t(5;17)(q33;p13) RABEP1/PDGFRB

The t(5;17)(q33;p13) rearrangement has been observed as sole cytogenetic abnormality in one case of chronic myelomonocytic leukemia, a soft-tissue aneurysmal bone cyst, and a case of myeloid and lymphoid neoplasms (MLNs) with eosinophilia. Rare occurrence of lymphoid and mixed MLNs with abnormalities of PDGFRB has been reported in two cases. The t(5;17)(q33;p13) generates a fusion gene, located on the rearranged chromosome 5, comprised of the 5' portion of RABEP1 (encoding the coiled-coil domain) and the 3' portion of PDGFRB (encoding the intracellular kinase domain). Expression of the resulting fusion protein has been demonstrated to cause myeloproliferative disease in mic

Tumor Suppression by Cell Competition Through Regulation of the Hippo Pathway

Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble (scrib) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib− cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib− cells are prevented from overproliferating. We report that cell competition between scrib− and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib− cells. Suppressing Yki activation is critical for scrib− clone elimination by cell competition, and experimental elevation of Yki activity in scrib−cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib− cells. Animals have evolved homeostatic mechanisms to eliminate abnormal and cancerous cells, protecting the animal from harm (1). A prominent example of an organism removing abnormal cells that have the potential to form tumors is the elimination of scribble mutant (scrib−) cells from Drosophila imaginal discs (2–8). scrib is a conserved tumor-suppressor gene that is essential for the establishment of apical–basal cell polarity (8–10). Scrib is a scaffold protein that localizes to basolateral cell junctions and functions together with the Discs large (Dlg) and Lethal giant larvae (Lgl) adaptor proteins to govern apical–basal cell polarity in epithelial cells (8, 10). Imaginal discs from Drosophila larvae that are homozygous mutant for scrib, dlg, or lgl grow into large tumorous masses of neoplastic cells that display several hallmarks of carcinomas: They lose apical–basal cell polarity, hyperproliferate, and have defects in differentiation (10). Interestingly, the neoplastic phenotype of scrib− cells depends on their cellular environment. When scrib− cells are produced in patches (clones) of mutant cells that are surrounded by normal cells, they do not hyperproliferate, remain small, and eventually are eliminated (2–7, 11–13). Similar effects are observed for lgl− and dlg− clones, although they may not be eliminated very efficiently (11, 14, 15). Thus, the presence of wild-type cells prevents scrib−, lgl−, and dlg−cells from manifesting their tumorigenic potential (2–7, 11–15). Several groups have shown that the JNK stress–response pathway is activated in scrib− clones, leading to engulfment and death or extrusion of mutant cells from the epithelium (2–4, 6, 11, 16). Activation of JNK is required for the elimination of scrib− cells because blocking JNK activity in scrib−cells results in massive overgrowth of clones that is reminiscent of the tumorous overgrowth of entirely mutant discs (2–4, 6, 12, 13). However, blocking apoptosis does not cause overproliferation of scrib− clones (2, 3). Therefore, in addition to inducing apoptosis, JNK suppresses the potential of scrib− cells to hyperproliferate (2, 3). However, how scrib−cells are prevented from hyperproliferating is not known. The presence of normal cells is required for the elimination of tumorigenic scrib− clones because genetically ablating the normal tissue surrounding scrib− cells results in hyperproliferation of the scrib− cells (2, 3). It has been suggested that cell competition, a process by which viable cells of lower fitness are removed from a tissue and replaced through extra proliferation of fitter neighbors (17), is responsible for the elimination of scrib−and lgl− cell clones (2, 14). However, the hypothesis that scrib− and lgl− clones are eliminated by cell competition is in conflict with other reports and thus is controversial. It has been reported that cells with compromised Scrib or Lgl function exhibit elevated activity of Yorkie (Yki), a transcriptional coactivator and downstream effector of the Hippo growth-control pathway (13, 14, 18–20). The Hippo pathway is a conserved tumor-suppressor pathway that suppresses growth by antagonizing the activity of Yki (21). Thus, loss of Hippo pathway activity or elevated levels of Yki activity result in hyperproliferation of imaginal disc cells and resistance to apoptosis that normally would eliminate extra cells (21). Notably, an increase in Yki activity can rescue weak cells, such as cells heterozygous for Minute (M) mutations, from being eliminated by cell competition (22). M mutations occur in ribosomal protein-encoding genes and were the first class of genes identified as having cell-competition phenotypes (23). Homozygous M mutations are lethal, but heterozygous Manimals are viable, although their cells have reduced growth rates (23). In genetic mosaics, however, interaction between wild-type and M+/− cells leads to the elimination of the M+/−cells and expansion of the wild-type population, a phenomenon termed “cell competition” (17). Thus, M+/− cells are less competitive than wild-type cells. Importantly, elevated levels of Yki can rescue M+/− cells from being eliminated by cell competition and also can transform normal cells into supercompetitors that induce apoptosis in their neighbors and proliferate at their neighbors’ expense (22, 24, 25). Yki may increase the competitiveness of cells by inducing the expression of Myc, a known regulator of cell competition (24–27). However, the reports that scrib− cells have high levels of Yki activity and the hypothesis that scrib− cells are eliminated by cell competition present a paradox. If scrib− cells indeed have elevated levels of Yki activity, why does that elevated Yki activity not protect scrib−cells from cell competition? Here we investigated this paradox further. We show that scrib− cells are indeed eliminated by cell competition. We found that for this elimination to occur, scrib− cells undergo a JNK-dependent suppression of Yki activity; this suppression of Yki activity prevents scrib− cells from hyperproliferating and enables their removal. The modulation of Yki activity in scrib−cells thus is a critical effect of the JNK-dependent cell-competition process that removes such tumorigenic cells from imaginal discs. Finally we show that the Myc and Ras oncogenes, which can rescue scrib− clones from elimination (2, 4, 15), do so by conferring competitive fitness to scrib− cells and thereby prevent the down-regulation of Yki activity in scrib− cells. Our results thus further characterize the effects of cell-competition pathways in removing tumorigenic scrib− cells from imaginal discs

A study of elective genome sequencing and pharmacogenetic testing in an unselected population

BACKGROUND: Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. METHODS: Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. RESULTS: Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty-four participants (85%) were carriers of a recessive or X-linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. CONCLUSION: Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS

Effect of Observing Change from Comparison Mammograms on Performance of Screening Mammography in a Large Community-based Population

To evaluate the effect of comparison mammograms on accuracy, sensitivity, specificity, positive predictive value (PPV1), and cancer detection rate (CDR) of screening mammography to determine the role played by identification of change on comparison mammograms

Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations

Infantile-onset Pompe disease (IOPD) is a rare, severe disorder of lysosomal storage of glycogen that leads to progressive cardiac and skeletal myopathy. IOPD is a fatal disease in childhood unless treated with enzyme replacement therapy (ERT) from an early age. Sickle cell anemia (SCA) is a relatively common hemoglobinopathy caused by a specific variant in the hemoglobin beta-chain. Here we report a case of a male newborn of African ancestry diagnosed and treated for IOPD and SCA. Molecular testing confirmed tw

Genomic landscape of TP53-mutated myeloid malignancies

TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance

Use of a beta-lactam graded challenge process for inpatients with self-reported penicillin allergies at an academic medical center

BackgroundThe Antimicrobial Stewardship Program (ASP) at Nebraska Medicine collaborated with a board-certified allergist to develop a penicillin allergy guidance document for treating inpatients with self-reported allergy. This guidance contains an algorithm for evaluating and safely challenging penicillin-allergic patients with beta-lactams without inpatient allergy consults being available.MethodsFollowing multi-disciplinary review, an order set for beta-lactam graded challenges (GC) was implemented in 2018. This contains recommended monitoring and detailed medication orders to challenge patients with various beta-lactam agents. Inpatient orders for GC from 3/2018–6/2022 were retrospectively reviewed to evaluate ordering characteristics, outcomes of the challenge, and whether documentation of the allergy history was updated. All beta-lactam challenges administered to inpatients were included, and descriptive statistics were performed.ResultsOverall, 157 GC were administered; 13 with oral amoxicillin and 144 with intravenous (IV) beta-lactams. Ceftriaxone accounted for the most challenges (43%). All oral challenges were recommended by an Infectious Diseases consult service, as were a majority of IV challenges (60%). Less than one in five were administered in an ICU (19%). Almost all (n = 150, 96%) were tolerated without any adverse event. There was one reaction (1%) of hives and six (4%) involving a rash, none of which had persistent effects. Allergy information was updated in the electronic health record after 92% of the challenges.ConclusionBoth intravenous and oral beta-lactam graded challenges were implemented successfully in a hospital without a regular inpatient allergy consult service. They were well-tolerated, administered primarily in non-ICU settings, and were often ordered by non-specialist services. In patients with a self-reported penicillin allergy, these results demonstrate the utility and safety of a broadly adopted beta-lactam GC process

Cytotoxicity Effects of Different Surfactant Molecules Conjugated to Carbon Nanotubes on Human Astrocytoma Cells

Phase contrast and epifluorescence microscopy were utilized to monitor morphological changes in human astrocytoma cells during a time-course exposure to single-walled carbon nanotube (SWCNT) conjugates with different surfactants and to investigate sub-cellular distribution of the nanotube conjugates, respectively. Experimental results demonstrate that cytotoxicity of the nanotube/surfactant conjugates is related to the toxicity of surfactant molecules attached on the nanotube surfaces. Both sodium dodecyl sulfate (SDS) and sodium dodecylbenzene sulfonate (SDBS) are toxic to cells. Exposure to CNT/SDS conjugates (0.5 mg/mL) for less than 5 min caused changes in cell morphology resulting in a distinctly spherical shape compared to untreated cells. In contrast, sodium cholate (SC) and CNT/SC did not affect cell morphology, proliferation, or growth. These data indicate that SC is an environmentally friendly surfactant for the purification and dispersion of SWCNTs. Epifluorescence microscopy analysis of CNT/DNA conjugates revealed distribution in the cytoplasm of cells and did not show adverse effects on cell morphology, proliferation, or viability during a 72-h incubation. These observations suggest that the SWCNTs could be used as non-viral vectors for diagnostic and therapeutic molecules across the blood–brain barrier to the brain and the central nervous system

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations