Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer.

BACKGROUND: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: Patients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 µg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 µg/ml was above the prespecified non-inferiority margin of - 12.5%. RESULTS: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 µg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%. CONCLUSIONS: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.

Talking to patients about biosimilars.

Biologic therapies target aberrant pathways in diseases including diabetes, cancer and autoimmune disorders. Despite recent scientific advances, patient access to these agents can be limited. Biosimilars are designed to be highly similar to the originator biologic, targeting the same biological pathways, with comparable efficacy and safety. Biosimilars have the advantage of lower treatment costs, offering the potential for increased clinical use and patient access. Several biosimilars are approved for clinical use in the USA and Europe; however, there is a lack of awareness about biosimilars among healthcare providers and patients. This overview of the scientific basis of biosimilars and current indications aim to enhance discussions with patients and increase understanding of the role of biosimilars in individual treatment plans.

"We're just two people in a relationship": A qualitative exploration of emotional bond and fairness experiences between transgender women and their cisgender partners.

Trans-including couples experience systemic marginalization impacting their relationships, yet studies on these relationships or narratives of strength are few. The purpose of this qualitative study was to explore emotional bonding and perceptions of fairness between transgender women and their cisgender partners. Interpretative Phenomenological Analysis was utilized to answer the research question: What are the experiences of emotional bond and fairness between transgender women and their cisgender partners? This research was situated within frameworks of minority stress, romantic attachment, and contextual therapy. Seven couples of transgender women and cisgender partners were interviewed. Three themes emerged: Minority Stress Contexts and Relational Strengths; The Experience of Emotional Bond; and Negotiating Balance. Processes of boundary creation, attunement, affirmations, and balance of care were noted. Findings reframe partner relationships as opportunities to construct transphobia-resistant and resilient narratives. Recommendations for clinicians include prioritizing the couple subsystem as an avenue for building resilience against minority stress.

A Contextual Perspective on Associations Between Reported Parental Infidelity and Relational Ethics of the Adult Children.

This study's aim was to apply a Contextual theory lens on exploring whether knowledge of parental infidelity affects the Relational Ethics (RE) of adult children. The Relational Ethics Scale (RES) was used to capture horizontal (partner) and vertical (family of origin) relational ethics in a clinical sample of 195 participants. A repeated measures ANOVA tested the differences in RES scores among the participants who reported knowledge of parental infidelity and the participants who did not. Results showed that knowledge of parental infidelity is significantly associated with lower scores on the RES, which indicates problematic relationships, both in partners and with family of origin. Clinical implications on how parental infidelity can affect relational ethics are discussed.

Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems.

Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function-a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health.

Most calbindin-immunoreactive neurons, but few calretinin-immunoreactive neurons, express the m1 acetylcholine receptor in the middle temporal visual area of the macaque monkey.

INTRODUCTION: Release of the neuromodulator acetylcholine into cortical circuits supports cognition, although its precise role and mechanisms of action are not well understood. Little is known about functional differences in cholinergic modulatory effects across cortical model systems, but anatomical evidence suggests that such differences likely exist because, for example, the expression of cholinergic receptors differs profoundly both within and between species. METHODS: In the primary visual cortex (V1) of macaque monkeys, cholinergic receptors are strongly expressed by inhibitory interneurons. Using dual-immunofluorescence confocal microscopy, we examine m1 muscarinic acetylcholine receptor expression by two subclasses of inhibitory interneurons-identified by their expression of the calcium-binding proteins calbindin and calretinin-in the middle temporal extrastriate area (MT) of the macaque. RESULTS AND CONCLUSIONS: We find that the majority of calbindin-immunoreactive neurons (55%) and only few calretinin-immunoreactive neurons (10%) express the m1 acetylcholine receptor. These results differ from the pattern observed in V1 of the same species, lending further support to the notion that cholinergic modulation in the cortex is tuned such that different cortical compartments will respond to acetylcholine release in different ways.

Modulatory compartments in cortex and local regulation of cholinergic tone.

Neuromodulatory signaling is generally considered broad in its impact across cortex. However, variations in the characteristics of cortical circuits may introduce regionally-specific responses to diffuse modulatory signals. Features such as patterns of axonal innervation, tissue tortuosity and molecular diffusion, effectiveness of degradation pathways, subcellular receptor localization, and patterns of receptor expression can lead to local modification of modulatory inputs. We propose that modulatory compartments exist in cortex and can be defined by variation in structural features of local circuits. Further, we argue that these compartments are responsible for local regulation of neuromodulatory tone. For the cholinergic system, these modulatory compartments are regions of cortical tissue within which signaling conditions for acetylcholine are relatively uniform, but between which signaling can vary profoundly. In the visual system, evidence for the existence of compartments indicates that cholinergic modulation likely differs across the visual pathway. We argue that the existence of these compartments calls for thinking about cholinergic modulation in terms of finer-grained control of local cortical circuits than is implied by the traditional view of this system as a diffuse modulator. Further, an understanding of modulatory compartments provides an opportunity to better understand and perhaps correct signal modifications that lead to pathological states.

Impaired trace fear conditioning and diminished ERK1/2 phosphorylation in the dorsal hippocampus of adult rats administered alcohol as neonates.

Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N-methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec.