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1.
Obes Surg ; 32(5): 1610-1616, 2022 05.
Article in English | MEDLINE | ID: mdl-35277792

ABSTRACT

PURPOSE: With the global increase in life expectancy and the subsequent impaired quality of life in older obese adults, modalities such as bariatric surgery become crucial to help lose excess weight. This study was conducted to evaluate the effectiveness and safety of one anastomosis gastric bypass (OAGB) in patients 65 years old and above. MATERIALS AND METHODS: This retrospective cohort study was conducted on 61 patients with severe obesity aged ≥ 65 years through Iran National Obesity Surgery Database. The patients had undergone OAGB and were followed up for 12 to 60 months. The required data was extracted through national database. RESULTS: Mean age and BMI of the patients were 67.62 ± 2.03 years and 46.42 ± 5.46 kg/m2, respectively. Regarding gender, 90.1% of the participants were female. Mean operative time and length of hospital stay were 41.37 ± 13.91 min and 1.16 ± 0.61 days, respectively. Five patients (8.19%) required ICU admission. The changes in %TWL after 3, 6, 12, 24, 36, 48, and 60 month follow-up was 18.62%, 25.51%, 32.84%, 35.86%, 38.49%, 31.41%, and 29.52%, respectively. The resolution of gastroesophageal reflux disease, diabetes mellitus, dyslipidemia, obstructive sleep apnea, and hypertension after 24 month was about 100%, 65%, 73.33%, 100%, and 76%, respectively. The postoperative early and late complications were 6.53% and 11.46%, respectively. We did not find significant difference in above results between two age groups of 65-70 and > 70 years. CONCLUSIONS: OAGB can be a good choice in older obese adults because of its shorter operative time, higher potency, and low complication rate.


Subject(s)
Gastric Bypass , Obesity, Morbid , Adult , Aged , Female , Gastric Bypass/adverse effects , Gastric Bypass/methods , Humans , Obesity , Obesity, Morbid/surgery , Quality of Life , Retrospective Studies
3.
Neuron ; 109(11): 1876-1887.e6, 2021 06 02.
Article in English | MEDLINE | ID: mdl-33852896

ABSTRACT

The ability to adjust one's behavioral strategy in complex environments is at the core of cognition. Doing so efficiently requires monitoring the reliability of the ongoing strategy and, when appropriate, switching away from it to evaluate alternatives. Studies in humans and non-human primates have uncovered signals in the anterior cingulate cortex (ACC) that reflect the pressure to switch away from the ongoing strategy, whereas other ACC signals relate to the pursuit of alternatives. However, whether these signals underlie computations that actually underpin strategy switching or merely reflect tracking of related variables remains unclear. Here we provide causal evidence that the rodent ACC actively arbitrates between persisting with the ongoing behavioral strategy and temporarily switching away to re-evaluate alternatives. Furthermore, by individually perturbing distinct output pathways, we establish that the two associated computations-determining whether to switch strategy and committing to the pursuit of a specific alternative-are segregated in the ACC microcircuitry.


Subject(s)
Decision Making , Exploratory Behavior , Gyrus Cinguli/physiology , Animals , Feeding Behavior , Male , Pyramidal Tracts/physiology , Rats , Rats, Long-Evans
5.
Cell ; 175(4): 1131-1140.e11, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30343901

ABSTRACT

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.


Subject(s)
Channelrhodopsins/chemistry , Optogenetics/methods , Animals , Caenorhabditis elegans , Cell Membrane/chemistry , Cell Membrane/metabolism , Cells, Cultured , Channelrhodopsins/genetics , Channelrhodopsins/metabolism , Male , Mice , Protein Engineering/methods , Rats , Rats, Long-Evans
6.
J Multidiscip Healthc ; 10: 301-307, 2017.
Article in English | MEDLINE | ID: mdl-28860797

ABSTRACT

BACKGROUND AND OBJECTIVE: Colorectal cancer is one of the main causes of mortality in both developed and developing countries, including Iran. One of the treatments available for colorectal cancer is chemotherapy, of which nausea and emesis are the side effects. Owing to problems in controlling the side effects, a combination of medicine and non-medicine interventions is usually used. Self-care is one of the non-medicine interventions in this regard. The present study was aimed at surveying the effect of a self-care education program on severity of nausea and emesis in colorectal cancer patients under chemotherapy. METHODS: A semi-experimental study was carried out in Imam Reza Hospital of Kermanshah, Iran. The sample group comprised 52 patients with colorectal cancer under chemotherapy. Data gathering tools included a demographics questionnaire and Morrow Assessment of Nausea and Emesis. To control intensity of nausea and emesis, a package of self-care measures including muscular progressive relaxation, music, and education on nutrition was used. Afterward, the collected data were analyzed using statistical tests such as Shapiro-Wilk test (to check normal distribution of the data), Mann-Whitney U test, Wilcoxon test, and chi-square test with the help of SPSS 20. RESULTS: The results showed a considerable decrease in intensity and frequency of nausea and emesis after the intervention. The p-value of Mann-Whitney U test results with regard to intensity of nausea in the experiment and control groups after the intervention was 0.029; this figure for intensity of emesis was 0.009, which indicated effectiveness of the self-care program. CONCLUSION: As the results showed, using self-care program could be effective in attenuating intensity of emesis and nausea in colorectal cancer patients under chemotherapy. So, it can be concluded that the use of this program can increase the patient's self-care ability to control vomiting and nausea, which can be considered as a complementary approach to the antiemetic medications.

7.
Clujul Med ; 90(3): 286-293, 2017.
Article in English | MEDLINE | ID: mdl-28781525

ABSTRACT

BACKGROUND AND AIMS: Kidney cancer is among the cancers that have the highest growth rate in all age and racial groups in the world and is as the most deadly type of urinary tract cancer. Since awareness about this cancer incidence status and mortality is essential for better planning, this study aimed to investigate the incidence and mortality rate of kidney cancer and its relationship with the development index in the world in 2012. METHOD: This study was an ecological study conducted based on GLOBOCAN project of the World Health Organization (WHO) for the countries in the world. The correlation between Standardized Incidence Rates (SIRs) and Standardized Mortality Rates (SMRs) of kidney cancer with HDI and its components was assessed using SPSS18. RESULTS: In total, 337,860 incidence cases (213,924 were men and 123,936 women) and 143,406 deaths (90,802 cases in men and 52,604 in women) of kidney cancer were recorded in 2012. A positive correlation of 0.731 was seen between SIR of kidney cancer and HDI (p≤0.001). Also, a negative correlation of 0.627 was seen between SMR of kidney cancer and HDI (p≤0.001). CONCLUSION: The incidence and mortality rate of kidney cancer is higher in developed countries. A significant positive correlation has been seen between the standardized incidence and mortality rate of kidney cancer with the Human Development Index and its components. We need more studies to examine variation in incidence and mortality of kidney cancer and its related factors in the world.

8.
Asian Pac J Cancer Prev ; 17(8): 3777-83, 2016.
Article in English | MEDLINE | ID: mdl-27644616

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the incidence and mortality of stomach cancer, and its relationship with the Human Development Index (HDI) and its components in Asia in 2012. MATERIALS AND METHODS: This ecological study was conducted based on GLOBOCAN project of WHO for Asian countries. We assessed the correlations between standardized incidence rates (SIR) and standardized mortality rates (SMR) of stomach cancer with HDI and its components using SPSS18. RESULTS: A total of 696,231 cases (68.7% in males and 31.3% in females, ratio of 2.19:1) and 524,465 deaths (67.1% in men and 33.0% in women, ratio 2.03:1) were included in 2012. Five countries with the highest SIR of stomach cancer were Republic Korea, Mongolia, Japan, China and Tajikistan. Five countries with the highest SMR of stomach cancer were Mongolia, Tajikistan, Kyrgyzstan, Kazakhstan and China. Correlation between HDI and SIR was 0.241 (p = 0.106), in men 0.236 (p = 0.114) and in women -0.250 (p = 0.094). Also between HDI and SMR -0.250 (p = 0.871) in men -0.018 (p = 0.903) and in women -0.014 (p = 0.927). CONCLUSIONS: No significant correlation was observed between the SIR of stomach cancer, and the HDI and its dimensions, such as life expectancy at birth, mean years of schooling, and income level of the population.


Subject(s)
Stomach Neoplasms/etiology , Stomach Neoplasms/mortality , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Asia/epidemiology , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Life Expectancy , Male , Middle Aged , Mortality , Risk Factors , Time Factors , Young Adult
9.
Clin Interv Aging ; 11: 997-1002, 2016.
Article in English | MEDLINE | ID: mdl-27555754

ABSTRACT

BACKGROUND: Old age is a stage of life featured with many physiological and mental changes. The Iranian population is aging, and one of the problems that the elderly are faced with is sleep disorders. The present study is an attempt to examine the effectiveness of an exercise program on the sleep quality of the elderly. METHODS: A semi-experimental study was carried out on the elderly males referred to the Shahid Yari Elderly Center, Kermanshah, Iran. The sample group comprised of 46 participants: 23 in the experimental group and 23 in the control group. The study was carried out for a period of 2 months and follow-up was conducted every week. To improve the quality of sleep of the participants, a four-stage exercise program was implemented and the collected data were analyzed by SPSS version 20. RESULTS: The results of a Mann-Whitney test showed that the quality of sleep of the majority in the experimental group improved compared with that of the control group (P<0.05). In addition, a Wilcoxon test showed improvement of the Petersburg's sleep quality index based on subelements and the results of a total score of sleep in the experimental group after the intervention. CONCLUSION: The study showed effectiveness of scheduled exercising on the quality of sleep of the elderly. It is recommended, therefore, to add an exercise program to the daily program of the elderly.


Subject(s)
Aging , Exercise , Quality of Life , Sleep Wake Disorders/therapy , Aged , Aged, 80 and over , Humans , Iran , Male , Surveys and Questionnaires
10.
J Thorac Dis ; 8(6): 1094-102, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27293825

ABSTRACT

BACKGROUND: The highest incidence of lung cancer is seen in North America and the lowest incidence in central Africa. Socioeconomic factors of inequality reflect regional disparities in human development. Due to the importance of awareness about incidence and mortality of lung cancer in health programming and the possible role of the human development index (HDI), this study was done with the aim to investigate the epidemiology of lung cancer in the world and its relationship with HDI. METHODS: The study was conducted based on data from the world data of cancer and the World Bank (including the HDI and its components). Data about the age-specific incidence and mortality rate (ASR) for every country in 2012 were getting from the global cancer project. To analyze data, correlation tests between incidence and death rates, and HDI and its components were employed with a significance level of 0.05 using SPSS software. RESULTS: Lung cancer with standardized incidence rate (ASIR) and standardized mortality rate (ASMR), equal to 23.1 and 19.7 (in 100,000 people), respectively. The highest and lowest values of mortality incidence ratio (MIR) for lung cancer due to continents division were 0.93 and 0.71 for Eastern Africa and Australia/New Zealand, respectively. Univariate analysis showed significant relationship (P<0.0001) between ASIR and ASMR with life expectancy at birth and mean years of schooling. CONCLUSIONS: The highest MIR for lung cancer was for medium human development countries. Linear regression analysis showed a reverse significant relationship between MIR and HDI.

11.
Asian Pac J Cancer Prev ; 17(5): 2465-73, 2016.
Article in English | MEDLINE | ID: mdl-27268615

ABSTRACT

BACKGROUND: This study aimed to investigate the standardized incidence and mortality rate of colorectal cancer and its relationship with the human development index (HDI) across the world in 2012. MATERIALS AND METHODS: This ecologic study was conducted for assessment of the correlation between age-specific incidence rate (ASIR) and age-specific mortality rate (ASMR) with HDI and its components. Data for SIR and SMR for every country for the year 2012 were obtained from the global cancer project. We used a bivariate method for assessment of the correlation between SIR and SMR and HDI. Statistical significance was assumed at <0.05. Statistical analyses were performed using SPSS (Version 22.0, SPSS Inc.). RESULTS: Countries with the highest SIR of colorectal cancer in the world in 2012, were Republic of Korea, Slovakia, Hungary and countries with the highest SMR were Hungary, Croatia and Slovakia. The correlation between SIR of colorectal cancer and the HDI was 0.712 (P≤0.001), with life expectancy at birth 0.513 (P≤0.001), with mean years of schooling 0.641 (P≤0.001) and with level of income per each person of the population 0.514 (P=0.013). In addition, the correlation between SMR of colorectal cancer and the HDI was 0.628 (P≤0.001), with life expectancy at birth 0.469 (P≤0.001), with mean years of schooling 0.592 (P≤0.001) and with level of income per each person of the population 0.378 (P=0.013). CONCLUSIONS: The highest SIR and SMR of colorectal cancer was in the WHO Europe region. There was a positive correlation between HDI and SIR and SMR of colorectal cancer.


Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/mortality , Global Health , Human Development , Life Expectancy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Prognosis , Survival Rate , Young Adult
12.
Asian Pac J Cancer Prev ; 17(S3): 27-32, 2016.
Article in English | MEDLINE | ID: mdl-27165203

ABSTRACT

Stomach cancer, the fourth most common cancer and the second leading cause of cancer-related death through the world, is very common in parts of Iran. Geographic variation in the incidence of stomach cancer is due to many different factors. The aim of this study was to assess the geographical and spatial distribution of stomach cancer in Iran using data from the cancer registry program in Iran for the year 2009. The reported incidences of stomach cancer for different provinces were standardized to the world population structure. ArcGIS software was used to analyse the data. Hot spots and high risk areas were determined using spatial analysis (Getis-Ord Gi). Hot and cold spots were determined as more than or less than 2 standard deviations from the national average, respectively. A significance level of 0.10 was used for statistical judgment. In 2009, a total of 6,886 cases of stomach cancers were reported of which 4,891 were in men and 1,995 in women (standardized incidence rates of 19.2 and 10.0, respectively, per 100,000 population). The results showed that stomach cancer was concentrated mainly in northwest of the country in both men and women. In women, northwest provinces such as Ardebil, East Azerbaijan, West Azerbaijan, Gilan, and Qazvin were identified as hot spots (p<0.1). In men, all northwest provinces, Ardabil, East Azerbaijan, Gilan, Qazvin, Zanjan and Kurdistan, the incidences were higher than the national average and these were identified as hot spots (P<0.01). As stomach cancer is clustered in the northwest of the country, further epidemiological studies are needed to identify factors contributing to this concentration.


Subject(s)
Registries , Spatial Analysis , Stomach Neoplasms/epidemiology , Age Factors , Female , Follow-Up Studies , Humans , Incidence , Iran/epidemiology , Male , Prognosis , Retrospective Studies
13.
Asian Pac J Cancer Prev ; 17(S3): 33-7, 2016.
Article in English | MEDLINE | ID: mdl-27165204

ABSTRACT

Skin cancer is one of the most common cancers worldwide, including in Iran. Variations in its incidence rate among geographical areas are due to various contributing factors. Since there has been a lack of studies on this topic in our country, the present spatial analysis of skin cancer incidence in Iran in 2009 was conducted using data from the cancer registry system for the country. The reported incidences of the disease were standardized on the basis of the World Health Organization population and the direct method. Then the data were inserted into the GIS software, and finally, using the analysis of hot spots (Getis-Ord Gi), high-risk areas were drawn. Provinces that were 1.9 SD higher or lower than the national average were considered hot spots or cold spots, with significance at the level of 0.05. In 2009, a total of 9,964 cases of skin cancer occurred, 3,696 in women and 6,268 in men (standardized incidence rates of 15.8 and 22.6, respectively). The results of the study showed that in men and women, the disease demonstrated high incidence in the central provinces and desert regions. In women, Yazd Province and in men, Qom Province had significant hot spots (p =0.05). While Isfahan, Markazi, Tehran and Kurdistan provinces were expected to be hot spots, the differences from the national average were not significant at the 0.05 level. As well, the provinces of Sistan Va Baluchistan, Kerman, and Hormozgan were identified as cold or low-risk disease regions (p <0.05). The central provinces of the country due to hot weather conditions, more solar radiation, and closer vicinity to the central desert of Iran demonstrated higher incidence rates for skin cancer, so further epidemiological studies into the etiology and early detection are essential in these areas.


Subject(s)
Registries , Skin Neoplasms/epidemiology , Spatial Analysis , Age Factors , Female , Follow-Up Studies , Humans , Incidence , Iran/epidemiology , Male , Prognosis , Retrospective Studies
14.
Asian Pac J Cancer Prev ; 17(S3): 53-8, 2016.
Article in English | MEDLINE | ID: mdl-27165208

ABSTRACT

Colorectal cancer is one of the most common cancers. Due to demographic changes, it is predicted that the incidence of this cancer will increase. Variations of its incidence rate among geographical areas are due to various contributing factors. Since there have been a lack of studies on this topic in our country, the present assessment of spatial patterns of colorectal cancer incidence in Iran was performed. In this ecological study, the new cases of colon cancer were extracted from Cancer Registry Center report of the Health Deputy of Iran in 2009. The reported incidences of the disease were standardized on the basis of the World Health Organization population and the direct method. Then the data were inserted into the GIS software, and finally, using the analysis of hot spots (Getis-Ord Gi) high-risk areas were drawn. Provinces that are higher or lower than the national average (1.9 SD) were considered hot spots or cold spots, significant at the level of 0.05. A total of 6,210 cases of colorectal cancer were registered in Iran in 2009, of which 3,727 were in men and 2,783 in women (age-standardized rates of 11.3 and 10.9 per 100,000 population, respectively). The results showed that in central and northern Iran including Isfahan, Qom, Tehran, Qazvin and Mazandaran significant hot spots in men were present (p <0.05). In women also we have high incidence in northern and central states: Mazandaran province (p<0.01) and the province of Tehran (p<0.05) had higher incidences than the national average and were apparent as significant hot spots. Analysis of the spatial distribution of colorectal cancer showed significant differences between different areas pointing to the necessity for further epidemiological studies into the etiology and early detection.


Subject(s)
Colorectal Neoplasms/epidemiology , Registries , Spatial Analysis , Age Factors , Female , Follow-Up Studies , Humans , Incidence , Iran/epidemiology , Male , Prognosis , Retrospective Studies , Risk Factors
15.
World J Oncol ; 7(5-6): 109-118, 2016 Dec.
Article in English | MEDLINE | ID: mdl-28983375

ABSTRACT

BACKGROUND: One of the most common cancers in head and neck is nasopharynx. Knowledge about the incidence and mortality of this disease and its distribution in terms of geographical areas is necessary for further study, better planning and prevention. Therefore, this study aimed to determine the incidence and mortality of nasopharynx cancer and its relationship with human development index (HDI) in the world in 2012. METHODS: This study was an ecological study conducted based on GLOBOCAN project of World Health Organization (WHO) for the countries in world. The correlation between standardized incidence rates (SIRs) and standardized mortality rates (SMRs) of nasopharynx cancer with HDI and its components was assessed with correlation coefficient by using SPSS 15. RESULTS: In 2012, 86,691 nasopharynx cancer cases occurred in the world, so that 60,896 new cases were seen in men and 25,795 new cases in women (sex ratio = 2.36). SIR of the cancer was 1.2 per 100,000 (1.7 in men and 0.7 in women per 100,000) in the world. In 2012, 50,831 nasopharynx death cases occurred in the world, so that 35,756 death cases were seen in men and 15,075 death cases in women (sex ratio = 2.37). SIR of mortality from the cancer was 0.7 per 100,000 (0.7 in women and 1 in men per 100,000) in the world. The results of correlation analysis showed a negative correlation between the SIR and HDI (r = -0.037, P = 0.629), and also the results of correlation analysis showed a negative correlation between the SMR and HDI (r = -0.237, P = 0.002). CONCLUSION: Nasopharyngeal cancer is native to Southeast Asia and the highest incidence and mortality were seen in countries with moderate and low HDI. It is suggested that studies are conducted on determining the causes of the cancer incidence and mortality in the world and the differences between various regions.

16.
Iran J Otorhinolaryngol ; 26(77): 219-23, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25320699

ABSTRACT

INTRODUCTION: Nausea and vomiting after ear, nose and throat (ENT) surgery is one of the most common and notable problems facing anesthesiologists in this area. This study was conducted to determine the effect of a pharyngeal pack on the severity of nausea, vomiting, and sore throat among patients after ear, pharynx, and throat surgeries. MATERIALS AND METHODS: This randomized clinical study was performed in 140 patients (61 men and 79 women; age range, 20-40 years) who had undergone nasal surgery in 2010. Patients were divided into two groups: the first group were treated using a pharyngeal pack (case group) and the second group were managed without a pharyngeal pack (control group). Statistical analysis was performed using the Chi-square test and the Mann-Whitney U test. SPSS software was used for data analysis. RESULTS: The mean severity of nausea and vomiting in the two groups was 2.057, 1.371 and 1.100, respectively, with no significant differences between groups. However, the mean severity of sore throat was 1.714 in the group with the pharyngeal pack and 1.385 in the group without pharyngeal pack (P=0.010). CONCLUSION: Not only does a pharyngeal pack in ENT surgery not reduce the extent and severity of nausea and vomiting, but it also increases the severity of sore throat in patients when leaving the recovery room and discharging hospital.

17.
PLoS One ; 8(10): e77728, 2013.
Article in English | MEDLINE | ID: mdl-24155972

ABSTRACT

Fluorescent protein-based sensors for detecting neuronal activity have been developed largely based on non-neuronal screening systems. However, the dynamics of neuronal state variables (e.g., voltage, calcium, etc.) are typically very rapid compared to those of non-excitable cells. We developed an electrical stimulation and fluorescence imaging platform based on dissociated rat primary neuronal cultures. We describe its use in testing genetically-encoded calcium indicators (GECIs). Efficient neuronal GECI expression was achieved using lentiviruses containing a neuronal-selective gene promoter. Action potentials (APs) and thus neuronal calcium levels were quantitatively controlled by electrical field stimulation, and fluorescence images were recorded. Images were segmented to extract fluorescence signals corresponding to individual GECI-expressing neurons, which improved sensitivity over full-field measurements. We demonstrate the superiority of screening GECIs in neurons compared with solution measurements. Neuronal screening was useful for efficient identification of variants with both improved response kinetics and high signal amplitudes. This platform can be used to screen many types of sensors with cellular resolution under realistic conditions where neuronal state variables are in relevant ranges with respect to timing and amplitude.


Subject(s)
Calcium Signaling , Calcium/metabolism , Genes, Reporter , Neurons/metabolism , Action Potentials/physiology , Animals , Cells, Cultured , Electric Stimulation , Fluorescence , Glutamic Acid/metabolism , Humans , Indicators and Reagents , Rats , Receptors, GABA/metabolism , Solutions
18.
Biochem Biophys Res Commun ; 380(2): 361-5, 2009 Mar 06.
Article in English | MEDLINE | ID: mdl-19250647

ABSTRACT

The role of Groucho/transducin-like Enhancer of split (Gro/TLE) family members as corepressors of transcription is well documented. TLX1 is a homeodomain transcription factor involved in splenogenesis and neuron formation, and its aberrant expression gives rise to T-cell acute lymphoblastic leukemia. We demonstrate by glutathione-S-transferase pull-down assays, in vivo biotinylation tagging and confocal laser microscopy that TLX1 interacts with TLE1 via an Eh1-like motif. Paradoxically, we found that this motif is essential for optimal transcriptional activation of two TLX1 target genes, Aldh1a1 and Fhl1. Using a well characterized target of the Hairy/Enhancer of split 1 (HES1).TLE1 repressor complex, the ASCL1 gene, we show that TLX1 counteraction of ASCL1 repression by HES1 in SK-N-BE(2) neuroblastoma cells is associated with dismissal of TLE1 from the ASCL1 promoter and requires the Eh1-like motif for maximal effect. Collectively, these results indicate that TLX1-mediated target gene activation can occur in part via derepression strategies involving Gro/TLE corepressors.


Subject(s)
Homeodomain Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Transcriptional Activation , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase 1 Family , Amino Acid Motifs , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Line , Cell Line, Tumor , Co-Repressor Proteins , Homeodomain Proteins/genetics , Humans , Intracellular Signaling Peptides and Proteins/genetics , LIM Domain Proteins , Mice , Muscle Proteins/genetics , Promoter Regions, Genetic , Protein Interaction Mapping , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Retinal Dehydrogenase
19.
Transgenic Res ; 11(4): 425-35, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12212844

ABSTRACT

A uromodulin promoter has been isolated, sequenced, and used to generate two sets of transgenic mice for expression of the lacZ marker gene and for production of the human recombinant erythropoietin (rhEPO) in urine. We demonstrated that the 5.6-kb fragment of the uromodulin gene containing the 3.7-kb promoter area and, both the first exon and part of the second exon, were sufficient to provide kidney-specific expression of the lacZ gene. Histological analysis of the lacZ expression pattern revealed beta-galactosidase activity specifically in the thick limb of Henle's loop. However, due to random integration of the transgene, ectopic expression was detected in some transgenic lines. Analysis of the EPO-transgenic mice showed that rhEPO was secreted into the urine of founder mice (up to 6 ng/ml). We were able to breed and analyze only two sublines with a very low expression level of rhEPO (up to 260 pg/ml). All of our transgenic mice expressing rhEPO in urine developed disease symptoms similar to polycythemia in humans. These included a considerable increase in red blood cell counts, hemoglobin concentration, and hematocrit concomitant with severe thrombocytopenia, all of which were detected in the rhEPO-expressing mice. Although our model did not prove to be beneficial for commercial production of rhEPO, we concluded that the uromodulin promoter could be useful for expression of other important therapeutic proteins into the urine of transgenic animals.


Subject(s)
Erythropoietin/urine , Mucoproteins/genetics , Promoter Regions, Genetic , Recombinant Proteins/urine , Animals , DNA Primers , Erythropoietin/blood , Erythropoietin/genetics , Exons , Female , Gene Expression Regulation , Humans , Kidney/physiology , Mice , Mice, Transgenic , Organ Specificity , Polymerase Chain Reaction , TATA Box , Uromodulin , beta-Galactosidase/genetics
20.
Biochem J ; 365(Pt 1): 7-11, 2002 Jul 01.
Article in English | MEDLINE | ID: mdl-11982485

ABSTRACT

We have recently shown that the regulatory sequence of the uromodulin gene, containing the 3.7 kb promoter, exon 1 and a part of exon 2, provided for kidney-specific expression of the reporter lacZ gene in transgenic mice [Zbikowska, Soukhareva, Behnam, Chang, Drews, Lubon, Hammond and Soukharev (2002) Transgenic Res., in the press]. In the present study, we generated transgenic mice harbouring the regulatory sequence of the uromodulin gene to direct the expression of human alpha1-antitrypsin (alpha1AT) into urine. Of the 13 founder mice that tested positive by PCR, seven showed the presence of the human protein in their urine. The concentration of the recombinant human (rh) alpha1AT in the urine, estimated by using ELISA, ranged from 0.5 to 14 microg/ml in the F(0)-generation mice, and reached up to 65 microg/ml in the F1 generation. The transgenically produced rh alpha1AT was found to be N-glycosylated and biologically active. The N-terminal sequence analysis confirmed the identity of the human protein and revealed that the recombinant alpha1AT was correctly processed with the signal peptide cleaved off. Our results demonstrate for the first time that the uromodulin regulatory sequence provides a very attractive option for the potential large-scale production of functional therapeutic proteins in livestock.


Subject(s)
Mucoproteins/genetics , Promoter Regions, Genetic , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/urine , Amino Acid Sequence , Animals , Base Sequence , Gene Expression , Glycosylation , Humans , Mice , Mice, Transgenic , Molecular Sequence Data , Plasmids/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/urine , Uromodulin , alpha 1-Antitrypsin/chemistry
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