Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of ␤-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving ␤-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/␤-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3␤, axin 1, ␤-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3␤ kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3␤ have enhanced ␤-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3␤ reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3␤ in GMP LSC, enabling unphosphorylated ␤-catenin to participate in LSC self-renewal. Missplicing of GSK3␤ represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.blast crisis chronic myeloid leukemia ͉ wnt pathway ͉ xenograft ͉ self-renewal ͉ cancer stem cells

Caloric restriction (CR) is a daily reduction of total caloric intake without a decrease in micronutrients or disproportionate reduction of any one dietary component. CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline. Thus, we determined the effects of age and CR on key synaptic proteins in the CA3 region of the hippocampus and whether these changes were correlated with differences in behavior on a hippocampal-dependent learning and memory task. We observed an overall, age-related decline in the NR1, N2A and N2B subunits of the N-methyl-d-aspartate (NMDA)-type and the GluR1 and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-type ionotropic glutamate receptors. Interestingly, we found that CR initially lowers the glutamate receptor subunit levels as compared to young AL animals, and then stabilizes the levels across lifespan. Synaptophysin, a presynaptic vesicle protein, showed a similar pattern. We also found that both CR and ad libitum (AL) fed animals exhibited age-related cognitive decline on the Morris water maze task. However, AL animals declined between young and middle age, and between middle age and old, whereas CR rats only declined between young and middle age. Thus, the decrease in key synaptic proteins in CA3 and cognitive decline occurring across lifespan are stabilized by CR. This age-related decrease and CR-induced stabilization are likely to affect CA3 synaptic plasticity and, as a result, hippocampal function.

This list serves as a starting point to enhance coping with stressors as a healthcare student or professional in order to help mitigate burnout, depression, and suicidality. The next steps include adapting digital health strategies to specifically fit the needs of healthcare providers, with the ultimate goal of facilitating in-person care when warranted.

Caloric restriction (CR) extends life span and ameliorates the aging-related decline in hippocampal-dependent cognitive function. In the present study, we compared subunit levels of NMDA and AMPA types of the glutamate receptor and quantified total synapses and multiple spine bouton (MSB) synapses in hippocampal CA1 from young (10 months), middle-aged (18 months), and old (29 months) Fischer 344xBrown Norway rats that were ad libitum (AL) fed or caloric restricted (CR) from 4 months of age. Each of these parameters has been reported to be a potential contributor to hippocampal function. Western blot analysis revealed that NMDA and AMPA receptor subunits in AL animals decrease between young and middle age to levels that are present at old age. Interestingly, young CR animals have significantly lower levels of glutamate receptor subunits than young AL animals and those lower levels are maintained across life span. In contrast, stereological quantification indicated that total synapses and MSB synapses are stable across life span in both AL and CR rats. These results indicate significant aging-related losses of hippocampal glutamate receptor subunits in AL rats that are consistent with altered synaptic function. CR eliminates that aging-related decline by inducing stable NMDA and AMPA receptor subunit levels.

Coronavirus disease 2019 (COVID-19) is a highly transmissible disease that has affected more than 90% of the countries worldwide. At least 17 million individuals have been infected, and some countries are still battling first or second waves of the pandemic. Nucleic acid tests, especially reverse transcription polymerase chain reaction (RT-PCR), have become the workhorse for early detection of COVID-19 infection. Positive controls for the molecular assays have been developed to validate each test and to provide high accuracy. However, most available positive controls require cold-chain distribution and cannot serve as full-process control. To overcome these shortcomings, we report the production of biomimetic virus-like particles (VLPs) as SARS-CoV-2 positive controls. A SARS-CoV-2 detection module for RT-PCR was encapsidated into VLPs from a bacteriophage and a plant virus. The chimeric VLPs were obtained either by in vivo reconstitution and coexpression of the target detection module and coat proteins or by in vitro assembly of purified detection module RNA sequences and coat proteins. These VLP-based positive controls mimic SARS-CoV-2 packaged ribonucleic acid (RNA) while being noninfectious. Most importantly, we demonstrated that the positive controls are scalable, stable, and can serve broadly as controls, from RNA extraction to PCR in clinical settings.

Radiologists play a central role in the assessment of patient response to locoregional therapies for hepatocellular carcinoma (HCC). The identification of viable tumor following treatment guides further management and potentially affects transplantation eligibility. Liver Imaging Reporting and Data Systems (LI-RADS) first introduced the concept of LR-treated in 2014, and a new treatment response algorithm is included in the 2017 update to assist radiologists in image interpretation of HCC after locoregional therapy. In addition to offering imaging criteria for viable and nonviable HCC, new concepts of nonevaluable tumors as well as tumors with equivocal viability are introduced. Existing guidelines provided by response evaluation criteria in solid tumors (RECIST) and modified RECIST address patient-level assessments and are routinely used in clinical trials but do not address the variable appearances following different locoregional therapies. The new LI-RADS treatment response algorithm addresses this gap and offers a comprehensive approach to assess treatment response for individual lesions after a variety of locoregional therapies, using either contrast-enhanced CT or MRI.

Fluoroscopy operators and staff can greatly reduce their radiation exposure by wearing properly fitted protective garments, positioning protective devices to block scatter radiation, and adhering to good radiation practices. By understanding the essentials of radiation physics, protective equipment, and the features of each imaging system, operators and staff can capitalize on opportunities for radiation protection while minimizing ergonomic strain. Practicing and promoting a culture of radiation safety can help fluoroscopy operators and staff enjoy long, productive careers helping patients.

Caloric restriction (CR) attenuates aging-related degenerative processes throughout the body. It is less clear, however, whether CR has a similar effect in the brain, particularly in the hippocampus, an area important for learning and memory processes that often are compromised in aging. In order to evaluate the effect of CR on synapses across lifespan, we quantified synapses stereologically in the middle molecular layer of the dentate gyrus (DG) of young, middle aged and old Fischer 344 x Brown Norway rats fed ad libitum (AL) or a CR diet from 4 months of age. The results indicate that synapses are maintained across lifespan in both AL and CR rats. In light of this stability, we addressed whether aging and CR influence neurotransmitter receptor levels by measuring subunits of NMDA (NR1, NR2A and NR2B) and AMPA (GluR1, GluR2) receptors in the DG of a second cohort of AL and CR rats across lifespan. The results reveal that the NR1 and GluR1 subunits decline with age in AL, but not CR rats. The absence of an aging-related decline in these subunits in CR rats, however, does not arise from increased levels in old CR rats. Instead, it is due to subunit decreases in young CR rats to levels that are sustained in CR rats throughout lifespan, but that are reached in AL rats only in old age.