Robert Penn Warren, Cleanth Brooks, and the Southern Literary Tradition

The illustrious biographer of Faulkner and Warren provides an overview of the role the Southern tradition in American letters played in the making of Warren and Brooks, both of whom he knew as friends as well as subjects of professional interest

William Faulkner: Author-at-Law

Symposium - The Law and Southern Literatur

Biopsychosocial risk factors for the development of conduct problems in children with autism spectrum disorder

BACKGROUND: The aim of this systemic review and meta-analysis was to estimate the rates at which oppositional defiant disorder (ODD) and conduct disorder (CD) occur in children and adolescents with a diagnosis of autism spectrum disorder (ASD). Furthermore, the study aimed to explore moderating factors which might influence prevalence rates of these co-occurring conditions between studies. METHODS: A systematic search was conducted on August 10, 2020 using the PsycInfo and Medline databases to identify relevant literature using key words and MeSH terms. Only studies of children and adolescents aged between 3-25 were included in the meta-analysis. A modified Hoy’s risk of bias tool was used to assess the bias of the included studies. Following the identification and selection of relevant articles, a meta-analysis was conducted using R-studio software. Moderator analysis was performed to explore whether participant characteristics and methodological design of studies were associated with differences in reported ODD and CD prevalence rates. Potential moderators included age, gender, intellectual ability, ethnicity, nationality, sample type, detection bias, and sampling bias. RESULTS: Nineteen eligible studies were identified including a total sample of 6,085 individuals with a diagnosis of ASD. The diagnostic rates of comorbid ODD and CD within the pooled sample were 14.03% [95% CI 9.0-21.22] and 3.13% [95% CI 1.4-5.4] respectively. There was significant heterogeneity in the rates of diagnosis between studies. Greater study bias was associated with increased rates of co-occurring diagnoses. Recruitment bias moderated the prevalence of CD but not ODD diagnoses. Detection bias moderated the number of ODD but not CD diagnoses. Study demographics, sample type, and intelligence were not associated with the prevalence rate of comorbidity found in the pooled sample. DISCUSSION: Study bias played a significant role over the rates of co-occurring CD and ODD reported in the ASD population, yet the findings should be interpreted with some caution. The meta-analysis was based on a predominantly Caucasian male sample and studies which used DSM-IV criteria to assign diagnoses. This lack of participant heterogeneity limits the generalizability of the study and underscores the importance of studying both population characteristic and methodology in meta-analyses. Future research should explore the impact that the updated DSM-5 have over co-occurring ODD and CD and focus on including more minoritized populations

Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in \u3e20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967

The Informative Process Model as a New Intervention for Attitude Change in Intractable Conflicts: Theory and Empirical Evidence

Peacemaking is especially challenging in situations of intractable conflict. Collective narratives in this context contribute to coping with challenges societies face, but also fuel conflict continuation. We introduce the Informative Process Model (IPM), proposing that informing individuals about the socio-psychological processes through which conflict-supporting narratives develop, and suggesting that they can change via comparison to similar conflicts resolved peacefully, can facilitate unfreezing and change in attitudes. Study 1 established associations between awareness of conflict costs and conflict-supporting narratives, belief in the possibility of resolving the conflict peacefully and support for pursuing peace among Israeli-Jews and Palestinians. Studies 2 and 3 found that exposure to IPM-based original videos (vs. control) led Israeli-Jews to deliberation of the information presented, predicting acceptance of the IPM-based message, which, in turn, predicted support for negotiations. Study 3 also found similar effects across IPM-based messages focusing on different conflict-supporting themes. We discuss the implications to attitude change in intractable conflicts

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: Results from MyPathway, a phase IIa multiple basket study

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease \u3e4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination

Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.

BACKGROUND: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. METHODS: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141. FINDINGS: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. INTERPRETATION: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. FUNDING: F Hoffmann-La Roche/Genentech