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Barthelemy Diouf Claudia Wing John C. Panetta Donnie Eddins Wenwei Lin Wenjian Yang Yiping Fan Deqing Pei Cheng Cheng Shannon M. Delaney Wei Zhang Erik J. Bonten Kristine R. Crews Steven W. Paugh Lie Li Burgess B. Freeman rd Robert J. Autry Jordan A. Beard Daniel C. Ferguson Laura J. Janke Kirsten K. Ness Taosheng Chen Stanislav S. Zakharenko Sima Jeha ChingHon Pui Mary V. Relling M. Eileen Dolan William E. Evans 《CTS Clinical and Translational Science》2021,14(4):1490
Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose‐limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR‐induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human‐induced pluripotent stem cell‐derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR’s antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication. Study Highlights
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Se Yong Jung Min Seo Kim Han Li Keum Hwa Lee Ai Koyanagi Marco Solmi Andreas Kronbichler Elena Dragioti Kalthoum Tizaoui Sarah Cargnin Salvatore Terrazzino Sung Hwi Hong Ramy Abou Ghayda Nam Kyun Kim Seo Kyoung Chung Louis Jacob JoeElie Salem Dong Keon Yon Seung Won Lee Karel Kostev Ah Young Kim Jo Won Jung Jae Young Choi Jin Soo Shin SoonJung Park Seong Woo Choi Kiwon Ban SungHwan Moon Yun Young Go Jae Il Shin Lee Smith 《CTS Clinical and Translational Science》2022,15(2):501
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Treatment effectiveness in a rare oncology indication: Lessons from an external control cohort study
Dina Oksen Patricia Prince Emmanuelle Boutmy Elizabeth M. Garry Barbara EllersLenz Adina Estrin Andreas Johne Patrice Verpillat Nicolle M. Gatto 《CTS Clinical and Translational Science》2022,15(8):1990
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Sydney Thomas Julia M. Gauglitz Anupriya Tripathi Fernando Vargas Kerri Bertrand Jae H. Kim Christina Chambers Pieter C. Dorrestein Shirley M. Tsunoda 《CTS Clinical and Translational Science》2022,15(11):2576
Human milk is the optimal infant nutrition. However, although human‐derived metabolites (such as lipids and oligosaccharides) in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n = 996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules, such as medications and their metabolites, and industrial sources, such as plasticizers, cosmetics, and other personal care products, are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn''s stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent. Study Highlights
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6.
Junxiang Wen Yinyin Cao Yang Li Fenhua Zhu Meifen Yuan Jin Xu Jian Li 《CTS Clinical and Translational Science》2021,14(4):1327
Pediatric urolithiasis is a common urologic disease with high morbidity and recurrence rates. Recent studies have shown that metabolic dysfunction plays a vital role in the pathogenesis of urolithiasis, especially in children, but the specific mechanism is still unclear. Metabolomics is an ideal technology for exploring the mechanism of metabolic disorders in urolithiasis. In the present study, a serum metabolomics based on ultra‐performance liquid chromatography mass spectrometry was performed. A total of 50 children subjects were recruited for the study, including 30 patients with kidney stones and 20 normal controls (NCs). Principal component analysis and orthogonal partial least‐squares determinant analysis were carried, and 40 metabolites were found to be significantly altered in patients with kidney stones, mainly involving retinol metabolism, steroid hormone biosynthesis, and porphyrin and chlorophyll metabolism. The kidney stone group appeared to have a lower serum level of bilirubin, but a relative higher level of retinal, all‐transretinoic acid, progesterone, and prostaglandin E2 compared with those of the NC group. All the findings suggest that patients with urolithiasis have several metabolic characteristics, which are related to stone formation or compensation. These metabolites and pathways are very likely associated with development of kidney stones and should be considered as potential novel targets for treatment and prevention. Study Highlights
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Michael Boettcher Gerd Mikus Dietmar Trenk HansDirk Düngen Frank Donath Nikos Werner Mahir Karakas Nina Besche Dominik SchulzBurck Mireille Gerrits James Hung Corina Becker 《CTS Clinical and Translational Science》2022,15(5):1204
Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long‐acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co‐administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double‐blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co‐administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty‐five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline‐ and placebo‐adjusted vital signs showed reductions of 1.4–5.1 mmHg (systolic blood pressure) and 0.4–2.9 mmHg (diastolic blood pressure) and increases of 0.0–1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose‐dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well‐tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate. Study Highlights
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Andrea Edwards Ashley TeusinkCross Lisa J. Martin Cynthia A. Prows Parinda A. Mehta Laura B. Ramsey 《CTS Clinical and Translational Science》2022,15(3):610
Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings. Study Highlights
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Johan L. van der Plas Michiel J. van Esdonk Ingrid M. C. Kamerling Adam F. Cohen 《CTS Clinical and Translational Science》2021,14(6):2391
Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy. Clinical trial simulations were used to assess the effects of utilizing these so‐called “hot spot strategy” compared to a traditional vaccine field trial. We used preset parameters of a pandemic outbreak and incorporated realistic aspects of conducting a trial in a pandemic setting. Our simulations demonstrated that incorporating a hot spot strategy shortened the duration of the vaccine trial considerably, even if only one hot spot was identified during the clinical trial. The active hot spot strategy described in this paper has clear advantages compared to a “wait‐and‐see” approach that is used in traditional vaccine efficacy trials. Completion of a clinical trial can be expedited by adapting to resurgences and outbreaks that will occur in a population during a pandemic. However, this approach requires a speed of response that is unusual for a traditional phase III clinical trial. Therefore, several recommendations are made to help accomplish rapid clinical trial setup in areas identified as local outbreaks. The described model and hot spot vaccination strategy can be adjusted to disease‐specific transmission characteristics and could therefore be applied to any future pandemic threat. Study Highlights
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12.
Darius L. Mason Kavitha Godugu Daryl Nnani Shaker A. Mousa 《CTS Clinical and Translational Science》2022,15(2):353
Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values. Study Highlights
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Solne M. Laville Oriane Lambert Aghiles Hamroun Marie Metzger Christian Jacquelinet Maurice Laville Luc Frimat Denis Fouque Christian Combe Carole Ayav Roberto PecoitsFilho Bndicte Stengel Ziad A. Massy Sophie Liabeuf the CKDREIN Study Collaborators 《CTS Clinical and Translational Science》2021,14(6):2242
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Shinji Yamazaki 《CTS Clinical and Translational Science》2021,14(4):1412
The primary goal of precision medicine is to maximize the benefit‐risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene‐drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA‐PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug‐metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate. Study Highlights
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Lisa B. Mahoney Charles R. Esther Jr Kara May Rachel Rosen 《CTS Clinical and Translational Science》2021,14(5):2025
Although respiratory symptoms in children are often attributed to gastroesophageal reflux disease, establishing a clear diagnosis of extraesophageal reflux disease (EERD) can be challenging, as there are no sensitive or specific EERD biomarkers. The aim of this study was to evaluate the metabolite profile in bronchoalveolar (BAL) fluid from children with suspected EERD and assess the impact of reflux treatment on these metabolites. In this prospective pilot study, we performed nontargeted global metabolomic profiling on BAL fluid from 43 children undergoing testing with bronchoscopy, upper endoscopy, and multichannel intraluminal impedance with pH (pH‐MII) for evaluation of chronic respiratory symptoms. Twenty‐three (54%) patients had an abnormal pH‐MII study. Seventeen (40%) patients were on proton pump inhibitors (PPIs) for testing. Levels of histamine, malate, adenosine 5′‐monophosphate, and ascorbate were significantly lower in subjects with abnormal pH‐MII studies compared to those normal studies. Furthermore, in children off PPI therapy, those with abnormal pH‐MII studies had robust increases in a number of glycerophospholipids within phospholipid metabolic pathways, including derivatives of glycerophosphorylcholine, glycerophosphoglycerol, and glycerophosphoinositol, compared to those with normal pH‐MII studies. These findings offer insight into the impact of reflux and PPIs on the lungs and provide a foundation for future studies using targeted metabolomic analysis to identify potential biomarkers of EERD. Study Highlights
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16.
Rui Zhang Zaixiao Tao Jing Gong Zhenjun Ji Mingming Yang Genshan Ma Yongjun Li 《CTS Clinical and Translational Science》2022,15(5):1187
In‐stent restenosis is a common complication after percutaneous coronary intervention (PCI) for coronary heart disease requiring revascularization. We performed a retrospective analysis to assess the value of inflammatory biomarker albumin to globulin ratio (AGR) in clinical prognosis of PCI. In total, 992 patients with coronary heart disease who underwent the first drug‐eluting stent implantation and re‐examination angiography in our hospital were enrolled in this study. The AGR was measured. At mean follow‐up of 11.2 ± 4 months, the in‐stent restenosis (ISR) and revascularization events (including target lesion revascularization, target vessel revascularization, and revascularization of de novo lesions) occurred in 127 and 284 patients, respectively. Compared with the non‐ISR or non‐event group, AGR was significantly lower in the ISR group and the events group. Beyond that, albumin was significantly lower, whereas urea nitrogen, glucose, and Gensini score, as well as the proportions of a history of diabetes and peripheral vascular diseases were significantly higher in the ISR group and the events group. Age, heart rate, white blood cell, neutrophils, lymphocyte, monocyte, and incidence of ischemic stroke were significantly higher in the events group. Multivariate Cox regression analysis showed that AGR was independently associated with ISR (p = 0.032) and events (p = 0.024). Besides, Kaplan‐Meier analysis indicated that the higher quartile of AGR had a lower rate of ISR (p = 0.038) and events (p ≤ 0.001). Finally, the receiver operating characteristic curve for AGR in diagnosing ISR and events indicated that the area under the curve were 0.56 and 0.57, respectively. Therefore, AGR is one of the most important factors that independently associate with the ISR and revascularization events after PCI. Study Highlights
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17.
Xun Bao Jianmei Wu Jun Jiang AnChi Tien Nader Sanai Jing Li 《CTS Clinical and Translational Science》2021,14(4):1265
This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies. Study Highlights
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18.
Jason N. Barreto Joel M. Reid Carrie A. Thompson Kristin C. Mara Andrew D. Rule Kianoush B. Kashani Nelson Leung Thomas
R. Larson Renee M. McGovern Thomas E. Witzig Erin F. Barreto 《CTS Clinical and Translational Science》2022,15(1):105
High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management. Study Highlights
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19.
Rahul K. Goyal Shamir N. Kalaria Susan L. McElroy Mathangi Gopalakrishnan 《CTS Clinical and Translational Science》2022,15(12):2878
Randomized, placebo‐controlled trials for binge eating disorder (BED) have revealed highly variable, and often marked, rates of short‐term placebo response. Several quantitative based analyses in patients with BED have inconsistently demonstrated which patient factors attribute to an increase in placebo response. The objective of this study is to utilize machine learning (ML) algorithms to identify moderators of placebo response in patients with BED. Data were pooled from 12 randomized placebo‐controlled trials evaluating different treatment options for BED. The final dataset consisted of 189 adults receiving placebo with complete information of baseline variables. Placebo responders were defined as patients experiencing ≥75% reduction in binge eating frequency (BEF) at study end point. Nine patient prerandomization variables were included as predictors. Patients were divided into training and testing subsets according to an 75%:25% distribution while preserving the proportion of placebo responders. All analysis was performed in the software Pumas 2.0. Gaussian Naïve Bayes algorithm showed the best cross‐validation accuracy (~64%) and was chosen as the final algorithm. Shapley analysis suggested that patients with low baseline BEF and anxiety status were strong moderators of placebo response. Upon applying the final algorithm on the test dataset, the resulting sensitivity was 88% and prediction accuracy was 72%. This is the first application of ML to identify moderators of placebo response in BED. The results of this analysis confirm previous findings of lesser baseline disease severity and adds that patients with no anxiety are more susceptible to placebo response. Study Highlights
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Jihyun Kang Andrew HyoungJin Kim Inseung Jeon Jaeseong Oh InJin Jang SeungHwan Lee JooYoun Cho 《CTS Clinical and Translational Science》2022,15(5):1104
Five‐fluorouracil (5‐FU) is a chemotherapeutic agent that is mainly metabolized by the rate‐limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5‐FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography‐quantitative time‐of‐flight‐mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q‐value < 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency. Study Highlights
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