Publications by authors named "Stephen Kurtz"
The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303.
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- Emerging research highlights how factors in the leukemia microenvironment protect cancer cells from treatments and contribute to drug resistance, signaling the need for targeted therapies in acute myeloid leukemia (AML).
- A study involving around 300 AML patient samples found that higher levels of the cytokine CCL2 correlate with reduced effectiveness of MEK inhibitors, leading to further investigations into the mechanisms behind this resistance.
- The findings suggest that targeting both CCL2 and the MEK pathway can improve treatment responses in AML, proposing a combination therapy as a promising strategy to overcome drug resistance and enhance patient outcomes.
Article Synopsis
- Venetoclax, when combined with azacytidine, shows promise in treating acute myeloid leukemia (AML), but some patients develop resistance, which can limit the treatment's effectiveness.
- Researchers tested 25 different drug combinations with venetoclax on AML patient samples to discover which combinations might work better than the standard venetoclax + azacytidine approach.
- By analyzing tumor cell states and incorporating clinical features, the study identified new drug combinations that could be more effective for certain patient subtypes, paving the way for personalized treatment strategies in AML.
Article Synopsis
- The study examined the effects of a 2011 trial comparing the effectiveness of the long-acting injectable antipsychotic Risperidone Consta® with oral treatments in veterans diagnosed with schizophrenia or schizoaffective disorder, but found no positive results for either effectiveness or cost-effectiveness.
- Following the trial, there was a significant decline in the initiation of new patients on LAI risperidone, alongside a decrease in total annual users and expenditures on the drug.
- The decline in LAI risperidone usage was largely due to the emergence of a newer treatment, LAI paliperidone, which gained popularity two years prior to the trial, suggesting that the results of the CSP#555 study may have further
Multi-site randomized effectiveness trials evaluate treatments under real-world conditions. Whether results change practice is under-studied. A 6-month 26-site Veterans Health Administration (VHA) cooperative study published in 2011 compared an oral second-generation antipsychotic, risperidone, to placebo for refractory PTSD with null results.
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- Acute myeloid leukemia (AML) is a challenging cancer with few treatment options, and the study combines ex vivo drug sensitivity with genomic data from 805 patients to better understand treatment responses.
- This research identifies key features influencing drug sensitivity, particularly focusing on the differentiation state of AML cells, which has implications for how they respond to therapy.
- Notably, the gene PEAR1 emerges as a strong predictor of survival in young AML patients, highlighting its potential role in guiding treatment decisions and future drug development.
Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild-type (WT) and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations.
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- * CG-806 (luxeptinib) is a promising dual BTK/SYK inhibitor that has shown effectiveness in preclinical trials, killing MCL cells and overcoming resistance seen with ibrutinib by suppressing anti-apoptotic proteins.
- * In studies, CG-806 improved survival rates in certain MCL models, revealing that understanding the Bcl-2 network and combining it with other treatments could enhance drug efficacy, making it a focus for future cancer therapy research. *
Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity.
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- * The effectiveness of each drug alone depended on the specific differentiation state of the tumor cells, with certain leukemia profiles responding better to each drug, while the combination treatment reduced these distinctions.
- * The enhanced effectiveness of the combination may be due to DORA blocking p38 MAPK-mediated phosphorylation of BCL2, thereby increasing sensitivity to VEN and presenting a promising strategy for future AML treatments.
Article Synopsis
- The FDA approved eight new targeted therapies for acute myeloid leukemia (AML), including the drug venetoclax, highlighting the need for better patient selection to maximize treatment effectiveness.
- A study of AML patient samples revealed a common "general response across drugs" (GRD) linked to FLT3-ITD mutations and overall survival, suggesting this response could improve predictions of how patients will respond to treatments.
- Specifically for venetoclax, its effectiveness was not connected to GRD but rather to the expression of certain monocyte-associated genes, identified using a new Bayesian regression method that combines data from multiple studies to find relevant biomarkers for drug response.
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- Bcl-2 targeting has been effective for treating lymphoid cancers, but resistance is common, prompting research into new drugs like AZD5991 which selectively inhibits Mcl-1.
- In preclinical studies, AZD5991 effectively restricted the growth of various types of lymphoma cells, including those resistant to other treatments, by causing mitochondrial dysfunction and impairing oxidative phosphorylation.
- The findings suggest that targeting Mcl-1 could be a promising therapeutic strategy, with metabolic changes playing a role in sensitivity to this treatment.
Article Synopsis
- Drug resistance in acute myeloid leukemia (AML) limits the effectiveness of targeted therapies like FLT3 inhibitors, which is common in about 25% of AML patients with FLT3 mutations.
- A CRISPR screen revealed that specific genes (LZTR1, NF1, TSC1, TSC2) are involved in the resistance to sorafenib, highlighting the role of the MAPK and MTOR pathways.
- Combining FLT3 inhibitors with MEK inhibitors has shown promise in overcoming resistance in AML patients, suggesting a potential new treatment approach.
Article Synopsis
- Targeting Bcl-2 family proteins is vital for cancer treatment, prompting the development of AZD4320, a dual inhibitor that effectively addresses resistance mechanisms, particularly from Bcl-x.
- Through structure-based chemistry, AZD4320 was designed to bind strongly to Bcl-2 and Bcl-x, leading to enhanced apoptosis in cancer cells, especially in acute myeloid leukemia (AML).
- Initial results show that AZD4320 can shrink tumors while temporarily lowering platelet counts, which recovers quickly, indicating its promise as a weekly treatment option across various cancers linked to Bcl-2 dysregulation.
Article Synopsis
- Acute myeloid leukemia (AML) is caused by the excessive growth and poor maturation of blood stem cells.
- A study found that combining two drugs, ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor), shows improved effectiveness against AML in lab tests and animal models.
- Specific genetic traits, like 11q23 MLL rearrangements, make AML patients more responsive to this drug combination, suggesting it could be a strong treatment option.
Objective: Antibiotics are widely used by all specialties in the hospital setting. We evaluated previously defined high-risk antibiotic use in relation to Clostridioides difficile infections (CDIs).
Methods: We analyzed 2016-2017 data from 171 hospitals.
Article Synopsis
- The study investigates why some acute myeloid leukemia (AML) cells become resistant to the BCL2 inhibitor venetoclax by using CRISPR/Cas9 to find specific gene knockouts linked to this resistance.
- Key findings highlight that loss of the BAX gene, reduced BCL2 expression, and reliance on other BCL2 family members contribute to the inability of these cells to undergo apoptosis, leading to drug resistance.
- The research suggests that addressing changes in the apoptotic network and mitochondrial function could improve patient responses to venetoclax and emphasizes the need for innovative combinations of therapies to treat AML effectively.
Article Synopsis
- Advances in understanding acute myeloid leukemia (AML) are not translating to improved survival rates, highlighting the need for better predictive tools for treatment response.
- Researchers combined genomics, computational modeling, and chemosensitivity assays on 100 patients to assess the effectiveness of a BET inhibitor (JQ1) in targeting AML.
- The study found that 93% of predictions for treatment response matched lab results, identifying specific genomic markers that could help tailor therapies for patients with certain chromosomal abnormalities.
Article Synopsis
- The Beat AML program analyzed tumor specimens from 562 AML patients to examine complex mutations and drug responses using whole-exome and RNA sequencing.* -
- The study discovered previously undetected mutations and identified how certain drug responses are linked to specific combinations of these mutations.* -
- Findings, including gene expression signatures related to drug responses, are available through the Beat AML data viewer, enabling further research on AML biology.*
This project sought to identify Medicaid members with intellectual and developmental disabilities (IDD) in five states (Delaware, Iowa, Massachusetts, New York, and South Carolina) to develop a cohort for subsequent analyses of medical conditions and service utilization. We estimated that over 300,000 Medicaid members in these states had IDD. All members with diagnostic codes for IDD were identified and the three most frequent diagnoses were unspecified intellectual disability, autism or pervasive developmental disorder, and cerebral palsy.
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- IRAK1 is a key player in innate immunity and is found to be overactive in various cancers, including acute myeloid leukemia (AML), where it helps leukemia cells survive.
- The study showed that blocking IRAK1 using the multikinase inhibitor pacritinib significantly decreased leukemia burden in AML models, highlighting its potential as a therapeutic target.
- Pacritinib effectively inhibits IRAK1 alongside other kinases and demonstrated a strong impact on AML cells with diverse genetic mutations, suggesting its broader applicability in treating different AML subtypes.
Article Synopsis
- The study aimed to assess the link between consistent smoking cessation support from healthcare professionals and achieving long-term quitting success among smokers.
- Utilizing a large cohort of over 33,000 patients from six different health systems in the U.S., the research analyzed data from electronic health records over several years.
- Results showed that patients receiving smoking cessation support in at least 75% of their primary care visits were nearly three times more likely to quit smoking long-term compared to those receiving minimal assistance, highlighting the benefits of regular support in helping smokers quit.