88 research outputs found
Move-minimizing puzzles, diamond-colored modular and distributive lattices, and poset models for Weyl group symmetric functions
The move-minimizing puzzles presented here are certain types of one-player
combinatorial games that are shown to have explicit solutions whenever they can
be encoded in a certain way as diamond-colored modular and distributive
lattices. Such lattices can also arise naturally as models for certain
algebraic objects, namely Weyl group symmetric functions and their companion
semisimple Lie algebra representations. The motivation for this paper is
therefore both diversional and algebraic: To show how some recreational
move-minimizing puzzles can be solved explicitly within an order-theoretic
context and also to realize some such puzzles as combinatorial models for
symmetric functions associated with certain fundamental representations of the
symplectic and odd orthogonal Lie algebras
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 scribâ cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scribâ cells are prevented from overproliferating. We report that cell competition between scribâ and wild-type cells prevents hyperproliferation by suppressing Yki activity in scribâ cells. Suppressing Yki activation is critical for scribâ clone elimination by cell competition, and experimental elevation of Yki activity in scribâcells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scribâ 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 (scribâ) cells from Drosophila imaginal discs (2â8). scrib is a conserved tumor-suppressor gene that is essential for the establishment of apicalâbasal cell polarity (8â10). 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 apicalâbasal 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 apicalâbasal cell polarity, hyperproliferate, and have defects in differentiation (10). Interestingly, the neoplastic phenotype of scribâ cells depends on their cellular environment. When scribâ 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 (2â7, 11â13). Similar effects are observed for lglâ and dlgâ clones, although they may not be eliminated very efficiently (11, 14, 15). Thus, the presence of wild-type cells prevents scribâ, lglâ, and dlgâcells from manifesting their tumorigenic potential (2â7, 11â15). Several groups have shown that the JNK stressâresponse pathway is activated in scribâ clones, leading to engulfment and death or extrusion of mutant cells from the epithelium (2â4, 6, 11, 16). Activation of JNK is required for the elimination of scribâ cells because blocking JNK activity in scribâcells results in massive overgrowth of clones that is reminiscent of the tumorous overgrowth of entirely mutant discs (2â4, 6, 12, 13). However, blocking apoptosis does not cause overproliferation of scribâ clones (2, 3). Therefore, in addition to inducing apoptosis, JNK suppresses the potential of scribâ cells to hyperproliferate (2, 3). However, how scribâcells are prevented from hyperproliferating is not known. The presence of normal cells is required for the elimination of tumorigenic scribâ clones because genetically ablating the normal tissue surrounding scribâ cells results in hyperproliferation of the scribâ 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 scribâand lglâ cell clones (2, 14). However, the hypothesis that scribâ and lglâ 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, 18â20). 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+/â cells leads to the elimination of the M+/âcells and expansion of the wild-type population, a phenomenon termed âcell competitionâ (17). Thus, M+/â cells are less competitive than wild-type cells. Importantly, elevated levels of Yki can rescue M+/â 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 neighborsâ expense (22, 24, 25). Yki may increase the competitiveness of cells by inducing the expression of Myc, a known regulator of cell competition (24â27). However, the reports that scribâ cells have high levels of Yki activity and the hypothesis that scribâ cells are eliminated by cell competition present a paradox. If scribâ cells indeed have elevated levels of Yki activity, why does that elevated Yki activity not protect scribâcells from cell competition? Here we investigated this paradox further. We show that scribâ cells are indeed eliminated by cell competition. We found that for this elimination to occur, scribâ cells undergo a JNK-dependent suppression of Yki activity; this suppression of Yki activity prevents scribâ cells from hyperproliferating and enables their removal. The modulation of Yki activity in scribâcells 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 scribâ clones from elimination (2, 4, 15), do so by conferring competitive fitness to scribâ cells and thereby prevent the down-regulation of Yki activity in scribâ cells. Our results thus further characterize the effects of cell-competition pathways in removing tumorigenic scribâ 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
Teaching Mathematics with Technology: TPACK and Effective Teaching Practices
This paper examines how 17 secondary mathematics teacher candidates (TCs) in four university teacher preparation programs implemented technology in their classrooms to teach for conceptual understanding in online, hybrid, and face to face classes during COVID-19. Using the Professional Development: Research, Implementation, and Evaluation (PrimeD) framework, TCs, classroom mentor teachers, field experience supervisors, and university faculty formed a Networked Improvement Community (NIC) to discuss a commonly agreed upon problem of practice and a change idea to implement in the classroom. Through Plan-Do-Study-Act cycles, participants documented their improvement efforts and refinements to the change idea and then reported back to the NIC at the subsequent monthly meeting. The Technology Pedagogical Content Knowledge framework (TPACK) and the TPACK levels rubric were used to examine how teacher candidates implemented technology for Mathematics conceptual understanding. The Mathematics Classroom Observation Protocol for Practices (MCOP2) was used to further examine how effective mathematics teaching practices (e.g., student engagement) were implemented by TCs. MCOP2 results indicated that TCs increased their use of effective mathematics teaching practices. However, growth in TPACK was not significant. A relationship between TPACK and MCOP2 was not evident, indicating a potential need for explicit focus on using technology for mathematics conceptual understanding
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 3/2018â6/2022 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 (nâ=â150, 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
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