Bcl11b mutations identified in murine lymphomas increase the proliferation rate of hematopoietic progenitor cells

<p>Abstract</p> <p>Background</p> <p>The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The <it>Bcl11b </it>gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether <it>Bcl11b </it>is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis.</p> <p>Methods</p> <p>Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the <it>Bcl11b </it>gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant Bcl11b in the cytokine-dependent hematopoietic progenitor cell line FDC-P1, lacking endogenous Bcl11b expression.</p> <p>Results</p> <p>Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between amino acids 778–844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type Bcl11b suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold.</p> <p>Conclusion</p> <p>The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of Bcl11b are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type Bcl11b but enhanced by mutant Bcl11b, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors.</p

Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement

As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s−1 mM−1 and 9.6–17.2 s−1 mM−1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed

The Q705K Polymorphism in NLRP3 Is a Gain-of-Function Alteration Leading to Excessive Interleukin-1β and IL-18 Production

Background: The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study, we determine the functional role of this commonly occurring polymorphism using an in-vitro system. Methods / Principle findings: NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1β and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1β and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3-Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased production of IL-1β, IL-18 and TNF-α, in a caspase-1 and IL-1 receptor-dependent manner. Conclusions: Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1β blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments

Исследование различных факторов, влияющих на окалинообразование и потери металла на угар при нагреве

Материалы XIV Междунар. науч.-техн. конф. студентов, аспирантов и молодых ученых, Гомель, 24–25 апр. 2014 г

Значение пластики лоскутом на временной питающей ножке в замещении раневых дефектов

РАНЫ И ТРАВМЫ /ХИРКОЖИ ТРАНСПЛАНТАЦИЯПЕРЕСАДКА КОЖИДЕРМАТОПЛАСТИКАЛОСКУТЫХИРУРГИЧЕСКИЕ ЛОСКУТЫХИРУРГИЧЕСКИЕ ОПЕРАЦИИ ВОССТАНОВИТЕЛЬНЫЕ /МЕТОДЫИТАЛЬЯНСКАЯ ПЛАСТИКАПЛАСТИКА ИТАЛЬЯНСКАЯРАНЕВЫЕ ПОКРЫТИЯЦель. Провести комплексный анализ возможностей, технических особенностей и недостатков методики пластики ран перемещенным из отдаленных областей сложносоставным кожным лоскутом на временной питающей ножке при закрытии раневых дефектов конечностей. Материал и методы. В исследование включено 14 пациентов с раневыми дефектами конечностей различного происхождения, которым на восстановительном этапе лечения применен метод пластики перемещенным из отдаленных областей сложносоставным кожным лоскутом на временной питающей ножке. Раневые дефекты имели различное происхождение (глубокие отморожения, хронический остеомиелит, нейротрофические нарушения), локализацию и площадь. Показанием к данному виду полнослойной пластики служила необходимость закрытия раны в функционально значимой зоне и невозможность применения других, более простых методов кожной пластики. Результаты. Положительный ближайший результат лечения получен во всех 14 случаях перемещения полнослойных кожных лоскутов из отдаленных частей тела. В 3 случаях в раннем послеоперационном периоде отмечено развитие осложнений (критический перегиб ножки лоскута, подлоскутная гематома, краевой некроз лоскута), не повлиявших существенно на ближайший результат операции. Отдаленные результаты лечения оценены у 8 пациентов в сроки от 1 до 22 лет после операции. Ключевым моментом, определяющим отдаленный результат лечения, стала комплаентность пациента в условиях денервации лоскута и закрытия ран в функционально значимых областях. В двух случаях у пациентов, не соблюдающих рекомендации, произошел некроз лоскута в зоне опорной поверхности стопы. В остальных наблюдениях получен стойкий положительный результат. Заключение. Пластика ран перемещенным из отдаленных областей сложносоставным кожным лоскутом является эффективным методом реконструкции в функционально значимых областях в условиях ограниченных пластических резервов окружающей кожи. Денервация таких лоскутов предъявляет дополнительные требования к пациентам в плане соблюдения рекомендаций. Успех операции в отдаленные сроки во многом определяется комплаентностью пациента.Objective. Comprehensive analysis of opportunities, technical features and disadvantages of wound plasty with distant pedicled flap closing wound defects of the limbs was performed. Methods. The study included 14 patients with limb wounds of different origin, who were treated using distant pedicled flaps grafting. Wounds were of different origin (deep frostbites, chronic osteomyelitis, neurotrophic disorders), diverse localization and perimeter. The indication for this type of full-layer plastics was the need to treat the wound in a functionally significant zone and the impossibility of using other, less complex methods of skin grafting. Results. A positive immediate result of treatment was obtained in all 14 cases of distant flaps grafting. The development of complications (critical bend of the pedicle of the flap, sub-flap hematoma, the flap’s edge necrosis) was registered in 3 cases in the early postoperative period, those complications did not significantly affect the immediate outcome of the operation. Long-term outcomes of treatment were evaluated in 8 patients in terms from 1 to 22 years after the operation. The key point determining the long-term treatment outcome was the patient’s compliance in the conditions of denervation of the flap and closure of wounds in functionally important areas. A flap necrosis in the plantar area occurred in two cases in patients, who did not follow the recommendations. In the remaining observations a stable positive result was obtained. Conclusions. The distant pedicled flaps grafting is an effective method of reconstruction in functionally important areas under the conditions of limited plastic reserves of the surrounding skin. Denervation of such flaps exposes additional requirements to patients in terms of compliance with recommendations. The success of the operation in the long term period is largely determined by the patient’s compliance

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results: FDRs-BD had significantly larger ICV (d = +0.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct