Faculty Bibliography
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15
Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407.
PMID: 39891928
ISSN: 1538-7445
CID: 5781392
Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths
BACKGROUND:Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS:In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS:During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS:In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).
PMCID:11761538
PMID: 38884347
ISSN: 1533-4406
CID: 5791882
Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment
Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.
PMID: 38199587
ISSN: 1872-7980
CID: 5707822
Addressing Data Aggregation and Data Inequity in Race and Ethnicity Reporting and the Impact on Breast Cancer Disparities
Collecting and reporting data on race and ethnicity is vital to understanding and addressing health disparities in the United States. These health disparities can include increased prevalence and severity of disease, poorer health outcomes, decreased access to healthcare, etc., in disadvantaged populations compared with advantaged groups. Without these data, researchers, administrators, public health practitioners, and policymakers are unable to identify the need for targeted interventions and assistance. When researching or reporting on race and ethnicity, typically broad racial categories are used. These include White or Caucasian, Black or African American, Asian American, Native Hawaiian or Other Pacific Islander, or American Indian and Alaska Native, as well as categories for ethnicity such as Latino or Hispanic or not Latino or Hispanic. These categories, defined by the Office of Management and Budget, are the minimum standards for collecting and reporting race and ethnicity data across federal agencies. Of note, these categories have not been updated since 1997. The lack of accurate and comprehensive data on marginalized racial and ethnic groups limits our understanding of and ability to address health disparities. This has implications for breast cancer outcomes in various populations in this country. In this paper, we examine the impact data inequity and the lack of data equity centered processes have in providing appropriate prevention and intervention efforts and resource allocations.
PMID: 37840113
ISSN: 1534-4681
CID: 5590182
Radial Scars/Complex Sclerosing Lesions of the Breast: Is Routine Excision Always Necessary? [Meeting Abstract]
ISI:000538247800277
ISSN: 1068-9265
CID: 5054082
Tumor and immune cell profiling in breast cancer using highly multiplexed imaging mass cytometry single-cell technology demonstrates tumor heterogeneity and immune phenotypic abnormality in Ethiopian women. [Meeting Abstract]
ISI:000587913100082
ISSN: 0008-5472
CID: 5054102
Flushing due to niacin deficiency in a patient with crohn's disease [Meeting Abstract]
Background: There have been rare reports of niacin deficiency in patients with Crohn's disease. We report a case in which a patient presented with flushing. Clinical case: A 31-year old woman with a history of Crohn's disease was referred by her dermatologist for flushing. Six months prior, she began experiencing erythema of the chest area every other day. The flushing was described as uncomfortable and pruritic, and she found it distressing. There were no identifiable precipitating factors, such as foods, exercise, or stress. There had been no new medications prescribed. She denied use of dietary supplements or herbal remedies. The patient was evaluated by an allergist & immunologist and it was determined that the rash was not due to an allergic reaction. The patient's history was notable for necrotizing enterocolitis as a newborn, requiring a partial colectomy, and an ileostomy that was reversed 2 years later. At age 10 years she was diagnosed with rectal and perianal Crohn's disease. Due to lack of response to glucocorticoids, sulfasalazine, and infliximab, the patient underwent an ileostomy 4 months prior to the onset of flushing. Of note, the patient did not have evidence of ileal Crohn's disease. She also has a history of polycystic ovarian syndrome. Her medications at the time of presentation were an estradiol-norelgestromin 150-35 mcg transdermal patch twice weekly and sulfasalazine 2000mg daily. Laboratory evaluation revealed a low vitamin 25(OH)D level at 16 ng/ml. Normal blood test results were found for CBC, Sma20, TSH, FT4, lipid profile, as well as an evaluation for polycystic ovarian syndrome including PL, testosterone, DHEAS, 17OHP, ACTH, serum cortisol, and HbA1c. Normal laboratory values were found for flushing and nutritional parameters included vitamin A and B12, 24 hour urine 5HIAA/creatinine, plasma metanephrines, and histamine, serum calcitonin, chromogranin A, and tryptase. The pattern of the rash was reminiscent of a milder form of textbook pictures of pellagra, a condition commonly referred to as the 3 D's: dermatitis, diarrhea, and dementia. Niacin is primarily absorbed in the ileum, much of which had been surgically resected in this patient. Therefore nicotinic acid and nicotinamide levels were sent and found to be undetectable, <20 ng/ml. The patient was prescribed one flush-free niacin tablet (Nature Made, USP, 500mg inositol hexanicotinate), along with B complex and vitamin D3 2000IU daily. The flushing resolved within two weeks. A repeat serum nicotinamide level at that time had risen to 26 ng/nl. Seven months later, the patient remains symptom free. Conclusion: Niacin deficiency should be included in the differential diagnosis of flushing, particularly in patients with a history of surgically resected ileum, or active ileal disease, which can both interfere with niacin absorption
EMBASE:617152883
ISSN: 0163-769x
CID: 2631992
Journal of the National Comprehensive Cancer Network : JNCCN. 2015:13(7):880-915.DOI: 10.6004/jnccn.2015.0105
Breast Cancer Risk Reduction, Version 2.2015
Breast cancer is the most frequently diagnosed malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. To assist women who are at increased risk of developing breast cancer and their physicians in the application of individualized strategies to reduce breast cancer risk, NCCN has developed these guidelines for breast cancer risk reduction.
PMID: 26150582
ISSN: 1540-1413
CID: 5749652
Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States [Case Report]
CONTEXT/BACKGROUND:More than 50% of Americans use dietary supplements, and 60-70% fail to report this use to their physicians. Intoxication from vitamin D supplements has been rarely reported but may now occur more frequently. This may be attributable to an increase in vitamin D supplement intake due to the findings that deficiency is common and has been associated with a number of disease states. OBJECTIVE:We report two cases of vitamin D intoxication with dietary supplements made in the United States caused by manufacturing and labeling errors. METHODS:Case histories were obtained, and serial laboratory data (calcium and vitamin D metabolites) were measured. Each dietary supplement was analyzed by UV spectrophotometry followed by HPLC. RESULTS:In both cases, repetitive inquiries were required to elicit the use of dietary supplements. Because of significant manufacturer errors and a labeling error, patients had been consuming more than 1000 times the recommended daily dose of vitamin D(3). Hypercalcemia is directly proportional to serum 25-hydroxyvitamin D [25(OH)D] but not 1,25-dihydroxyvitamin D levels. It took approximately 1 yr to normalize 25(OH)D levels. However, once 25(OH)D levels decreased below 400 ng/ml, both patients became normocalcemic and asymptomatic without long-term sequelae. CONCLUSIONS:Although rare, vitamin D intoxication should be considered in the differential diagnosis of hypercalcemia. Patients should be asked whether they are using dietary supplements, and serial questioning may be required because patients may not consider these supplements to be potential health risks. Errors in the manufacturing and labeling of dietary supplements made in the United States may place individuals at increased risks for side effects.
PMID: 21917864
ISSN: 1945-7197
CID: 3764392
Clinical cancer advances 2010: annual report on progress against cancer from the American Society of Clinical Oncology
PMID: 21060039
ISSN: 1527-7755
CID: 120617
