Publications by authors named "Zoltan N Oltvai"

Anaplastic thyroid carcinoma (ATC) is a rare and aggressive thyroid malignancy typically comprised of undifferentiated tumor cells with various histologic morphologies, which makes the diagnosis challenging. These tumors commonly show loss of thyroglobulin and TTF1 with preservation of cytokeratin (67%) and Paired Box Gene 8 (PAX8) (55%) expression. Identification of a sensitive immunohistochemical stain to aid in the diagnosis of ATC would be beneficial.

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mutation identification is important for the diagnosis and treatment of several tumor types, both solid and hematologic. Rapid identification of mutations is required to determine eligibility for targeted inhibitor therapy. The Idylla mutation assay is a rapid, multiplex allele-specific PCR test designed to detect the most common oncogenic V600 mutations in formalin-fixed paraffin-embedded (FFPE) tissue samples.

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Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on growth in three different growth environments.

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Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2).

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Molecular diagnostics for lung cancer is a well-established standard of care, but how to use the available diagnostic tools for optimal and cost-effective patient care remains unresolved. Here, we show that DNA-only, small gene next-generation sequencing (sNGS) panels (<50 genes) combined with ultra-rapid reflex testing for common fusion transcripts using the Idylla Genefusion assay provide a cost-effective and sufficiently comprehensive testing modality for the majority of lung cancer cases. We also demonstrate the need for additional reflex testing capability on larger DNA and fusion panels for a small subset of lung cancers bearing rare single-nucleotide variants, indels and fusion transcripts and secondary, post-treatment resistance mutations.

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Statins are cholesterol-lowering drugs that have exhibited potential as cancer therapeutic agents. However, as some cancer cells are resistant to statins, broadening an anticancer spectrum of statins is desirable. The upregulated expression of the statin target enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), in statin-treated cancer cells is a well-known mechanism of statin resistance, which can be counteracted by the downregulation of HMGCR gene expression, or degradation of the HMGCR protein.

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Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignant neoplasms with aggressive behavior. The diagnosis remains challenging due to ever-changing terminologies and morphologic overlaps with other disease entities. Herein, we seek to better define anorectal NECs by high-risk human papillomavirus (HPV) status and molecular profiling.

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Statins have anticancer effects and may be used as anticancer agents via drug repositioning. In reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays, the internal reference gene must not be affected by any experimental conditions. As statins exert a wide range of effects on cells by inhibiting the mevalonate pathway, it is possible that statin treatment might alter the expression of housekeeping genes used as internal reference genes, thereby misleading the assessment of obtained gene expression data.

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Article Synopsis
  • Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has changed the treatment landscape for blood cancers, yet challenges remain in predicting related complications.* -
  • A case study illustrates donor-derived T-cell clonal lymphocytosis and cytopenia in a patient with a history of T-cell leukemia, revealing clonal unrelatedness through advanced genetic analyses.* -
  • Despite the patient experiencing increased mutation loads, their clonal lymphocytosis and anemia resolved, suggesting that genetic changes can influence the blood environment and restore balance, highlighting the importance of comprehensive testing for understanding post-HSCT changes.*
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Aims: Statins, cholesterol-lowering drugs, are potential therapeutic agents for inhibiting cancer proliferation. However, the mechanisms that mediate the effects of statins, the homeostatic responses of tumor cells to statin therapy, and the modes underlying the antitumor effects of statins remain unclear.

Main Methods: To uncover the effects of statins on cancer cells in vitro, we performed transcriptome and metabolome analyses on atorvastatin-treated statin-resistant and statin-sensitive lung cancer cells.

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Liquid biopsy is considered an alternative to standard next-generation sequencing (NGS) of solid tumor samples when biopsy tissue is inadequate for testing or when testing of a peripheral blood sample is preferred. A common assumption of liquid biopsies is that the NGS data obtained on circulating cell-free DNA is a high-fidelity reflection of what would be found by solid tumor testing. Here, we describe a case that challenges this widely held assumption.

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Testing of tumors by next generation sequencing (NGS) is impacted by relatively long turnaround times and a need for highly trained personnel. Recently, Idylla oncology assays were introduced to test for , , , and common hotspot mutations that do not require specialized trained personnel. Moreover, the interpretation of results is fully automated, with rapid turnaround time.

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Epithelial-mesenchymal transition (EMT) in primary tumor cells is a key prerequisite for metastasis initiation. Statins, cholesterol-lowering drugs, can delay metastasis formation in vivo and attenuate the growth and proliferation of tumor cells in vitro. The latter effect is stronger in tumor cells with a mesenchymal-like phenotype than in those with an epithelial one.

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Article Synopsis
  • * The patient case study involved the IDH1 mutation p.R132C, where treatment with the drug ivosidenib resulted in an initial positive response, but ultimately, the disease relapsed and progressed.
  • * Advanced sequencing techniques revealed another mutation, p.S280F, that promotes resistance to ivosidenib by preventing the drug from effectively binding to the altered IDH1 protein, highlighting the importance of monitoring for drug resistance in AML treatment.
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The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant.

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Motivation: The biological effects of human missense variants have been studied experimentally for decades but predicting their effects in clinical molecular diagnostics remains challenging. Available computational tools are usually based on the analysis of sequence conservation and structural properties of the mutant protein. We recently introduced a new machine learning method that demonstrated for the first time the significance of protein dynamics in determining the pathogenicity of missense variants.

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The mechanisms of bacterial chemotaxis have been extensively studied for several decades, but how the physical environment influences the collective migration of bacterial cells remains less understood. Previous models of bacterial chemotaxis have suggested that the movement of migrating bacteria across obstacle-laden terrains may be slower compared with terrains without them. Here, we show experimentally that the size or density of evenly spaced obstacles do not alter the average exit rate of cells from microchambers in response to external attractants, a function that is dependent on intact cell-cell communication.

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Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers.

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Background: Metastasis in breast cancer foreshadows mortality, as clinically evident disease is aggressive and generally chemoresistant. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies.

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HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (reflective of in-circulation metastatic tumor cells) to achieve the same degree of growth inhibition. Here, we show that attenuation of HMGCR expression in the presence of atorvastatin leads to stronger growth inhibition than dual target blockade of the mevalonate pathway in relatively statin resistant cell lines, mainly through inhibition of protein prenylation pathways.

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Cell-to-cell differences in protein expression in normal tissues and tumors are a common phenomenon, but the underlying principles that govern this heterogeneity are largely unknown. Here, we show that in monolayer cancer cell-line cultures, the expression of the five metabolic enzymes of serine-glycine synthesis (SGS), including its rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), displays stochastic cell-to-cell variation. By contrast, in cancer cell line-derived three-dimensional (3D) microtumors PHGDH expression is restricted to the outermost part of the microtumors' outer proliferative cell layer, while the four other SGS enzymes display near uniform expression throughout the microtumor.

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Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells 'assess' cellular damage and make a 'life' or 'death' decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics.

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Statins are potent cholesterol reducing drugs that have been shown to reduce tumor cell proliferation in vitro and tumor growth in animal models. Moreover, retrospective human cohort studies demonstrated decreased cancer-specific mortality in patients taking statins. We previously implicated membrane E-cadherin expression as both a marker and mechanism for resistance to atorvastatin-mediated growth suppression of cancer cells; however, a transcriptome-profile-based biomarker signature for statin sensitivity has not yet been reported.

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Bacteria are able to coordinate their movement, growth and biochemical activities through cell-cell communication. While the biophysical mechanism of bacterial chemotaxis has been well understood in individual cells, the role of communication in the chemotaxis of bacterial populations is not clear. Here we report experimental evidence for cell-cell communication that significantly enhances the chemotactic migration of bacterial populations, a finding that we further substantiate using numerical simulations.

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Overflow metabolism is a metabolic phenotype of cells characterized by mixed oxidative phosphorylation (OxPhos) and fermentative glycolysis in the presence of oxygen. Recently, it was proposed that a combination of a protein allocation constraint and a higher proteome fraction cost of energy generation by OxPhos relative to fermentation form the basis of overflow metabolism in the bacterium, Escherichia coli. However, we argue that the existence of a maximum or optimal macromolecular density is another essential requirement.

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