J Clin Pharmacol. 2021 Jun;61 Suppl 1:S188-S192. doi: 10.1002/jcph.1891.

ABSTRACT

Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic associations are frequently used in children, and therefore pharmacogenomics-guided precision medicine is readily applicable to the pediatric population. Although heritable genetics are considered immutable, the impact of genetic variation in pharmacogenes is modified by other factors such as age-dependent changes in gene expression. Early evidence has emerged indicating that the interaction between ontogeny and pharmacogenomics determines whether or how genetics-based dosing algorithms should be adjusted in children versus adults. However, there is still a paucity of data describing pharmacogenomic associations in patient populations across the life span. Future research is much needed to evaluate the impact of pharmacogenomics on drug dosing specific to the pediatric population, along with consideration of other developmental and physiological factors uniquely related to drug disposition in this population.

PMID:34185912 | DOI:10.1002/jcph.1891

Clin Pharmacol Ther. 2021 Jun 29. doi: 10.1002/cpt.2349. Online ahead of print.

ABSTRACT

The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genome-wide association studies (GWAS) that uncover genetic determinants of drug response. GWAS have discovered associations between genetic variants and both drug efficacy and adverse drug reactions. Despite these successes, the design of GWAS in pharmacogenomics faces unique challenges. In this review we analyze the last decade of GWAS in pharmacogenomics. We review trends in publications over time, including the drugs and drug classes studied and the clinical phenotypes used. Several data sharing consortia have contributed substantially to the PGx GWAS literature. We anticipate increased focus on biobanks and highlight phenotypes that would best enable future pharmacogenomics discoveries.

PMID:34185318 | DOI:10.1002/cpt.2349

Bioinformatics. 2021 Jun 29:btab478. doi: 10.1093/bioinformatics/btab478. Online ahead of print.

ABSTRACT

MOTIVATION: Multi-omics data in molecular biology has accumulated rapidly over the years. Such data contains valuable information for research in medicine and drug discovery. Unfortunately, data-driven research in medicine and drug discovery is challenging for a majority of small research labs due to the large volume of data and the complexity of analysis pipeline.

RESULTS: We present BioVLAB-Cancer-Pharmacogenomics, a bioinformatics system that facilitates analysis of multi-omics data from breast cancer to analyze and investigate intratumor heterogeneity and pharmacogenomics on Amazon Web Services. Our system takes multi-omics data as input to perform tumor heterogeneity analysis in terms of TCGA data and deconvolve-and-match the tumor gene expression to cell line data in CCLE using DNA methylation profiles. We believe that our system can help small research labs perform analysis of tumor multi-omics without worrying about computational infrastructure and maintenance of databases and tools.

AVAILABILITY: http://biohealth.snu.ac.kr/software/biovlab_cancer_pharmacogenomics.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34185062 | DOI:10.1093/bioinformatics/btab478

BJPsych Open. 2021 Jun 29;7(4):e121. doi: 10.1192/bjo.2021.945.

ABSTRACT

BACKGROUND: Schizophrenia is a severe and complex psychiatric disorder that needs treatment based on extensive experience. Antipsychotic drugs have already become the cornerstone of the treatment for schizophrenia; however, the therapeutic effect is of significant variability among patients, and only around a third of patients with schizophrenia show good efficacy. Meanwhile, drug-induced metabolic syndrome and other side-effects significantly affect treatment adherence and prognosis. Therefore, strategies for drug selection are desperately needed. In this study, we will perform pharmacogenomics research and set up an individualised preferred treatment prediction model.

AIMS: We aim to create a standard clinical cohort, with multidimensional index assessment of antipsychotic treatment for patients with schizophrenia.

METHOD: This trial is designed as a randomised clinical trial comparing treatment with different kinds of antipsychotics. A total sample of 2000 patients with schizophrenia will be recruited from in-patient units from five clinical research centres. Using a computer-generated program, the participants will be randomly assigned to four treatment groups: aripiprazole, olanzapine, quetiapine and risperidone. The primary outcomes will be measured as changes in the Positive and Negative Syndrome Scale of schizophrenia, which reflects the efficacy. Secondary outcomes include the measure of side-effects, such as metabolic syndromes. The efficacy evaluation and side-effects assessment will be performed at baseline, 2 weeks, 6 weeks and 3 months.

RESULTS: This trial will assess the efficacy and side effects of antipsychotics and create a standard clinical cohort with a multi-dimensional index assessment of antipsychotic treatment for schizophrenia patients.

CONCLUSION: This study aims to set up an individualized preferred treatment prediction model through the genetic analysis of patients using different kinds of antipsychotics.

PMID:34183088 | DOI:10.1192/bjo.2021.945

Oral Oncol. 2021 Jun 25;119:105363. doi: 10.1016/j.oraloncology.2021.105363. Online ahead of print.

ABSTRACT

OBJECTIVE: To provide information about hospitalization costs and length of stay (LOS) for inpatients undergoing oral cancer (OC) surgery, and to investigate the association of hospitalization costs and LOS with demographics, tumor subsite, surgery-related and hospital characteristics.

METHODS: Data extracted from Chinese National Health Statistics Network Reporting System database in Hunan, China during 2017-2019 were analyzed using quantile regression models.

RESULTS: A total of 6,420 OC patients undergoing surgery were identified. After controlling potential compounding variables, the median hospitalization cost was significantly higher in male than in female patientsby $515.70 at the median (p < 0.001). Patients aged over 60 hadsignificantly less costs by $294.85 at the meanthan did those below 60, while no differenceof LOS existed across age. OC patients with neck dissection had significantly higher costs by $1,983.33 at the median than those without (P < 0.001). Regional flaps were the most economical, with lower costs than free flaps by $3,084 (P < 0.001) and the pectoralis major myocutaneous flap (PMMF) by $549.45 (P < 0.001) at the median.

CONCLUSION: Male is a significant driver of hospitalization costs and LOS for OC, and age over 60 is associated with lower costs, but not with LOS. Mouth primary site is associated with the highest costs and LOS, while lip primary site the lowest. Absence of neck dissection in early-stage OC can significantly reduce costs and LOS, but its oncological validity needs more evidence. Regional flaps are less expensive than free flaps and the PMMF for oral reconstruction, and are recommended in select patients.

PMID:34182278 | DOI:10.1016/j.oraloncology.2021.105363

Med Sci (Paris). 2021 Jun-Jul;37(6-7):563-564. doi: 10.1051/medsci/2021105. Epub 2021 Jun 28.

NO ABSTRACT

PMID:34180808 | DOI:10.1051/medsci/2021105

Front Oncol. 2021 Jun 10;11:678008. doi: 10.3389/fonc.2021.678008. eCollection 2021.

ABSTRACT

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy with a dismal prognosis. For over four decades, AML has primarily been treated by cytarabine combined with an anthracycline. Although a significant proportion of patients achieve remission with this regimen, roughly 40% of children and 70% of adults relapse. Over 90% of patients with resistant or relapsed AML die within 3 years. Thus, relapsed and resistant disease following treatment with standard therapy are the most common clinical failures that occur in treating this disease. In this study, we evaluated the relationship between AML cell line global metabolomes and variation in chemosensitivity.

METHODS: We performed global metabolomics on seven AML cell lines with varying chemosensitivity to cytarabine and the anthracycline doxorubicin (MV4.11, KG-1, HL-60, Kasumi-1, AML-193, ME1, THP-1) using ultra-high performance liquid chromatography - mass spectrometry (UHPLC-MS). Univariate and multivariate analyses were performed on the metabolite peak intensity values from UHPLC-MS using MetaboAnalyst to identify cellular metabolites associated with drug chemosensitivity.

RESULTS: A total of 1,624 metabolic features were detected across the leukemic cell lines. Of these, 187 were annotated to known metabolites. With respect to doxorubicin, we observed significantly greater abundance of a carboxylic acid (1-aminocyclopropane-1-carboxylate) and several amino acids in resistant cell lines. Pathway analysis found enrichment of several amino acid biosynthesis and metabolic pathways. For cytarabine resistance, nine annotated metabolites were significantly different in resistance vs. sensitive cell lines, including D-raffinose, guanosine, inosine, guanine, aldopentose, two xenobiotics (allopurinol and 4-hydroxy-L-phenylglycine) and glucosamine/mannosamine. Pathway analysis associated these metabolites with the purine metabolic pathway.

CONCLUSION: Overall, our results demonstrate that metabolomics differences contribute toward drug resistance. In addition, it could potentially identify predictive biomarkers for chemosensitivity to various anti-leukemic drugs. Our results provide opportunity to further explore these metabolites in patient samples for association with clinical response.

PMID:34178663 | PMC:PMC8222790 | DOI:10.3389/fonc.2021.678008

Front Oncol. 2021 Jun 11;11:674604. doi: 10.3389/fonc.2021.674604. eCollection 2021.

ABSTRACT

Resistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R EGFR sensitive mutation. The patient developed multiple TKI resistance mechanisms: T790M EGFR resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and MET amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and de novo MET amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure.

PMID:34178662 | PMC:PMC8226241 | DOI:10.3389/fonc.2021.674604

Front Immunol. 2021 Jun 11;12:631603. doi: 10.3389/fimmu.2021.631603. eCollection 2021.

ABSTRACT

OBJECTIVE: Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.

MATERIALS AND METHODS: In total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.

RESULTS: In the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.

CONCLUSIONS: The obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

PMID:34177886 | PMC:PMC8226138 | DOI:10.3389/fimmu.2021.631603

Pharmacogenomics J. 2021 Jun 26. doi: 10.1038/s41397-021-00247-3. Online ahead of print.

ABSTRACT

Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

PMID:34175889 | DOI:10.1038/s41397-021-00247-3

Pharmacol Ther. 2021 Jun 24:107924. doi: 10.1016/j.pharmthera.2021.107924. Online ahead of print.

ABSTRACT

DLBCL is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP. Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting. This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a GWAS analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to gene involved in drug transport (i.e. ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis. Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively. Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed.

PMID:34175369 | DOI:10.1016/j.pharmthera.2021.107924

Part Fibre Toxicol. 2021 Jun 25;18(1):24. doi: 10.1186/s12989-021-00417-y.

ABSTRACT

BACKGROUND: Exposure to air pollution exerts direct effects on respiratory organs; however, molecular alterations underlying air pollution-induced pulmonary injury remain unclear. In this study, we investigated the effect of air pollution on the lung tissues of Sprague-Dawley rats with whole-body exposure to traffic-related PM1 (particulate matter < 1 μm in aerodynamic diameter) pollutants and compared it with that in rats exposed to high-efficiency particulate air-filtered gaseous pollutants and clean air controls for 3 and 6 months. Lung function and histological examinations were performed along with quantitative proteomics analysis and functional validation.

RESULTS: Rats in the 6-month PM1-exposed group exhibited a significant decline in lung function, as determined by decreased FEF25-75% and FEV20/FVC; however, histological analysis revealed earlier lung damage, as evidenced by increased congestion and macrophage infiltration in 3-month PM1-exposed rat lungs. The lung tissue proteomics analysis identified 2673 proteins that highlighted the differential dysregulation of proteins involved in oxidative stress, cellular metabolism, calcium signalling, inflammatory responses, and actin dynamics under exposures to PM1 and gaseous pollutants. The presence of PM1 specifically enhanced oxidative stress and inflammatory reactions under subchronic exposure to traffic-related PM1 and suppressed glucose metabolism and actin cytoskeleton signalling. These factors might lead to repair failure and thus to lung function decline after chronic exposure to traffic-related PM1. A detailed pathogenic mechanism was proposed to depict temporal and dynamic molecular regulations associated with PM1- and gaseous pollutants-induced lung injury.

CONCLUSION: This study explored several potential molecular features associated with early lung damage in response to traffic-related air pollution, which might be used to screen individuals more susceptible to air pollution.

PMID:34172050 | DOI:10.1186/s12989-021-00417-y

Int J Hematol. 2021 Jun 25. doi: 10.1007/s12185-021-03184-w. Online ahead of print.

ABSTRACT

This study aimed to establish a predictive model to identify children with hematologic malignancy at high risk for delayed clearance of high-dose methotrexate (HD-MTX) based on machine learning. A total of 205 patients were recruited. Five variables (hematocrit, risk classification, dose, SLC19A1 rs2838958, sex) and three variables (SLC19A1 rs2838958, sex, dose) were statistically significant in univariable analysis and, separately, multivariate logistic regression. The data was randomly split into a "training cohort" and a "validation cohort". A nomogram for prediction of delayed HD-MTX clearance was constructed using the three variables in the training dataset and validated in the validation dataset. Five machine learning algorithms (cart classification and regression trees, naïve Bayes, support vector machine, random forest, C5.0 decision tree) combined with different resampling methods were used for model building with five or three variables. When developed machine learning models were evaluated in the validation dataset, the C5.0 decision tree combined with the synthetic minority oversampling technique (SMOTE) using five variables had the highest area under the receiver operating characteristic curve (AUC 0.807 [95% CI 0.724-0.889]), a better performance than the nomogram (AUC 0.69 [95% CI 0.594-0.787]). The results support potential clinical application of machine learning for patient risk classification.

PMID:34170480 | DOI:10.1007/s12185-021-03184-w

Mol Neurobiol. 2021 Jun 24. doi: 10.1007/s12035-021-02454-2. Online ahead of print.

ABSTRACT

First-line therapy with interferon beta (IFN-β), involved in gene expression modulation in immune response, is widely used for multiple sclerosis. However, 30-50% of patients do not respond optimally. Variants in CBLB, CTSS, GRIA3, OAS1 and TNFRSF10A genes have been proposed to contribute to the variation in the individual response. The purpose of this study was to evaluate the influence of gene polymorphisms on the IFN-β response in relapsing-remitting multiple sclerosis (RRMS) patients. CBLB (rs12487066), GRIA3 (rs12557782), CTSS (rs1136774), OAS1 (rs10774671) and TNFRSF10A (rs20576) polymorphisms were analysed by Taqman in 137 RRMS patients. Response to IFN-β and change in the Expanded Disability Status Scale (EDSS) after 24 months were evaluated using multivariable logistic regression analysis. Carriers of at least one copy of the C allele of CTSS-rs1136774 had a better response to IFN-β (p = 0.0423; OR = 2.94; CI95% = 1.03, 8.40). Carriers of TT genotype of TNFRSF10A-rs20576 had a higher probability of maintaining their EDSS stable after 24 months of IFN-β treatment (p = 0.0251; OR = 5.71; CI95% = 1.39, 31.75). No influence of CBLB (rs12487066), OAS1 (rs10774671) and GRIA3 (rs12557782) gene polymorphisms in the variation of the individual response to IFN-β was shown. Our results suggest that the TNFRSF10A-rs20576 and CTSS-rs1136774 gene polymorphisms influence the response to IFN-β after 24 months, while the CBLB (rs12487066), OAS1 (rs10774671) or GRIA3 (rs12557782) gene polymorphisms had no effect on the variation of the individual response to IFN-β.

PMID:34169444 | DOI:10.1007/s12035-021-02454-2

Med J Islam Repub Iran. 2021 Feb 11;35:22. doi: 10.47176/mjiri.35.22. eCollection 2021.

ABSTRACT

Background: Lung cancer accounts for about 13% of all cancers and about 60% of patients with lung cancer also experience weight loss during treatment. There seems to be a clear correlation between the therapeutic outcomes of patients based on their weight changes during treatment. The aim of this study was to investigate the relationship between weight changes during and after treatment and the therapeutic outcomes of a patient with metastatic lung cancer. Methods: This cohort study was performed on patients with the diagnosis of non-surgical metastatic lung cancer referred to Hematology and Oncology Clinic, Rasoul-e-Akram Hospital. Patients were divided into two groups with a weight gain of more than 5% and a weight gain of 5% and less. The information was entered into the SPSS version 21 software. In the descriptive analysis, mean and standard deviation (SD) were used. To compare quantitative variables, independent samples t-test, Mann-Whitney, chi-square or Fisher exact tests were used to compare qualitative variables and correlation test was used to determine the correlation between quantitative data. Survival curves were used to show differences in two groups of studies. A regression model was used to calculate the hazard ratio. The significance level was less than 0.05. Results: Sixty patients, including 40 males (66.7%) and 20 females (33.3%) were studied. The mean age of patients was 62.22±9.00 years (43-83 years). The mean weight changes in the patients were -1.28±6.11 kg (-16 to 16kg). Forty-seven patients (78.3%) had weight gain less than 5%. There was no significant difference in overall survival (OS) and progression-free survival (PFS) according to weight gain. Conclusion: Finally, the findings of the study showed that, despite the fact that PFS and OS in the weight gain group were greater than 5% of the original weight; the difference was not statistically significant.

PMID:34169034 | PMC:PMC8214037 | DOI:10.47176/mjiri.35.22

Neuropsychiatr Dis Treat. 2021 Jun 16;17:1953-1963. doi: 10.2147/NDT.S311429. eCollection 2021.

ABSTRACT

INTRODUCTION: Efforts have been made in assessing efficacy and tolerability to various antidepressants, but understanding personalized chances of stability to medication switching sequence is still inconclusive. This study aimed to identify naturalistic switching patterns of medication in stratifying MDD patients.

METHODS: MDD patients were stratified based on treatment difficulty evaluated with the "Treatment Resistance to Antidepressants Evaluation Scale for Unipolar Depression" (TRADES). The duration of the time of diagnoses until the final switch to another class of antidepressants was used as prediction of unstable to drug therapy. ROC analysis was used to determine the cutoff values. A continuous temporal events function from the visual analytic tool was employed to perform patterns of switching between distinct pharmacological class such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

RESULTS: TRADES scores of 4.5 and not-switching times of 12.5 months were used as cutoff values to divide patients into four subgroups: stable/easy-to-treat (SE), unstable/easy-to-treat (UE), stable/difficult-to-treat (SD) and unstable/difficult-to-treat (UD). A total of 80% and 76.9% of patients initially treated with the SSRIs paroxetine or fluoxetine, respectively, were predicted to be stable to drug therapy. Approximately 70%, 44.8% and 41.4% of patients initially treated with the SNRIs fluvoxamine, sertraline and venlafaxine, respectively, were predicted to be UD, and 60% of patients using duloxetine were predicted to be stable to drug therapy. Analysis of the switching phenomenon showed that SSRIs were the first prescribed medications and mostly taken by the stable subgroups, and SNRIs were the preferentially chosen switching alternative. Medication switching patterns in unstable MDD patients are discussed.

CONCLUSION: Paroxetine, fluoxetine and duloxetine users were mostly stable among MDD patients in Taiwan with various stability and difficulty to treatments. Although responsiveness to specific medication sequence is likely required for clinical application, the results provide a baseline for such studies.

PMID:34168454 | PMC:PMC8217841 | DOI:10.2147/NDT.S311429

Sci Rep. 2021 Jun 24;11(1):13206. doi: 10.1038/s41598-021-92592-3.

ABSTRACT

A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour. We performed in-depth analysis of 13 BCC-related genes (CSMD1, CSMD2, DPH3 promoter, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples. PTCH1 and TP53 mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in CSMD1 (63.2%), NOTCH1 (43.8%) and DPP10 (35.1%), and frequent non-coding mutations were identified in TERT (57.9%) and DPH3 promoter (49.1%). CSMD1 mutations significantly co-occurred with TP53 changes (p = 0.002). A significant association was observed between the superficial type of BCC and PTCH1 (p = 0.018) and NOTCH1 (p = 0.020) mutations. In addition, PTCH1 mutations were significantly associated with intermittent sun exposure (p = 0.046) and the occurrence of single lesions (p = 0.021), while NOTCH1 mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities (p = 0.001). In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.

PMID:34168209 | DOI:10.1038/s41598-021-92592-3

Clin Cancer Res. 2021 Jun 24:clincanres.0810.2021. doi: 10.1158/1078-0432.CCR-21-0810. Online ahead of print.

ABSTRACT

BACKGROUND: CD137 agonism and CSF-1R blockade augment stereotactic body radiotherapy (SBRT) and anti-PD1 in pre-clinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF-1R inhibitor).

PATIENTS AND METHODS: This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1-4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if {less than or equal to}33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.

RESULTS: Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n=3 grade 3, n=4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months (95% CI 2.9-4.8) and 17.0 months (95% CI 6.8-undetermined), respectively. No patients with elevated pre-SBRT serum interleukin-8 experienced a response.

CONCLUSIONS: SBRT to {less than or equal to}4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest anti-tumor activity.

PMID:34168049 | DOI:10.1158/1078-0432.CCR-21-0810

Clin Cancer Res. 2021 Jun 24:clincanres.0714.2021. doi: 10.1158/1078-0432.CCR-21-0714. Online ahead of print.

ABSTRACT

PURPOSE: While chemotherapy remains the standard treatment for TNBC, identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.

EXPERIMENTAL DESIGN: We performed transcriptional profiling of tumors from a Phase 2 clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.

RESULTS: We reveal the RAS-GTPase activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In TNBC patients, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic YAP. Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing.

CONCLUSIONS: These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.

PMID:34168046 | DOI:10.1158/1078-0432.CCR-21-0714

Sleep Med Rev. 2021 Jun 2;59:101512. doi: 10.1016/j.smrv.2021.101512. Online ahead of print.

ABSTRACT

Artificial intelligence (AI) allows analysis of "big data" combining clinical, environmental and laboratory based objective measures to allow a deeper understanding of sleep and sleep disorders. This development has the potential to transform sleep medicine in coming years to the betterment of patient care and our collective understanding of human sleep. This review addresses the current state of the field starting with a broad definition of the various components and analytic methods deployed in AI. We review examples of AI use in screening, endotyping, diagnosing, and treating sleep disorders and place this in the context of precision/personalized sleep medicine. We explore the opportunities for AI to both facilitate and extend providers' clinical impact and present ethical considerations regarding AI derived prognostic information. We cover early adopting specialties of AI in the clinical realm, such as radiology and pathology, to provide a road map for the challenges sleep medicine is likely to face when deploying this technology. Finally, we discuss pitfalls to ensure clinical AI implementation proceeds in the safest and most effective manner possible.

PMID:34166990 | DOI:10.1016/j.smrv.2021.101512