known for its antioxidant effects on nerve cell damage. The objective of this work was to evaluate the in vitro and in vivo effects of the Boswellic resin on anticholinesterase activity and Alzheimer’s disease (AD) induced by D-galactose and aluminum tetrachloride in Swiss mice. Chemical composition of the resin essential oil was identified by the CG-MS analysis. The antioxidant activity was also assessed by the DMPD and metal chelation methods. In order to understand the mechanism of memory improvement, the acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, inhibitory assays were performed. In vivo part of the study was achieved on Swiss mice divided into four groups: control, AD model, treated AD, and treated control group. The identification of chemical composition by CG-MS reach the 89.67% of the total extract compounds presented some very important molecules (p-Cymene, n-Octyl acetate, α-Pinene…). The present study proves that Boswellic resin improves memory and learning in treated Alzheimer’s group, modulates the oxidative stress and be involved in the protective effect against amyloid deposition and neurodegeneration, and stimulates the immune system in mice’s brain.

In Vitro Immunodetection of Prothymosin Alpha in Normal and Pathological Conditions

2020 ◽  
Vol 27 (29) ◽  
pp. 4840-4854 ◽  
Author(s):  
Chrysoula-Evangelia Karachaliou ◽  
Hubert Kalbacher ◽  
Wolfgang Voelter ◽  
Ourania E. Tsitsilonis ◽  
Evangelia Livaniou
Keyword(s):  
Mammalian Cells ◽  
Therapeutic Potential ◽  
Prothymosin Alpha ◽  
Disease States ◽  
Leading Role ◽  
Tissue Extracts ◽  
Biologic Response ◽  
Health And Disease ◽  
Almost All

Prothymosin alpha (ProT&#945;) is a highly acidic polypeptide, ubiquitously expressed in almost all mammalian cells and tissues and consisting of 109 amino acids in humans. ProT&#945; is known to act both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similar to molecules termed as “alarmins”. Antibodies and immunochemical techniques for ProT&#945; have played a leading role in the investigation of the biological role of ProT&#945;, several aspects of which still remain unknown and contributed to unraveling the diagnostic and therapeutic potential of the polypeptide. This review deals with the so far reported antibodies along with the related immunodetection methodology for ProT&#945; (immunoassays as well as immunohistochemical, immunocytological, immunoblotting, and immunoprecipitation techniques) and its application to biological samples of interest (tissue extracts and sections, cells, cell lysates and cell culture supernatants, body fluids), in health and disease states. In this context, literature information is critically discussed, and some concluding remarks are presented.

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