Deep learning transcriptomic model for prediction of pan-drug chemotherapeutic sensitivity

The emergence of precision oncology approaches has begun to inform clinical decision-making in diagnostic, prognostic, and treatment contexts. High-throughput technology has enabled machine learning algorithms to use the molecular characteristics of tumors to generate personalized therapies. However, precision oncology studies have yet to develop a predictive biomarker incorporating pan-cancer gene expression profiles to stratify tumors into similar drug sensitivity profiles. Here we show that a neural network with ten hidden layers accurately classifies pancancer cell lines into two distinct chemotherapeutic response groups based on a pan-drug dataset with 89.0% accuracy (AUC = 0.904). Using unsupervised clustering algorithms, we found a cohort of cell line gene expression data from the Genomics of Drug Sensitivity in Cancer could be clustered into two response groups with significant differences in pan-drug chemotherapeutic sensitivity. After applying the Boruta feature selection algorithm to this dataset, a deep learning model was developed to predict chemotherapeutic response groups. The model’s high classification efficacy validates our hypothesis that cell lines with similar gene expression profiles present similar pan-drug chemotherapeutic sensitivity. This finding provides evidence for the potential use of similar combinatorial biomarkers to select potent candidate drugs that maximize therapeutic response and minimize the cytotoxic burden. Future investigations should aim to recursively subcluster cell lines within the response clusters defined in this study to provide a higher resolution of potential patient response to chemotherapeutics.

Radiological progression of extremity soft tissue sarcoma following preoperative radiotherapy predicts for poor survival

Objectives: To determine if radiological response to preoperative radiotherapy is related to oncologic outcome in patients with extremity soft tissue sarcomas (STS). Methods: 309 patients with extremity STS who underwent preoperative radiation and wide resection were identified from a prospective database. Pre-and post-radiation MRI scans were retrospectively reviewed. Radiological response was defined by the modified Response Evaluation Criteria in Solid Tumours (RECIST).Local recurrence-free (LRFS), metastasis-free (MFS) and overall survival (OS) were compared across response groups. Results: Tumour volume decreased in 106 patients (34.3%; PR- Partial Responders), remained stable in 97 (31.4%; SD- Stable Disease), increased in 106 (34.3%; PD- Progressive Disease). The PD group were older (p = 0.007), had more upper extremity (p = 0.03) and high grade tumours (p < 0.001). 81% of myxoid liposarcomas showed substantial decrease in size. There was no difference in initial tumour diameter (p = 0.5), type of surgery (p = 0.5), margin status (p = 0.4), or complications (p = 0.8) between the three groups. There were ten (3.2%) local recurrences with no differences between the three response groups (p = 0.06). Five-year MFS was 52.1% for the PD group versus 73.8 and 78.5% for the PR and SD groups respectively (p < 0.001). OS was similar (p < 0.001). Following multivariable analysis, worse MFS and OS were associated with higher grade, larger tumour size at diagnosis and tumour growth following preoperative radiation. Older age was also associated with worse OS. Conclusion: STS that enlarge according to RECIST criteria following preoperative radiotherapy identify a high risk group of patients with worse systemic outcomes but equivalent local control. Advances in knowledge: Post radiation therapy, STS enlargement may identify patients with potential for worse systemic outcomes but equivalent local control. Therefore, adjunct therapeutic approaches could be considered in these patients.

The formation of writer identity through writing response groups in the classroom

<p>Supporting the formation of children's identity as writers in the context of interaction within a writing response group was the focus of this study. The children in the study were in a composite Year Seven and Eight class. The children were randomly placed in groups of five or six members. Talk in the groups, students' writing journals, and the teacher/researcher's journal were analysed from a socio-cultural perspective to investigate how the group contributed to the formation of children's literate identity. The analysis revealed that responses served to acknowledge children's writing as interesting and worthy of attention. The acknowledgement created a social energy that contributed to growth in children's writing, enabling children access to the roles they desired in the classroom. The study highlighted the importance of children being able to form an identity as a writer to enable them to successfully engage in literacy activities.</p>

The formation of writer identity through writing response groups in the classroom

<p>Supporting the formation of children's identity as writers in the context of interaction within a writing response group was the focus of this study. The children in the study were in a composite Year Seven and Eight class. The children were randomly placed in groups of five or six members. Talk in the groups, students' writing journals, and the teacher/researcher's journal were analysed from a socio-cultural perspective to investigate how the group contributed to the formation of children's literate identity. The analysis revealed that responses served to acknowledge children's writing as interesting and worthy of attention. The acknowledgement created a social energy that contributed to growth in children's writing, enabling children access to the roles they desired in the classroom. The study highlighted the importance of children being able to form an identity as a writer to enable them to successfully engage in literacy activities.</p>

Urinary Neutrophil Gelatinase-Associated Lipocalin as a Novel Predictor in Treatment of Active Lupus Nephritis

Introduction Lupus nephritis (LN) affects almost two-thirds of Systemic lupus erythematosus (SLE) patients. Despite initial aggressive therapy, up to 25% of patients with LN will progress to end stage renal disease (ESRD). Conventional serum markers for LN lack the sensitivity of an ideal biomarker. Urinary Neutrophil gelatinase-associated lipocalin (UNGAL) is an excellent biomarker for early diagnosis of acute kidney injury and predicting renal outcomes. Objectives To measure UNGAL among LN patients correlating its levels with renal disease activity to investigate its predictive performance in response to induction therapy. Patients and Methods 40 SLE patients with biopsy-proven LN, class III, IV, or V were randomly selected. The study was conducted in internal medicine department and Outpatient clinic in Ain Shams University Hospitals on and completed after six months. UNGAL was measured at baseline and after complete induction therapy. Results In LN patients at baseline; mean UNGAL levels of complete response, partial response, and no response groups were 14.48 ±2.99 ng/ml, 34.49 ±4.09, and 62.07 ±14.44 ng/ml respectively. Based on ROC curve, we found better performance of baseline UNGAL to discriminate complete response group from partial and non-response groups to predict response to induction, outperforming conventional biomarkers. The area under the curve was 0.943 (92.31% sensitivity, 88.89% specificity), and the best cut-off level was 26.5 ng/ml. Conclusion UNGAL performed better than conventional biomarkers in predicting response to treatment of active LN.

Measuring treatment effect on psoriatic arthritis-related domains: insights from the SPIRIT-H2H study at weeks 24 and 52

Introduction Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points• Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease.• A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis.• Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

Association of Interferon Regulatory Factor-3 Gene Polymorphisms With Infection and Antiviral Efficacy of Chronic Hepatitis C Virus

Background Hepatitis C virus (HCV) is a major public health concern in developing countries. Pathogenesis of hepatitis C infection is poorly understood. Previously, we found higher Interferon Regulatory Factor-3 (IRF-3) expression in HCV-infected patients. However, the effect of IRF-3 polymorphism on the incidence of HCV infection and antiviral efficacy has not been sufficiently evaluated.Methods We retrospectively enrolled 178 patients with chronic hepatitis C (CHC) and 82 matched healthy controls between 2016 and 2019 at the Second Hospital of Wenzhou Medical University, China. All patients received a standard dose of polyethylene glycol interferon + ribavirin (PR regimen), and were divided into the response, non-response, sustained virological response (SVR), and non-sustained virological response (NSVR) groups based on their HCV RNA levels. Gene polymorphisms were detected by DNA sequencing, and the plasma IRF-3 and IFN-β levels were measured by ELISA to assess the impact of IRF-3 gene variations and contents on the risk of HCV infection and antiviral efficacy.Results Plasma contents of IRF-3 and IFN-β were significantly different between the CHC and control groups, the response and non-response groups, and the SVR and non-SVR groups (p<0.05). rs2304206 C>T but not rs2304204A>G was associated with increased risk for CHC (OR= 2.35 (95% CI: 1.30 to 4.24), p = 0.004), and reduced antiviral efficacy between both response groups (OR= 1.86 (95% CI: 1.06 to 3.24), p = 0.028) and SVR groups (OR= 1.79 (95% CI:1.05 to 3.06), p = 0.030). Haplotype GT type suffered negative consequence between the CHC and control groups, the responder and non-responder groups, and the SVR and non-SVR groups (p=0.004, 0.028, 0.030). The content of IFR-3 in CT genotype of rs2304206 was higher than that in CC genotype.Conclusion The polymorphism of IFR-3 affects the plasma levels of IFR-3 and associated with HCV infection and interferon antiviral efficacy, where the T allele of rs2304206 may be a susceptibility factor for CHC and adversely impact interferon antiviral response.

Predicting the response of neoadjuvant chemotherapy in hormone receptor- positive and HER2-negative breast cancer with axillary lymph node metastasis by a multigene assay (GenesWell™ BCT)

The GenesWell™ BCT (BCT score) is a recently developed multigene assay that predicts the risk of distant recurrence in patients with hormone receptor-positive (HR+) and HER2 negative (HER2-) early breast cancer (BC). The ability of the assay to predict the response to neoadjuvant chemotherapy (NACT) has not been established to date. Biopsy specimens of HR+/HER2- BC patients with axillary lymph node (LN) metastasis who underwent NACT were analyzed using the BCT score. The modified breast cancer test (BCT) score was developed and classified into high-and low-response groups. A total of 88 patients were available for the BCT score among 108 eligible patients. The median follow-up duration was 35.9 (7.8-128.5) months. Among these, 61 (65.1%) had cN1 and 53 (60.2%) had cT1 or T2. The BCT score was low in 25 (28.4%) patients and high in 63 (71.6%) patients. Among 50 patients with pathologic complete response or partial response, 41 (82.0%) were in the high-response group, and 9 (18.0%) were in the low-response group. Among 38 patients with stable disease or progressive disease, 22 (57.9%) patients were in the high-response group, and 16 (42.1%) were in the low-response group (p = 0.025). Ki-67 before NACT was a significant factor for predicting tumor response (p = 0.006; 3.81 [1.50-10.16]). The BCT score showed a significant response to NACT (p = 0.016; 4.18 [1.34–14.28]). A significant difference was found in distant metastasis-free survival between the high and low response groups (p = 0.004). We demonstrated that the BCT score predicts NACT responsiveness of HR+/HER2- BC with LN metastasis and might help determine whether to undergo NACT or not. Further studies are warranted to validate these findings.