In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A^131R-chimeric receptor (CR), and those engineered with the low-affinity CD16^158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A^131R-CR T cells was 74 ± 10%, whereas the percentage of CD16^158F-CR T cells was 46 ± 15%. Only CD32A^131R-CR T cells bound panitumumab. CD32A^131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16^158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116^FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A^131R-CR on T cells by cetuximab or panitumumab and CD16^158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A^131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.     

Dacarbazine alone or associated with melanoma-bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.     

Risk factors and etiology of childhood hearing loss: a cohort review of 296 subjects

Abstract

Background: The association between the Joint Committee on Infant Hearing (JCIH) risk factors and etiology of hearing loss (HL) is not studied well in children.

Objectives: To clarify the etiologic causes and evaluate the JCIH risk characteristics of children with HL.

Methods: A retrospective study of 296 children with HL born between 2009.01 and 2013.12 in Stokholm. Demographic data, family and medical histories, audiologic results, imaging findings, and genetic results were ascertained and analyzed.

Results: In 221 with bilateral hearing loss (BHL), family history and neonatal risk indicators were the most common risks (59 each), followed by syndrome related risks. In 75 with unilateral hearing loss (UHL), craniofacial anomaly was the most common risk, followed by family history. Etiology was established in 93 with BHL, in which syndromic HL accounted for 37.2%, chromosomal aberrations for 21.3%, and environmental causes for 19.1%. Etiology was established in 35 with UHL, in which ear malformation accounted for the most (74.3%), followed by environmental causes (14.3%).

Conclusions and significance: Childhood HL can be attributed to a variety of causes with an etiology identifiable in 42.5% of BHL and 46.7% of UHL. BHL and UHL have different patterns of JCIH risk exposure and etiology.     

Editorial: Something new – what's next for child and adolescent psychiatry?

The start of a new decade is often the moment when people pause to reflect on what they have accomplished in the past 10–20 years and where they would like to be at the start of the next decade. Although not designed as such, the 2020 Annual Review issue engages in exactly this sort of a backwards and forwards look at the field of child and adolescent psychiatry and psychology. In doing so, it covers topics that are at the core of the field and have preoccupied researchers and clinicians for decades. It also covers research endeavors that have only more recently captured the attention of the field and that build bridges to disciplines that have not historically been involved in the study of neurodevelopment. In every case, the authors who have contributed to the 2020 Annual Research Review highlight exciting new directions for research and make novel recommendations for how to advance the state of our science.     

Smartphone applications available to pregnant women in the United Kingdom: An assessment of nutritional information

The importance of diet during pregnancy is critically important for the short‐ and long‐term health of both mother and child. The number of apps targeting pregnant women is rapidly increasing, yet the nutritional content of these tools remains largely unexplored. This review aimed to evaluate the coverage and content of nutrition information in smartphone apps available to U.K. pregnant women. Keyword searches were conducted in iTunes and Google Play stores in November 2018. Candidate apps were included if they targeted pregnant women, provided pregnancy‐specific nutritional information, had a user rating of at least 4+ based on at least 20 ratings, and were available in English. Nutritional content was assessed for accuracy against U.K. recommendations. Behaviour change techniques (BCTs) were also evaluated. Twenty‐nine apps were included, seven of which originated in the United Kingdom. There was a large variability in the quality of smartphone app nutritional information. The accuracy of nutrition information varied, and several apps conveyed inappropriate information for pregnancy. On average, 10 BCTs were identified per app (range 2–15). Overall, smartphone apps do not consistently provide accurate and useful nutritional information to pregnant women. This study highlights the need for the integration of evidence‐based nutritional information during app development and for increased regulatory oversight. App developers should also make it clear that nutritional content is intended for a specific geographical region or population or modify for the intended audience. These are important considerations for the design of future apps, which are increasingly used to complement existing maternity services.     

Early presentation of urinary retention in multiple system atrophy: can the disease begin in the sacral spinal cord?

Journal of Neurology - Lower urinary tract (LUT) dysfunction presents early in multiple system atrophy (MSA), usually initially as urinary urgency, frequency and incontinence, and voiding...     

Functional disconnection of the dentate nucleus in essential tremor

Journal of Neurology - Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of...