Front Oncol. 2021 Jul 20;11:687564. doi: 10.3389/fonc.2021.687564. eCollection 2021.

ABSTRACT

PURPOSE: The purpose of this study was to retrospectively analyze the safety and clinical efficacy of anlotinib combined with dose-dense temozolomide (TMZ) as the first-line therapy in the treatment of recurrent glioblastoma (rGBM).

PATIENTS AND METHODS: We collected the clinical data of 20 patients with rGBM. All patients received anlotinib (12 mg daily, orally for 2 weeks, discontinued for 1 week, repeated every 3 weeks) combined with dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until the disease progressed (PD) or adverse effects (AEs) above grade 4 appeared. Grade 3 AEs need to be restored to grade 2 before continuing treatment, and the daily dose of anlotinib is reduced to 10 mg. The patients were reexamined by head magnetic resonance imaging (MRI) every 1 to 3 months. The therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology (RANO) criteria. The survival rate was analyzed by Kaplan-Meier survival curve analysis. The baseline of all survival index statistics was the start of anlotinib combined with dose-dense of TMZ. National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 4.0) was used to evaluate AEs.

RESULTS: Twenty cases of rGBM were evaluated according to the RANO criteria after treatment with anlotinib and dose-dense TMZ, including five cases of stable disease (SD), thirteen cases of partial response (PR), one case of complete response (CR), and one case of PD. The median follow-up time was 13.4 (95% CI, 10.5-16.3) months. The 1-year overall survival (OS) rate was 47.7%. The 6-month progression-free survival (PFS) rate was 55%. In the IDH wild type group, the median PFS and median OS were 6.1 and 11.9 months, respectively. We observed that AEs associated with treatment were tolerable. One patient stopped taking the drug because of cerebral infarction. There were no treatment-related deaths.

CONCLUSION: Anlotinib combined with dose-dense TMZ for the first-line therapy showed good efficacy in OS, PFS, ORR, and DCR in the treatment of rGBM, and the AEs were tolerant. Randomized controlled clinical trials investigating the treatment of rGBM with anlotinib are necessary.

PMID:34354945 | PMC:PMC8330423 | DOI:10.3389/fonc.2021.687564

Nat Methods. 2021 Aug;18(8):903-911. doi: 10.1038/s41592-021-01222-3. Epub 2021 Aug 5.

ABSTRACT

The development of DNA-barcoded antibodies to tag cell surface molecules has enabled the use of droplet-based single-cell sequencing (dsc-seq) to profile protein abundances from thousands of cells simultaneously. As compared to flow and mass cytometry, the high per cell cost of current dsc-seq-based workflows precludes their use in clinical applications and large-scale pooled screens. Here, we introduce SCITO-seq, a workflow that uses splint oligonucleotides (oligos) to enable combinatorially indexed dsc-seq of DNA-barcoded antibodies from over 105 cells per reaction using commercial microfluidics. By encoding sample barcodes into splint oligos, we demonstrate that multiplexed SCITO-seq produces reproducible estimates of cellular composition and surface protein expression comparable to those from mass cytometry. We further demonstrate two modified splint oligo designs that extend SCITO-seq to achieve compatibility with commercial DNA-barcoded antibodies and simultaneous expression profiling of the transcriptome and surface proteins from the same cell. These results demonstrate SCITO-seq as a flexible and ultra-high-throughput platform for sequencing-based single-cell protein and multimodal profiling.

PMID:34354295 | DOI:10.1038/s41592-021-01222-3

PLoS One. 2021 Aug 5;16(8):e0254875. doi: 10.1371/journal.pone.0254875. eCollection 2021.

ABSTRACT

Evidence for the real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on preterm birth is unclear, as available series report composite pregnancy outcomes and/or do not stratify patients according to disease severity. The purpose of the research was to determine the real impact of asymptomatic/mild SARS-CoV-2 infection on preterm birth not due to maternal respiratory failure. This case-control study involved women admitted to Sant Anna Hospital, Turin, for delivery between 20 September 2020 and 9 January 2021. The cumulative incidence of Coronavirus disease-19 was compared between preterm birth (case group, n = 102) and full-term delivery (control group, n = 127). Only women with spontaneous or medically-indicated preterm birth because of placental vascular malperfusion (pregnancy-related hypertension and its complications) were included. Current or past SARS-CoV-2 infection was determined by nasopharyngeal swab testing and detection of IgM/IgG antibodies in blood samples. A significant difference in the cumulative incidence of Coronavirus disease-19 between the case (21/102, 20.5%) and the control group (32/127, 25.1%) (P= 0.50) was not observed, although the case group was burdened by a higher prevalence of three known risk factors (body mass index > 24.9, asthma, chronic hypertension) for severe Coronavirus disease-19. Logistic regression analysis showed that asymptomatic/mild SARS-CoV-2 infection was not an independent predictor of spontaneous and medically-indicated preterm birth due to pregnancy-related hypertension and its complications (0.77; 95% confidence interval, 0.41-1.43). Pregnant patients without comorbidities need to be reassured that asymptomatic/mild SARS-CoV-2 infection does not increase the risk of preterm delivery. Preterm birth and severe Coronavirus disease-19 share common risk factors (i.e., body mass index > 24.9, asthma, chronic hypertension), which may explain the high rate of indicated preterm birth due to maternal conditions reported in the literature.

PMID:34351922 | DOI:10.1371/journal.pone.0254875

Paediatr Drugs. 2021 Aug 5. doi: 10.1007/s40272-021-00463-1. Online ahead of print.

ABSTRACT

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

PMID:34351604 | DOI:10.1007/s40272-021-00463-1

JAMA Netw Open. 2021 Aug 2;4(8):e2119600. doi: 10.1001/jamanetworkopen.2021.19600.

ABSTRACT

IMPORTANCE: In the literature on opioid use disorder (OUD), opioid abstinence is used as an outcome measure for individuals receiving medication-assisted treatment (MAT), without consideration of patient-reported goals (PRGs).

OBJECTIVES: To identify common PRGs for youths receiving MAT for OUD and assess whether these patients achieve their stated goals.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study examined data from 152 individuals aged 16 to 25 years (noninclusive) recruited between May 22, 2018, and March 11, 2020, from 45 outpatient MAT clinics in the Pharmacogenetics of Opioid Substitution Treatment Response study. Youths receiving MAT for OUD were included and were followed up for 3 months.

EXPOSURES: Medication-assisted treatment for OUD.

MAIN OUTCOMES AND MEASURES: The frequency of each PRG; the success of goal attainment, compared between those who reported specific PRGs and those who did not; and associations between reporting certain goals and achieving them.

RESULTS: Among the 152 youths in the study, 82 were male (53.9%), and the mean (SD) age was 22.8 (1.8) years. Ten overarching goals were identified, with the most common being to taper the dose of or stop MAT (96 [63.2%]), avoid use of recreational substances (71 [46.7%]), manage OUD symptoms (25 [16.4%]), live a normal life (14 [9.2%]), improve mental health (11 [7.2%]), and gain employment (8 [5.3%]). Overall, individuals who reported PRGs had similar odds of achieving them as those who did not for the goals of taper dose of or stop MAT (OR, 1.98; 95% CI, 0.88-4.46; P = .10), avoid recreational substances (OR, 1.34; 95% CI, 0.65-2.74; P = .43), manage OUD symptoms (β coefficient, -0.93; 95% CI, -4.24 to 2.38; P = .58), and improve mental health (β coefficient, -0.76; 95% CI, -6.31 to 4.78; P = .79). Furthermore, multivariable logistic regression showed that goals to taper the dose of or stop MAT (odds ratio, 1.90; 95% CI, 0.78-4.63; P = .16) or avoid recreational substances (odds ratio, 1.27; 95% CI, 0.60-2.67; P = .53) were not associated with achieving these respective outcomes.

CONCLUSIONS AND RELEVANCE: This study suggests that youths have highly variable PRGs regarding MAT for OUD and that reporting a goal may not mean one is at higher odds of achieving it. There is a need to develop treatment plans that effectively incorporate PRGs. In addition, the finding that most youths aim to minimize or stop their MAT dose warrants the creation of a tapering protocol to guide clinicians. Because a diagnosis of OUD has substantial psychosocial implications in this population, clinicians must ensure that these dimensions of care are part of routine clinical practice.

PMID:34351402 | DOI:10.1001/jamanetworkopen.2021.19600

Br J Clin Pharmacol. 2021 Aug 4. doi: 10.1111/bcp.15022. Online ahead of print.

ABSTRACT

AIM: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS). Although genetic polymorphisms of the human leukocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients.

METHODS: Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined.

RESULTS: Only two HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% CI = 20.24-97.09, Pc = 6.80 x 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an OR of 81.00 (95% CI =32.39-202.56, Pc = 3.84 x 10-34 ). There is no association between EPHX1 c.337T>C polymorphism and all phenotypes of CBZ-induced SCARs.

CONCLUSION: The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.

PMID:34350628 | DOI:10.1111/bcp.15022

Oxid Med Cell Longev. 2021 Jul 24;2021:7571132. doi: 10.1155/2021/7571132. eCollection 2021.

ABSTRACT

The Glycyrrhiza genus, generally well-known as licorice, is broadly used for food and medicinal purposes around the globe. The genus encompasses a rich pool of bioactive molecules including triterpene saponins (e.g., glycyrrhizin) and flavonoids (e.g., liquiritigenin, liquiritin). This genus is being increasingly exploited for its biological effects such as antioxidant, antibacterial, antifungal, anti-inflammatory, antiproliferative, and cytotoxic activities. The species Glycyrrhiza glabra L. and the compound glycyrrhizin (glycyrrhizic acid) have been studied immensely for their effect on humans. The efficacy of the compound has been reported to be significantly higher on viral hepatitis and immune deficiency syndrome. This review provides up-to-date data on the most widely investigated Glycyrrhiza species for food and medicinal purposes, with special emphasis on secondary metabolites' composition and bioactive effects.

PMID:34349875 | PMC:PMC8328722 | DOI:10.1155/2021/7571132

J Asthma Allergy. 2021 Jul 28;14:929-941. doi: 10.2147/JAA.S316278. eCollection 2021.

ABSTRACT

BACKGROUND: Little information is known about the health-related quality of life (HRQOL) and the patient's preference values by the severity of asthma. We evaluated the HRQOL and health utility impairment associated with asthma severity using the SF-12 and SF-6D.

METHODS: We conducted a cross-sectional analysis of 2010-2016 Medical Expenditure Panel Survey database of asthma patients aged ≥18 years and categorized them into mild, moderate, and severe asthma. Study outcomes included the SF-12 physical component summary (PCS) and mental component summary (MCS) for measuring HRQOL and SF-6D for health utility. Survey regression models were used to estimate HRQOL and utilities for mild, moderate, and severe asthma.

RESULTS: Of 10,222 patients with asthma, 75.4%, 23.9%, and 0.8% had mild, moderate and severe asthma. We observed that the greater the severity, the lower the SF-6D scores: 0.731 in mild, 0.723 in moderate, and 0.659 in severe asthma (P < 0.001). Patients with severe asthma had a significantly lower PCS compared to those with mild asthma (-5.3; P < 0.001) but there was no significant difference in MCS (-1.9; P = 0.309) controlling for socioeconomic and clinical variables. Asthma severity, women, older age, and having a lower level education and public insurance were significantly associated with lower PCS (P < 0.01).

CONCLUSION: Asthma patients had worse physical HRQOL than mental health, especially patients with severe asthma. These data suggest that the management of physical health of female, older aged, and low education patients with asthma should be focused on improving HRQOL.

PMID:34349523 | PMC:PMC8326771 | DOI:10.2147/JAA.S316278

BMJ Open Diabetes Res Care. 2021 Aug;9(1):e002296. doi: 10.1136/bmjdrc-2021-002296.

ABSTRACT

INTRODUCTION: Zinc transporter 8 autoantibodies (ZnT8A) are biomarkers of beta cell autoimmunity in type 1 diabetes that have become more widely available to clinicians in recent years. Robust control population-defined thresholds are essential to ensure high clinical specificity in islet autoantibody testing. We aimed to determine the optimal cut-offs for ZnT8A testing.

RESEARCH DESIGN AND METHODS: 97.5th and 99th centile cut-offs were determined using residual clinical sera from 1559 controls aged between 0 and 83 years with no history of diabetes and a hemoglobin A1c level of less than 6.0% (<42 mmol/mol). ZnT8A were measured by ELISA (RSR, Cardiff, UK) on a Dynex DS2 ELISA robot (Dynex, Preston, UK). We assessed the impact of age-related cut-offs in comparison with the manufacturer's recommended threshold in a mixed cohort of young-onset (<age 30) diabetes (UNITED study (Using pharmacogeNetics to Improve Treatment in Early-onset Diabetes), n=145).

RESULTS: Using the manufacturer's limit of detection, 6 WHO U/mL, 16.2% of people in the control cohort had detectable levels of ZnT8A and those who had detectable ZnT8A were much more likely to be younger (p<0.0001). The 97.5th and 99th centile thresholds were substantially higher in younger participants: 18 and 127 WHO U/mL (tested under 30 years) in comparison with 9 and 21 WHO U/mL (tested 30 years and over). In the UNITED cohort some of those found to be ZnT8A-positive by the manufacturer's threshold but negative using the appropriate 99% centile cut-off (127 WHO U/mL) displayed characteristics suggestive of type 2 diabetes.

CONCLUSIONS: Age-related thresholds are needed for ZnT8A testing. In those aged <30 years, use of manufacturers' recommended cut-offs may result in low test specificity and potentially high rates of false positive test results in patients who do not have autoimmune diabetes.

PMID:34348918 | DOI:10.1136/bmjdrc-2021-002296

Anticancer Agents Med Chem. 2021 Aug 3. doi: 10.2174/1871520621666210804100547. Online ahead of print.

ABSTRACT

Breast cancer (BC) is a molecular heterogeneous disease and often patients with similar clinico-pathological characteristics may display different response to treatment. Cellular processes, including uncontrolled cell-cycle, constitutive activation of signalling pathways parallel to or downstream of HER2 and alterations in DNA-repair mechanisms are the main features altered in the tumor. These cellular processes play significant roles in the emergence of therapy resistance. The introduction of target therapies as well as immunotherapies has improved the management of breast cancer. Furthermore, several therapeutic options are available to overcome resistance and physicians could overcome the challenge of resistant BC using combinatorial drug strategies and incorporating novel biomarkers. Molecular profiling promises to help in refine personalized treatment decisions and catalyse the development of further strategies when resistances inevitably occur. The search for biological explanations for treatment failure helps to clarify the phenomenon and allows to incorporate new biomarkers into clinical practice that can lead to adequate solutions to overcome it. This review provides a summary of genetic and molecular aspects of resistance mechanisms to available treatments for BC patients, and its clinical implications.

PMID:34348634 | DOI:10.2174/1871520621666210804100547

J Asthma. 2021 Aug 4:1-12. doi: 10.1080/02770903.2021.1963769. Online ahead of print.

ABSTRACT

Objective: Benralizumab is a promising drug for severe uncontrolled asthma. This study aimed to clarify the effectiveness of benralizumab in a real-life setting.Methods: Subjects included 24 patients with severe type 2 asthma who received benralizumab between April 2018 and July 2019. Changes in parameters, exacerbation frequency, and oral corticosteroid (OCS) use after 4 and 24 weeks of administration were examined. The parameters included the Global Evaluation of Treatment Effectiveness (GETE) scale, Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), blood eosinophils, fractional exhaled nitric oxide (FeNO), and spirometry. The response to treatment was defined as follows: for patients with exacerbations or OCS use before treatment initiation, a reduction of ≥50% in exacerbation frequency or OCS use; and for patients without exacerbations or OCS use, an improvement of ≥0.5 in ACQ scores and ≥3 in ACT scores, or of ≥10.38% in FEV1.Results: Twenty-one patients completed the treatment for 24 weeks. Excellent and good GETE scales and ACQ and ACT improvement were found in 67% of the patients at 4 weeks, and the effect continued until 24 weeks. The patients' rate with exacerbations was significantly reduced compared to the previous 24 weeks before administration. In 17 patients receiving OCS, the use could be reduced or quit in 14 patients. Overall, 16 patients (76.2%) met the responder definition and could be predicted by the baseline eosinophil count and FeNO levels with the best cut-off values of 100/μL and 40 ppb, respectively.Conclusions: Blood eosinophil and FeNO could predict benralizumab effectiveness.

PMID:34348060 | DOI:10.1080/02770903.2021.1963769

PLoS One. 2021 Aug 4;16(8):e0255645. doi: 10.1371/journal.pone.0255645. eCollection 2021.

ABSTRACT

BACKGROUND: Dual antiplatelet therapy (DAPT) is currently the standard treatment for the prevention of ischemic events after stent implantation. However, the optimal DAPT duration remains elusive for patients with chronic kidney disease (CKD). Therefore, we aimed to compare the effectiveness and safety between long-term and short-term DAPT after coronary stenting in patients with CKD.

METHODS: This retrospective cohort study analyze data from the Taipei Medical University (TMU) Institutional and Clinical Database, which include anonymized electronic health data of 3 million patients that visited TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital. We enrolled patients with CKD after coronary stenting between 2008 and 2019. The patients were divided into the long-term (>6 months) and short-term DAPT group (≤ 6 months). The primary end point was major adverse cardiovascular events (MACE) from 6 months after the index date. The secondary outcomes were all-cause mortality and Thrombolysis in Myocardial Infarction (TIMI) bleeding.

RESULTS: A total of 1899 patients were enrolled; of them, 1112 and 787 were assigned to the long-term and short-term DAPT groups, respectively. Long-term DAPT was associated with similar risk of MACE (HR: 1.05, 95% CI: 0.65-1.70, P = 0.83) compare with short-term DAPT. Different CKD risk did not modify the risk of MACE. There was also no significant difference in all-cause mortality (HR: 1.10, 95% CI: 0.75-1.61, P = 0.63) and TIMI bleeding (HR 1.19, 95% CI: 0.86-1.63, P = 0.30) between groups.

CONCLUSIONS: Among patients with CKD and coronary stenting, we found that long-term and short-term DAPT tied on the risk of MACE, all-cause mortality and TIMI bleeding.

PMID:34347826 | DOI:10.1371/journal.pone.0255645

J Pediatr Gastroenterol Nutr. 2021 Aug 3. doi: 10.1097/MPG.0000000000003271. Online ahead of print.

ABSTRACT

BACKGROUND: Azithromycin has been shown to improve gastrointestinal motility in adults and may have fewer drug interactions and reduced arrhythmogenic effects than erythromycin. We hypothesized that azithromycin is comparable to erythromycin in eliciting pharmacodynamic outcomes for antral and small bowel motility.

OBJECTIVE: To compare the pharmacodynamic effectiveness of azithromycin and erythromycin for eliciting antral and duodenal motility in pediatric patients who underwent antroduodenal manometry for different indications.

METHODS: We conducted a retrospective comparison of clinic data and manometric pharmacodynamics outcomes in patients who underwent antroduodenal manometry between 2013 and 2017.

RESULTS: Fifty-one patients mean age (± SD) 9.7(5.4) years, received either azithromycin 3 mg/kg (n = 20) or erythromycin 2 mg/kg (n = 31) during antroduodenal manometry. For patients receiving erythromycin, mean AUC across all 8 pressure ports increased from median[95%CI] 2256[1585, 2602] to 8742[5876,11761] mmHg x sec (p < 0.001) and mean motility index increased from 8.63[7.87,9.42] to 11.98[11.20,12.21] (p < 0.001). For patients receiving azithromycin, mean AUC increased from 2255[1585,2602] to 8254[5649,10470] mm Hg x sec (p < 0.001) and motility index increased from 8.63[7.87,9.42] to 11.79[11.03,12.21] (p < 0.001). Neither mean stimulated AUC nor mean motility index was significantly different between azithromycin and erythromycin treatments. There was no significant difference in side effects between groups.

CONCLUSIONS: Azithromycin and erythromycin have similar pharmacodynamic effects on antral and small bowel contractility in children. Azithromycin should be considered an acceptable alternative to erythromycin as an upper GI tract prokinetic for children and has historically had fewer side effects than erythromycin.

PMID:34347676 | DOI:10.1097/MPG.0000000000003271

Brief Bioinform. 2021 Aug 4:bbab271. doi: 10.1093/bib/bbab271. Online ahead of print.

ABSTRACT

Drug combinations have exhibited promising therapeutic effects in treating cancer patients with less toxicity and adverse side effects. However, it is infeasible to experimentally screen the enormous search space of all possible drug combinations. Therefore, developing computational models to efficiently and accurately identify potential anti-cancer synergistic drug combinations has attracted a lot of attention from the scientific community. Hypothesis-driven explicit mathematical methods or network pharmacology models have been popular in the last decade and have been comprehensively reviewed in previous surveys. With the surge of artificial intelligence and greater availability of large-scale datasets, machine learning especially deep learning methods are gaining popularity in the field of computational models for anti-cancer drug synergy prediction. Machine learning-based methods can be derived without strong assumptions about underlying mechanisms and have achieved state-of-the-art prediction performances, promoting much greater growth of the field. Here, we present a structured overview of available large-scale databases and machine learning especially deep learning methods in computational predictive models for anti-cancer drug synergy prediction. We provide a unified framework for machine learning models and detail existing model architectures as well as their contributions and limitations, shedding light into the future design of computational models. Besides, unbiased experiments are conducted to provide in-depth comparisons between reviewed papers in terms of their prediction performance.

PMID:34347041 | DOI:10.1093/bib/bbab271

Eur J Oral Sci. 2021 Aug 4. doi: 10.1111/eos.12819. Online ahead of print.

ABSTRACT

Fascin 1 plays important pro-metastatic roles in head and neck carcinoma (HNSCC) migration, invasion, and metastasis. However, limited advancement in targeting metastasis remains a major obstacle in improving HNSCC patients' survival. Therefore, we assessed the therapeutic potential of fascin 1 targeted inhibition and its potential prognostic value in HNSCC patients. Using in vitro and in vivo approaches, we investigated the effect of compound G2, a novel fascin 1 inhibitor, on HNSCC cells migration, invasion, and metastasis. High-throughput screening (HTS) was used to assess cytotoxic activity of compound G2 alone or combined with irradiation. We also evaluated the prognostic potential of fascin 1 in HNSCC patients. Interestingly, compound G2 reduced carcinoma cells migration and invasion in vitro and inhibited metastasis in vivo. Moreover, HTS revealed a modest cytotoxic activity of the compound G2 on HNSCC cell lines. Irradiation did not synergistically enhance the compound G2-mediated cytotoxic activity. Survival analyses showed that high fascin 1 immunoexpression, at the tumor invasive front, was associated with cancer-specific mortality in the advanced stages of HNSCC. Collectively, our findings suggest that fascin 1 represents a promising anti-metastatic therapeutic target and a useful prognostic marker in patients with HNSCC. Novel anti-metastatic agents could provide a valuable addition to cancer therapy.

PMID:34346523 | DOI:10.1111/eos.12819

Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):e2019318118. doi: 10.1073/pnas.2019318118.

ABSTRACT

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.

PMID:34344824 | DOI:10.1073/pnas.2019318118

Pharmacogenomics. 2021 Aug 4. doi: 10.2217/pgs-2021-0090. Online ahead of print.

NO ABSTRACT

PMID:34344160 | DOI:10.2217/pgs-2021-0090

J Clin Pharm Ther. 2021 Aug 3. doi: 10.1111/jcpt.13493. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (FK506), an effective and potent calcineurin inhibitor, is the cornerstone of immunosuppression after kidney transplantation. Wuzhi capsule (WZC), a prescribed ethanol extract of Nan-Wuweizi (Schisandra sphenanthera), is widely prescribed for kidney transplant recipients for the maintenance of tacrolimus concentration in clinical settings. Previous studies have demonstrated that WZC can increase the blood concentration of tacrolimus. However, it remains controversial whether to use WZC can be used to increase tacrolimus concentration in clinical practice. Our study aimed to evaluate the efficacy and safety of WZC combined with tacrolimus in the treatment of kidney transplant recipients.

METHODS: One hundred and ninety four Chinese kidney transplant recipients were included in this retrospective study. The recipients were divided into two groups (non-WZC group and WZC group). We investigated the effects of WZC on tacrolimus in terms of tacrolimus metabolism, laboratory tests, pharmacogenomics, renal function and adverse reactions.

RESULTS AND DISCUSSION: The concentration/dose (C0 /D) of tacrolimus was significantly higher in the WZC group than the non-WZC group. The laboratory findings of blood routine tests, liver and kidney function were not significantly different between the two groups. The CYP3A5 genotype showed clearly associated with tacrolimus C0 /D, whereas no significant difference was observed in patients with CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. The improvement of C0 /D by administration of WZC was significant in CYP3A5 expressers compared to non-expressers. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached the target tacrolimus concentration than the non-WZC group. No significant differences in renal function and adverse reactions were observed between the groups.

WHAT IS NEW AND CONCLUSION: Wuzhi capsule can increase tacrolimus concentration without negative effects on renal function and adverse reactions, especially in CYP3A5 expressers. Efficient and economical synergistic effects can be achieved by the combined administration of WZC in kidney transplant recipients.

PMID:34342024 | DOI:10.1111/jcpt.13493

Cancer Biother Radiopharm. 2021 Aug 2. doi: 10.1089/cbr.2021.0152. Online ahead of print.

ABSTRACT

The landscape of nuclear oncology is rapidly changing. The advent of molecular radionuclide theranostics, multidisciplinary tumor board decision making, artificial intelligence and radiomics interpretation of diagnostic imaging, evolution of pharmacogenomics prediction of tumor response, and regulatory requirements for prospective individual dosimetry are just some of the elements which are broadening the essence of physician responsibility. The burgeoning knowledge base essential for mastering the emergent technologies, and their profound effect on moral philosophic aspects of provision of cancer care, are challenging. The new relationship of the theranostic nuclear physician with respect to shared care of the individual patient, particularly with regard to transparency, accountability, and responsibility for targeted radionuclide diagnosis and therapy of cancer, will be explored in this update.

PMID:34339288 | DOI:10.1089/cbr.2021.0152

Clin Pharmacol Drug Dev. 2021 Aug 2. doi: 10.1002/cpdd.966. Online ahead of print.

ABSTRACT

Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

PMID:34337876 | DOI:10.1002/cpdd.966