Should Autism Spectrum Conditions Be Characterised in a More Positive Way in Our Modern World?

In a special issue that focuses on complex presentations related to Autism, we ask the question in this editorial whether an Autism Spectrum Condition without complexity is a disorder, or whether it represents human diversity? Much research into Autism Spectrum Conditions (ASCs) over the years has focused on comparisons between neuro-typical people and people with Autism Spectrum Conditions. These comparisons have tended to draw attention to 'deficits' in cognitive abilities and descriptions of behaviours that are characterised as unwanted. Not surprisingly, this is reflected in the classification systems from the World Health Organisation and the American Psychiatric Association. Public opinion about ASC may be influenced by presentations in the media of those with ASC who also have intellectual disability. Given that diagnostic systems are intended to help us better understand conditions in order to seek improved outcomes, we propose a more constructive approach to descriptions that uses more positive language, and balances descriptions of deficits with research finding of strengths and differences. We propose that this will be more helpful to individuals on the Autism Spectrum, both in terms of individual self-view, but also in terms of how society views Autism Spectrum Conditions more positively. Commentary has also been made on guidance that has been adjusted for people with ASC in relation to the current COVID-19 pandemic.

Role of adjuvant radiation or re-excision for early stage vulvar squamous cell carcinoma with positive or close surgical margins.

OBJECTIVES: This study aims to evaluate whether re-excision or adjuvant radiation for stage I vulvar squamous cell carcinoma (SCC) with either a close or positive surgical margin improves recurrence-free survival. METHODS: Patients with pathologically confirmed FIGO stage I vulvar SCC who underwent primary surgical management between January 1, 1995 and September 30, 2017 and had positive or close (<8 mm) surgical margins were included. Kaplan-Meier curves were generated and compared using the log-rank test. RESULTS: Of 150 patients with stage I vulvar SCC, 47 (31.3%) had positive or close margins. Median follow-up time was 25 months (IQR 13-59 months). Twenty-one (44.6%) patients received additional treatment with re-excision (n = 17) or vulvar radiation (n = 4); 26 (55.3%) patients received no additional therapy. Patients with positive margins were more likely to receive additional therapy compared to patients with close margins (80% vs 35.1%, p = 0.03). The 2-year recurrence rates were similar between the no further therapy and the re-excision/vulvar radiation groups (11.5% vs 4.8%, p = 0.62). Local recurrence-free survival (RFS) and overall survival (OS) were similar between patients who received re-excision/vulvar radiation and patients who received no further therapy (p = 0.10 and p = 0.16, respectively). Subgroup analysis of the 37 patients with close margins demonstrated no difference in RFS or OS when patients received re-excision or adjuvant vulvar radiation compared to no additional therapy (p = 0.74 and p = 0.82, respectively). CONCLUSIONS: In our study, any additional treatment following primary surgical resection did not improve RFS or OS in stage IA and IB vulvar SCC. Larger studies are warranted in order to definitively determine the role of re-excision and adjuvant radiation in early stage disease.

The Flashed Face Distortion Effect Does Not Depend on Face-Specific Mechanisms.

When normal faces are rapidly presented in the visual periphery, they are perceived as grotesque and distorted. This phenomenon, "The flashed-face distortion effect" (FFDE) is a powerful illusion that may reveal important properties of how faces are coded in peripheral vision. Despite the strength of the illusion (and its popularity), there has been almost no follow-up work to examine what governs the strength of the illusion or to develop a clear account of its phenomenology. Presently, our goal was to address this by manipulating aspects of facial appearance and spatial/temporal properties of the flashed-face stimulus to determine what factors modulate the illusion's strength. In three experiments, we investigated the extent to which local contrast (operationalized by the presence or absence of makeup), image eccentricity, image size, face inversion, and presentation rate of images within the sequence each contributed to the strength of the FFDE. We found that some of these factors (eccentricity and presentation rate) mattered a great deal, while others (makeup, face inversion and image size) made little contribution to the strength of the FFDE. We discuss the implications of these results for a mechanistic account of the FFDE, and suggest several avenues for future research based on this compelling visual illusion.

The Effects of Blur and Inversion on the Recognition of Ambient Face Images.

When viewing unfamiliar faces that vary in expressions, angles, and image quality, observers make many recognition errors. Specifically, in unconstrained identity-sorting tasks, observers struggle to cope with variation across different images of the same person while succeeding at telling different people apart. The use of ambient face images in this simple card-sorting task reveals the magnitude of these face recognition errors and suggests a useful platform to reexamine the nature of face processing using naturalistic stimuli. In the present study, we chose to investigate the impact of two basic stimulus manipulations (image blur and face inversion) on identity sorting with ambient images. Although these manipulations are both known to affect face processing when well-controlled, frontally viewed face images are used, examining how they affect performance for ambient images is an important step toward linking the large body of research using controlled face images to more ecologically valid viewing conditions. Briefly, we observed a high cost of image blur regardless of blur magnitude, and a strong inversion effect that affected observers' sensitivity to extrapersonal variability but did not affect the number of unique identities they estimated were present in the set of images presented to them.

MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents.

The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.

Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR.

Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.

Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2, and HER3. Here, we examined pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, pan-HER treatment decreased all three receptors' protein levels and downstream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared with mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with pan-HER exhibited significant growth delay compared with vehicle/cetuximab controls. These results suggest that targeting multiple HER family receptors simultaneously with pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. Mol Cancer Ther; 15(9); 2175-86. ©2016 AACR.

Adaptive responses to antibody based therapy.

Receptor tyrosine kinases (RTKs) represent a large class of protein kinases that span the cellular membrane. There are 58 human RTKs identified which are grouped into 20 distinct families based upon their ligand binding, sequence homology and structure. They are controlled by ligand binding which activates intrinsic tyrosine-kinase activity. This activity leads to the phosphorylation of distinct tyrosines on the cytoplasmic tail, leading to the activation of cell signaling cascades. These signaling cascades ultimately regulate cellular proliferation, apoptosis, migration, survival and homeostasis of the cell. The vast majority of RTKs have been directly tied to the etiology and progression of cancer. Thus, using antibodies to target RTKs as a cancer therapeutic strategy has been intensely pursued. Although antibodies against the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) have shown promise in the clinical arena, the development of both intrinsic and acquired resistance to antibody-based therapies is now well appreciated. In this review we provide an overview of the RTK family, the biology of EGFR and HER2, as well as an in-depth review of the adaptive responses undertaken by cells in response to antibody based therapies directed against these receptors. A greater understanding of these mechanisms and their relevance in human models will lead to molecular insights in overcoming and circumventing resistance to antibody based therapy.

AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical. EXPERIMENTAL DESIGN: In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC. RESULTS: AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance. CONCLUSIONS: This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.

Overcoming acquired resistance to cetuximab by dual targeting HER family receptors with antibody-based therapy.

BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used to treat several cancers. However, many patients who initially respond to cetuximab acquire resistance. To examine mechanisms of acquired resistance, we developed a series of cetuximab-resistant (Ctx(R)) clones derived from the cetuximab sensitive (CtxS) non-small cell lung cancer (NSCLC) cell line H226. Previous studies characterizing this model revealed that: 1) EGFR was robustly overexpressed in Ctx(R) clones due to decreased EGFR ubiquitination and degradation and 2) Ctx(R) clones expressed increased HER2 and HER3 activation resulting in constitutive activation of the PI3K/AKT signaling axis. These findings suggest that dual targeting HER family receptors would be highly beneficial in the Ctx(R) setting. RESULTS: Since HER3 has been implicated in resistance to EGFR inhibitors, the efficacy of dually targeting both EGFR and HER3 in Ctx(R) models was evaluated. First, EGFR and HER3 expression were knocked down with siRNAs. Compared to the Ctx(S) parental cell line (HP), all Ctx(R) clones exhibited robust decreases in cell proliferation upon dual knockdown. Analysis of Ctx(R) clones indicated that neuregulin-1 was highly overexpressed compared to HP cells. Incubation of HP cells with neuregulin-1 rendered them resistant to cetuximab. Next, dual treatment of Ctx(R) clones with cetuximab and the HER3 neutralizing monoclonal antibody (mAb) U3-1287 led to potent anti-proliferative effects. Blockade of EGFR with cetuximab resulted in inactivation of MAPK, while blockade of HER3 with U3-1287 resulted in the inactivation of AKT. Treatment with both mAbs resulted in knockdown of both signaling pathways simultaneously. HER2 was also strongly inactivated upon dual mAb therapy, suggesting that this treatment regimen can diminish signaling from three HER family receptors. De novo CtxR H226 mouse xenografts were established to determine if dual therapy could overcome acquired resistance to cetuximab in vivo. Tumors that had acquired resistance to cetuximab were significantly growth delayed upon dual treatment of U3-1287 and cetuximab compared to those continued on cetuximab only. Combinatorial-treated xenograft tumors expressed decreased Ki67 and increased cleaved caspase-3 levels compared to tumors treated with either monotherapy. CONCLUSIONS: These studies demonstrate that dually targeting HER family receptors with antibody-based therapies can overcome acquired resistance to cetuximab.

Participating in a virtual reality balance exercise program can reduce risk and fear of falls.

OBJECTIVE: The objective of this study was to quantify the effectiveness of virtual reality balance games (VRBG) to decrease risk and fear of falls among women. METHODS: Thirty six community dwelling women aged 56 and above were randomly divided into experimental (exercises using VRBG focus on improving balance) and control (conventional balance exercises) groups. Both groups attended a twice 6 weekly exercise session for an hour. Risk and fear of falls were measured with Physiological Profile Approach (PPA) and Activity Specific Balance Scale (ABC-6). Pre and post intervention differences between the groups were examined using two way repeated measures ANOVA. RESULTS: Both VRBG and conventional balance exercise groups had significant decrease in PPA (p<0.001) and ABC-6 (p<0.01) after the interventions. However, no significant effects were demonstrated between the groups in PPA (p=0.18) and ABC-6 (p=0.25) post intervention. Time and group interaction effect were not significant for PPA (p=0.18) and ABC-6 (p=0.45). CONCLUSIONS: Practising VRBG can increase balance confidence and decrease risk of falls among community dwelling women.