The DNA-recognition mode shared by archaeal feast/famine-regulatory proteins revealed by the DNA-binding specificities of TvFL3, FL10, FL11 and Ss-LrpB

The DNA-binding mode of archaeal feast/famine-regulatory proteins (FFRPs), i.e. paralogs of the Esherichia coli leucine-responsive regulatory protein (Lrp), was studied. Using the method of systematic evolution of ligands by exponential enrichment (SELEX), optimal DNA duplexes for interacting with TvFL3, FL10, FL11 and Ss-LrpB were identified as TACGA[AAT/ATT]TCGTA, GTTCGA[AAT/ATT]TCGAAC, CCGAAA[AAT/ATT]TTTCGG and TTGCAA[AAT/ATT]TTGCAA, respectively, all fitting into the form abcdeWWWedcba. Here W is A or T, and e.g. a and a are bases complementary to each other. Apparent equilibrium binding constants of the FFRPs and various DNA duplexes were determined, thereby confirming the DNA-binding specificities of the FFRPs. It is likely that these FFRPs recognize DNA in essentially the same way, since their DNA-binding specificities were all explained by the same pattern of relationship between amino-acid positions and base positions to form chemical interactions. As predicted from this relationship, when Gly36 of TvFL3 was replaced by Thr, the b base in the optimal DNA duplex changed from A to T, and, when Thr36 of FL10 was replaced by Ser, the b base changed from T to G/A. DNA-binding characteristics of other archaeal FFRPs, Ptr1, Ptr2, Ss-Lrp and LysM, are also consistent with the relationship

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents

Incidence and risk factors of oral feeding intolerance in acute pancreatitis: Results from an international, multicenter, prospective cohort study

Background: Inability to advance to an oral diet, or oral feeding intolerance, is a common complication in patients with acute pancreatitis associated with worse clinical outcomes. The factors related to oral feeding intolerance are not well studied. Objective: We aimed to determine the incidence and risk factors of oral feeding intolerance in acute pancreatitis. Methods: Patients were prospectively enrolled in the Acute Pancreatitis Patient Registry to Examine Novel Therapies in Clinical Experience, an international acute pancreatitis registry, between 2015 and 2018. Oral feeding intolerance was defined as worsening abdominal pain and/or vomiting after resumption of oral diet. The timing of the initial feeding attempt was stratified based on the day of hospitalization. Multivariable logistic regression was performed to assess for independent risk factors/predictors of oral feeding intolerance. Results: Of 1233 acute pancreatitis patients included in the study, 160 (13%) experienced oral feeding intolerance. The incidence of oral feeding intolerance was similar irrespective of the timing of the initial feeding attempt relative to hospital admission day (p = 0.41). Patients with oral feeding intolerance were more likely to be younger (45 vs. 50 years of age), men (61% vs. 49%), and active alcohol users (44% vs. 36%). They also had higher blood urea nitrogen (20 vs. 15 mg/dl; p < 0.001) and hematocrit levels (41.7% vs. 40.5%; p = 0.017) on admission; were more likely to have a nonbiliary acute pancreatitis etiology (69% vs. 51%), systemic inflammatory response syndrome of 2 or greater on admission (49% vs. 35%) and at 48 h (50% vs. 26%), develop pancreatic necrosis (29% vs. 13%), moderate to severe acute pancreatitis (41% vs. 24%), and have a longer hospital stay (10 vs. 6 days; all p < 0.04). The adjusted analysis showed that systemic inflammatory response syndrome of 2 or greater at 48 h (odds ratio 3.10; 95% confidence interval 1.83-5.25) and a nonbiliary acute pancreatitis etiology (odds ratio 1.65; 95% confidence interval 1.01-2.69) were independent risk factors for oral feeding intolerance. Conclusion: Oral feeding intolerance occurs in 13% of acute pancreatitis patients and is independently associated with systemic inflammatory response syndrome at 48 h and a nonbiliary etiology

Development of radiolabeled dextran coated iron oxide nanoparticles with 111In and its biodistribution studies

Background: The main aim of this study is to radiolabel dextran coated iron oxide nanopartcles (NPs) (with 80 nm hydrodynamic size) with the Indium-111 and evaluaton their biodistributon after intravenous injecton normal mice. Materials and Method: The chelator Diethylenetriamine Pentaacetc Acid (DTPA) dianhydride was conjugated to SPION using a small modificaton of the well-known cyclic anhydride method at a rato of 1:5 (NPs:DTPA) molar rato. The reacton was purified with magnetc assortng columns (MACs) using high gradient magnetc field following incubaton. Then the radiochemical purity of the radiolabeled NPs were determined using RTLC method. The magnetc propertes of nanopartcles were measured by a 1.5 tesla clinical human MRI. Results: The NPs showed high super paramagnetc propertes whereas their r2/r1was 17.6. The RTLC showed that the purity of compound was above 99% after purificaton and the compound has shown a good in-vitro stability untl 6 hours in the presence of human serum. The biodistributon of 111In-DTPA-NPs in mice demonstrated high uptake in the retculoendothelial system (RES) and the blood clearance was so fast. Conclusion: Due to magnificent uptakes of this radiotracer in the liver and spleen, its stability and their fast clearance from other tssues, especially in blood, it is suggested that this radiotracer would be suitable for RES theranostcs purposes

Assessment of effective absorbed dose of 111in-DTPA-buserelin in human on the basis of biodistribution rat data

In this study, the effective absorbed dose to human organs was estimated, following intra vascular administration of 111In-DTPA-Buserelin using biodistribution data from rats. Rats were sacrificed at exact time intervals of 0.25, 0.5, 1, 2, 4 and 24 h post injections. The Medical Internal Radiation Dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs. From rat data, it was estimated that a 185-MBq injection of 111In-DTPA-Buserelin into the human might result in an estimated absorbed dose of 24.27 mGy to the total body and the highest effective absorbed dose was in kidneys, 28.39 mSv. The promising results of this study emphasises the importance of absorbed doses in humans estimated from data on rats

Estimation of human effective absorbed dose of 67Ga-cDTPA-gonadorelin based on biodistribution rat data

OBJECTIVE: In this investigation, we estimated the effective absorbed dose of radiation into human organs, after an intravenous administration of gallium-67 (Ga)-labeled gonadorelin, one of the gonadotropin-releasing hormone (GnRH) agonists, using biodistribution data from injected normal rats. METHODS: Five rats were killed at exact time intervals (0.25, 0.5, 1, 2, 4, 24, and 48 h post injections) and the percentage of injected dose per gram of each organ was measured by direct counting from rat data. The Medical Internal Radiation Dose formulation was applied to extrapolate from rat to human and to project the absorbed radiation dose for various organs in humans. RESULTS: From rat data we estimated that a 185-MBq injection of Ga-cDTPA-GnRH into the humans might result in an estimated absorbed dose of 5.26 mGy in the whole body with the highest effective absorbed dose was in the lungs (2.73 mSv), and the organs that received the next highest doses were the bladder wall (1.59 mSv), liver (0.80 mSv), and bone marrow (0.52 mSv). CONCLUSION: The biodistribution of Ga-cDTPA-GnRH in rats showed high breast uptake and low muscle and blood uptake. These results suggest that it should be possible to perform early imaging of the breast anomalies and GnRH receptors indicating potential malignant lesions

Estimated human absorbed dose for 68Ga-ECC based on mice data : comparison with 67Ga-ECC

Objective: Nowadays, the efficacies of 68Ga-based tracers are comparable to that of 18F-based agents and have stimulated researchers to investigate the potential of 68Ga-based positron emission tomography (PET) imaging agents. In this study, the human absorbed dose of 68Ga labeled with ethylenecysteamine cysteine 68Ga-ECC and 67Ga-ECC was estimated based on biodistribution data in mice by the medical internal radiation dose (MIRD) method. Methods: For biodistribution of 67Ga/68Ga-ECC, three mice were killed by CO2 asphyxiation at each selected times after injection (15, 30, 45, 60, 120 min for 68Ga-ECC and 0.5, 2 and 48 h for 67Ga-ECC), and then the tissue (heart, lung, brain, intestine, skin, stomach, kidneys, liver, muscle and bone) was removed. Results: 68Ga-ECC as a new PET renal imaging agent was prepared with radiochemical purity of &gt;97 % in less than 30 min. The biodistribution data for 68Ga-ECC showed that the most of the activity extracted from the urinary tract very fast. Comparison between human absorbed dose estimation for these two agents indicated that the absorbed dose of the most organs after injection of 67Ga-ECC is approximately tenfold higher than the amount after 68Ga-ECC injection. Conclusion: The results showed that 68Ga-ECC is a more appropriate agent rather than 67Ga-ECC and generally can be a good candidate for PET renal imaging applications

Assessment of human effective absorbed dose of 67 Ga–ECC based on biodistribution rat data

Methods: For biodistribution data, the animals were sacrificed by CO2 asphyxiation at selected times after injection (0.5, 2 and 48 h, n = 3 for each time interval), then the tissue (blood, heart, lung, brain, intestine, feces, skin, stomach, kidneys, liver, muscle and bone) were removed. The absorbed dose was determined by Medical Internal Radiation Dose (MIRD) method after calculating cumulated activities in each organ.Objective: In a diagnostic context, determination of absorbed dose is required before the introduction of a new radiopharmaceutical to the market to obtain marketing authorization from the relevant agencies. In this work, the absorbed dose of [67 Ga]-ethylenecysteamine cysteine [(67 Ga)ECC] to human organs was determined by using distribution data for rats.Results: Our prediction shows that a 185-MBq injection of 67Ga-ECC into the humans might result in an estimated absorbed dose of 0.029 mGy in the whole body. The highest absorbed doses are observed in the spleen and liver with 33.766 and 16.847 mGy, respectively.Conclusion: The results show that this radiopharmaceutical can be a good SPECT tracer since it can be produced easily and also the absorbed dose in each organ is less than permitted absorbed dose