Biomedical use of radiation is utilized in effective diagnostic and treatment tools, yet can introduce risks to healthy tissues. High energy photons used for diagnostic purposes have high penetration ...depth and can discriminate multiple tissues based on attenuation properties of different materials. Likewise, the ability to deposit energy at various targets within tumors make the use of photons effective treatment for cancer. Radiation focused on a tumor will deposit energy when it interacts with a biological structure (e.g. DNA), which will result in cell kill should repair capacity of the tissue be overwhelmed. Likewise, damage to normal, non-cancerous tissues is a consequence of radiation that can lead to acute or late, chronic toxicity profiles. Adipose derived stem cells (ADSCs) are mesenchymal stem cells that have been proven to have similar characteristics to bone marrow derived stem cells, except that they are much easier to obtain. Within the body, ADSCs act as immunomodulators and assist with the maintenance and repair of tissues. They have been shown to have excellent differentiation capability, making them an extremely viable option for stem cell therapies and regenerative medicine applications. Due to the tissue ADSCs are derived from, they are highly likely to be affected by radiation therapy, especially when treating tumors localized to structures with relatively high ADSC content (eg., breast cancer). For this reason, the purpose behind this research is to better understand how ADSCs are affected by doses of radiation comparable to a single fraction of radiation therapy. We also measured the response of ADSCs to exposure at different dose rates to determine if there is a significant difference in the response of ADSCs to radiation therapy relevant doses of ionizing radiation. Our findings indicate that ADSCs exposed to Cesium (Cs 137)-gamma rays at a moderate dose of 2Gy and either a low dose rate (1.40Gy/min) or a high dose rate (7.31Gy/min) slow proliferation rate, and with cell cycle arrest in some populations. These responses ADSCs were not as marked as previously measured in other stem cell types. In addition, our results indicate that differences in dose rate in the Gy/min range typically utilized in small animal or cell irradiation platforms have a minimal effect on the function of ADSCs. The potential ADSCs have in the space of regenerative medicine makes them an ideal candidate for study with ionizing radiation, as they are one of the main cell types to promote tissue healing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell ...culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial "pause" in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of ionizing radiation within medicine creates an interesting paradox. First, x-rays can be used as an excellent diagnostic tool, allowing doctors to view internal biological structures ...without having to perform surgery. This can be done thanks to the characteristics of high energy photons, namely excellent penetration depth and various levels of absorption based upon the density of a material. These same characteristics make ionizing radiation a very effective treatment method for cancer. Radiation focused on a tumor will deposit energy when it interacts with a biological structure (e.g. DNA), eventually causing enough damage to kill the cell. That same damage can be done to healthy cells and tissue, slowing the natural healing and repair response of the body. Adipose derived stem cells (ADSCs) are a mesenchymal stem cell line that has been proven to have similar characteristics to bone marrow derived stem cells, except that they much easier to obtain. Within the body, ADSCs act as immunomodulators and assist with the maintenance and repair of tissues. They have been shown to have excellent differentiation capability, making them an extremely viable option for stem cell therapies and regenerative medicine applications. Due to the tissue ADSCs are derived from, they are highly likely to be affected by radiation therapy, especially when treating something like breast cancer. For this reason, the purpose behind this research is to better understand how ADSCs are affected by doses of radiation similar to a single fraction of radiation therapy. We will also explore different dose rates to determine if there is a significant difference in the response of ADSCs. Finally, a method for researching ultra-low doses of radiation will be developed, allowing experimental doses closer to what is experienced from a diagnostic imaging procedure like computed tomography to be performed. The results shown from this research will help fill in the gap regarding how ADSCs respond to radiation therapy relevant doses of ionizing radiation. The potential ADSCs have in the space of regenerative medicine makes them an ideal candidate for study with ionizing radiation, as they are one of the main cell types to promote tissue healing.
A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project ...will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
Apnea of prematurity is an important and common clinical problem, and is often the rate-limiting process in NICU discharge. Accurate detection of episodes of clinically important neonatal apnea using ...existing chest impedance (CI) monitoring is a clinical imperative. The technique relies on changes in impedance as the lungs fill with air, a high impedance substance. A potential confounder, however, is blood coursing through the heart. Thus, the cardiac signal during apnea might be mistaken for breathing. We report here a new filter to remove the cardiac signal from the CI that employs a novel resampling technique optimally suited to remove the heart rate signal, allowing improved apnea detection. We also develop an apnea detection method that employs the CI after cardiac filtering. The method has been applied to a large database of physiological signals, and we prove that, compared to the presently used monitors, the new method gives substantial improvement in apnea detection.
Objective To compare the frequency and severity of apneic events in very low birth weight (VLBW) infants before and after blood transfusions using continuous electronic waveform analysis. Study ...design We continuously collected waveform, heart rate, and oxygen saturation data from patients in all 45 neonatal intensive care unit beds at the University of Virginia for 120 weeks. Central apneas were detected using continuous computer processing of chest impedance, electrocardiographic, and oximetry signals. Apnea was defined as respiratory pauses of >10, >20, and >30 seconds when accompanied by bradycardia (<100 beats per minute) and hypoxemia (<80% oxyhemoglobin saturation as detected by pulse oximetry). Times of packed red blood cell transfusions were determined from bedside charts. Two cohorts were analyzed. In the transfusion cohort, waveforms were analyzed for 3 days before and after the transfusion for all VLBW infants who received a blood transfusion while also breathing spontaneously. Mean apnea rates for the previous 12 hours were quantified and differences for 12 hours before and after transfusion were compared. In the hematocrit cohort, 1453 hematocrit values from all VLBW infants admitted and breathing spontaneously during the time period were retrieved, and the association of hematocrit and apnea in the next 12 hours was tested using logistic regression. Results Sixty-seven infants had 110 blood transfusions during times when complete monitoring data were available. Transfusion was associated with fewer computer-detected apneic events ( P < .01). Probability of future apnea occurring within 12 hours increased with decreasing hematocrit values ( P < .001). Conclusions Blood transfusions are associated with decreased apnea in VLBW infants, and apneas are less frequent at higher hematocrits.
In 2006 the apnea of prematurity (AOP) consensus group identified inaccurate counting of apnea episodes as a major barrier to progress in AOP research. We compare nursing records of AOP to events ...detected by a clinically validated computer algorithm that detects apnea from standard bedside monitors.
Waveform, vital sign, and alarm data were collected continuously from all very low-birth-weight infants admitted over a 25-month period, analyzed for central apnea, bradycardia, and desaturation (ABD) events, and compared with nursing documentation collected from charts. Our algorithm defined apnea as > 10 seconds if accompanied by bradycardia and desaturation.
Of the 3,019 nurse-recorded events, only 68% had any algorithm-detected ABD event. Of the 5,275 algorithm-detected prolonged apnea events > 30 seconds, only 26% had nurse-recorded documentation within 1 hour. Monitor alarms sounded in only 74% of events of algorithm-detected prolonged apnea events > 10 seconds. There were 8,190,418 monitor alarms of any description throughout the neonatal intensive care unit during the 747 days analyzed, or one alarm every 2 to 3 minutes per nurse.
An automated computer algorithm for continuous ABD quantitation is a far more reliable tool than the medical record to address the important research questions identified by the 2006 AOP consensus group.
Background Analysis and modeling of data monitoring vital signs and waveforms in patients in a surgical/trauma intensive care unit (STICU) may allow for early identification and treatment of patients ...with evolving respiratory failure. Methods Between February 2011 and March 2012, data of vital signs and waveforms for STICU patients were collected. Every-15-minute calculations ( n = 172,326) of means and standard deviations of heart rate (HR), respiratory rate (RR), pulse-oxygen saturation (SpO2 ), cross-correlation coefficients, and cross-sample entropy for HR-RR, RR-SpO2 , and HR-SpO2 , and cardiorespiratory coupling were calculated. Urgent intubations were recorded. Univariate analyses were performed for the periods <24 and ≥24 hours before intubation. Multivariate predictive models for the risk of unplanned intubation were developed and validated internally by subsequent sample and bootstrapping techniques. Results Fifty unplanned intubations (41 patients) were identified from 798 STICU patients. The optimal multivariate predictive model (HR, RR, and SpO2 means, and RR-SpO2 correlation coefficient) had a receiving operating characteristic (ROC) area of 0.770 (95% confidence interval CI, 0.712–0.841). For this model, relative risks of intubation in the next 24 hours for the lowest and highest quintiles were 0.20 and 2.95, respectively (15-fold increase, baseline risk 1.46%). Adding age and days since previous extubation to this model increased ROC area to 0.865 (95 % CI, 0.821–0.910). Conclusion Among STICU patients, a multivariate model predicted increases in risk of intubation in the following 24 hours based on vital sign data available currently on bedside monitors. Further refinement could allow for earlier detection of respiratory decompensation and intervention to decrease preventable morbidity and mortality in surgical/trauma patients.
Abstract
Relapsed/refractory DLBCL remains an incurable disease, and single-agent therapies typically show low response rates and/or transient clinical responses. Oncogenic MYD88 mutations occur in ...~25% of DLBCL and drive constitutive NFkB activation, promoting proliferation and survival. Despite its role in tumor biology, targeting MYD88MT by inhibiting or degrading IRAK4 alone, a key component of the MYD88 complex, does not drive significant antitumor activity in preclinical models. One potential reason is the frequent redundant NFkB pathway activation by co-mutations, highlighting the need for combination therapies to effectively target the NFkB pathway in DLBCL. To address this challenge, we have developed IRAKIMiDs, heterobifunctional degraders that simultaneously degrade both IRAK4 and IMiD substrates, as a rational therapeutic combination in a single molecule. IRAKIMiDs show increased antitumor activity in vitro and in vivo in MYD88MT cells as compared to IMiD or IRAK4-targeting alone, highlighting suggesting their potential as single agents in R/R DLBCL.Our lead IRAKIMiD, KT-413, is a potent degrader of IRAK4 (DC50 6nM) and IMiD substrates (Ikaros/Aiolos DC50 2nM), inducing rapid and potent cell killing in vitro and complete and sustained tumor regressions in vivo in MYD88MT models of DLBCL. This activity is superior to the IMiD CC-220, which has similar activity against IMiD substrates (Ikaros/Aiolos DC50 1 nM), supporting the synergistic role of IRAK4 degradation in the context of IMiD biology. We show here that the combined activity of these 2 mechanisms drives a synergistic effect on NFkB and IRF4 signaling with greater downstream effect on NFkB and type 1 interferon (IFN) signaling and cell cycle gene expression than either mechanism alone. In THP1 cells engineered with NFkB and IRF4 reporters, KT-413 but not CC-220 inhibits TLR-stimulated NFkB and IRF4 transcription, supporting a role for IRAK4 but not IMiDs in MYD88-driven survival and proliferation signals. IMiDs have previously been shown to modulate type1 IFN signaling through downregulation of IRF4. We propose that simultaneous targeting of both NFkB and type 1 IFN signaling with KT-413 drives synergistic cell killing in MYD88MT cells. In MYD88MT OCI-Ly10 cells, KT-413 leads to greater IRF4 downregulation, increased type 1 IFN signaling, and preferential downregulation of NFkB pathway and cell cycle transcripts when compared to CC-220. These data support the hypothesis that the synergistic activity of targeting IRAK4 and IMiD substrates by KT-413 in MYD88MT DLBCL is a result of dual targeting of NFkB and IRF4/Type1 IFN through degradation of both IRAK4 and IMiD substrates,driving significantly greater cell killing as compared to either mechanism alone, supporting the potential for the first single agent targeted therapy in MYD88MT DLBCL. KT-413 is on track for initiation of a Phase 1 trial in B cell lymphoma in 2H 2021.
Citation Format: Christine R. Klaus, Scott F. Rusin, Kirti Sharma, Samyabrata Bhaduri, Matthew M. Weiss, Alice A. McDonald, Michele F. Mayo, Duncan Walker, Rahul Karnik. Mechanisms underlying synergistic activity in MYD88MTDLBCL of KT-413, a targeted degrader of IRAK4 and IMiD substrate abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB118.
Data and insights from fishers are essential sources of information to advance understanding of fishery and ecosystem dynamics. Incorporating fisher and industry knowledge holds prospects for ...improving marine science and fisheries management. We address cooperative research in the context of collaboration between fishers, scientists, industries, universities, and agencies to develop applied research to understand marine ecosystems, inform fishery management, enhance sustainability, govern resource use, and investigate social-economic dynamics. We leverage the insights of more than 100 research scientists, fisheries managers, industry representatives, and fishers to outline actionable recommendations for effective approaches and mechanisms to integrate industry data, perspectives, and insights in fisheries science. We also highlight opportunities and address challenges and limitations to such collaboration.
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