Search

Trastuzumab deruxtecan (T‐DXd, DS‐8201a) is an antibody–drug conjugate, comprising an anti‐HER2 antibody at a drug‐to‐antibody ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, the concentrations of antibody‐conjugated DXd and total antibody were determined and observed to decrease over time following intravenous administration of T‐DXd to monkeys. The drug‐to‐antibody ratio of T‐DXd also decreased in a time‐dependent manner, which reached approximately 2.5 in 21 days after administration. It was suggested that antibody‐conjugated DXd of T‐DXd was relatively stable in vivo compared with that of other reported antibody–drug conjugates. [ABSTRACT FROM AUTHOR]

CD147 is an immunoglobulin-like receptor that is highly expressed in various cancers and involved in the growth, metastasis, and activation of inflammatory pathways via interactions with various functional molecules, such as integrins, CD44, and monocarboxylate transporters. Through screening of CD147-targeting antibodies with antitumor efficacy, we discovered a novel rat monoclonal antibody #147D. This humanized IgG4-formatted antibody, h4#147D, showed potent antitumor efficacy in xenograft mouse models harboring the human PDAC cell line MIA PaCa-2, HCC cell line Hep G2, and CML cell line KU812, which featured low sensitivity to the corresponding standard-of-care drugs (gemcitabine, sorafenib, and imatinib, respectively). An analysis of tumor cells derived from MIA PaCa-2 xenograft mice treated with h4#147D revealed that cell surface expression of CD147 and its binding partners, including CD44 and integrin α3β1/α6β1, was significantly reduced by h4#147D. Inhibition of focal adhesion kinase (FAK), activation of multiple stress responsible signal proteins such as c-JunN-terminal kinase (JNK) and mitogen-activated protein kinase p38 (p38MAPK), and expression of SMAD4, as well as activation of caspase-3 were obviously observed in the tumor cells, suggesting that h4#147D induced tumor shrinkage by inducing multiple stress responsible signals. These results suggest that the anti-CD147 antibody h4#147D offers promise as a new antibody drug candidate. [ABSTRACT FROM AUTHOR]

Traditional cognitive linguistic theories acknowledge that human emotions are embodied, yet they fail to distinguish the dimensions that reflect the direction of neural signaling between the brain and body. Differences exist across languages and cultures in whether embodied emotions are conceptualized as afferent (feelings from the body) or efferent (enacted through the body). This important distinction has been neglected in academic discourse, arguably as a consequence of the 'lexical approach', and the dominance within the affective psychology of the cognitive and semantic models that overlook the role of interoception as an essential component of affective experience. Empirical and theoretical advances in human neuroscience are driving a reappraisal of the relationships between the mind, brain and body, with particular relevance to emotions. Allostatic (predictive) control of the internal bodily states is considered fundamental to the experience of emotions enacted through interoceptive sensory feelings and through the evoked physiological and physical actions mediated through efferent neural pathways. Embodied emotion concepts encompass these categorized outcomes of bidirectional brain–body interactions yet can be differentiated further into afferent or interoceptive and efferent or autonomic processes. Between languages, a comparison of emotion words indicates the dominance of afferent or interoceptive processes in how embodied emotions are conceptualized in Chinese, while efferent or autonomic processes feature more commonly in English. Correspondingly, in linguistic expressions of emotion, Chinese-speaking people are biased toward being more receptive, reflective, and adaptive, whereas native English speakers may tend to be more reactive, proactive, and interactive. Arguably, these distinct conceptual models of emotions may shape the perceived divergent values and 'national character' of Chinese- and English-speaking cultures. [ABSTRACT FROM AUTHOR]

Purpose: To identify specific bacterial communities in vaginal and endometrial microbiotas as biomarkers of implantation failure by comprehensively analyzing their microbiotas using next‐generation sequencing. Methods: We investigated α‐ and β‐diversities of vaginal and endometrial microbiotas using 16S rRNA gene sequencing and compared their profiles between 145 women with repeated implantation failure (RIF) and 21 controls who lacked the factors responsible for implantation failure with a high probability of being healthy and fertile to identify specific bacteria that induce implantation failure. Results: The endometrial microbiotas had higher α‐diversities than did the vaginal microbiotas (P <.001). The microbiota profiles showed that vaginal and endometrial samples in RIF patients had significantly higher levels of 5 and 14 bacterial genera, respectively, than those in controls. Vaginal Lactobacillus rates in RIF patients were significantly lower at 76.4 ± 38.9% compared with those of the controls at 91.8 ± 22.7% (P =.018), but endometrial Lactobacillus rates did not significantly differ between the RIF patients and controls (56.2 ± 36.4% and 58.8 ± 37.0%, respectively, P =.79). Conclusions: Impaired microbiota communities containing specific bacteria in both the endometrium and vagina were associated with implantation failure. The vaginal Lactobacillus rates, but not the endometrial, may be a biomarker for RIF. [ABSTRACT FROM AUTHOR]

The rate constants for the gas-phase reactions of methyl- and ethylperoxy radicals with NO were studied at room temperature and 4 Torr of pressure. The alkyl peroxy radicals were generated by the reaction of corresponding alkyl radicals with excess O2, where alkyl radicals were prepared by laser photolysis of several precursor molecules.

Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species. Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing. Biodistribution studies revealed that intact DS-8201a was present mostly in the blood without tissue-specific retention. The major pathway of excretion for DXd was the faecal route following iv administration of radiolabelled DS-8201a. The only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is a substrate of organic anion transporting polypeptides, P-gp, and breast cancer resistance protein. In conclusion, the stable linker in circulation and the high clearance of DXd upon release resulted in the low systemic exposure to DXd. Furthermore, the minimal tissue-specific retention and rapid excretion of DXd into faeces as its unmetabolized form with potentially limited impact on drug − drug interaction as a victim were also critical elements of the PK profile of DS-8201a. [ABSTRACT FROM AUTHOR]

Studies suggest that persisting intrauterine bacterial infectious conditions such as chronic endometritis potentially impair the embryo implantation process. The microbial environment in the female reproductive tract, however, remains largely undetermined in infertile patients with a history of repeated implantation failure (RIF). Using next-generation sequencing, we aimed to characterize the microbiota in the endometrial fluid (EF) and vaginal secretions (VS) in women with RIF. Twenty-eight infertile women with a history of RIF and eighteen infertile women undergoing the first in vitro fertilization-embryo transfer attempt (the control group) were enrolled in the study. On days 6-8 in the luteal phase of the natural, oocyte-pickup, or hormone replacement cycle, the paired EF and VS samples were obtained separately. Extracted genomic DNA was pyrosequenced for the V4 region of 16S ribosomal RNA using a next-generation sequencer. The EF microbiota had higher α-diversity and broader bacterial species than the VS microbiota both in the RIF and control groups. The analysis of the UniFrac distance matrices between EF and VS also revealed significantly different clustering. Additionally, the EF microbiota, but not the VS microbiota, showed significant variation in community composition between the RIF group and the control group. Burkholderia species were not detected in the EF microbiota of any samples in the control group but were detectable in a quarter of the RIF group. To our best knowledge, this is the first study investigating the microbiota in the paired EF and VS samples in infertile women with RIF. [ABSTRACT FROM AUTHOR]

Objectives: Dynamic changes in psychophysiological arousal are directly expressed in the sympathetic innervation of the skin. This activity can be measured as tonic and phasic fluctuations in electrodermal activity [Galvanic Skin Response (GSR)/skin conductance]. Biofeedback training can enable an individual to gain voluntary control over this autonomic response and its central correlates. Theoretically, control of psychophysiological arousal may be harnessed as a therapy for epilepsy, to mitigate pre-ictal states. Evidence is accumulating for the clinical efficacy of GSR biofeedback training in the management of drug resistant epilepsy. In this review, we analyse current evidence of efficacy with GSR biofeedback and evaluate the methodology of each study. Method: We searched published literature pertaining to interventional studies of GSR biofeedback for epilepsy, through MEDLINE and Cochrane databases (1950–2018). Using percentage seizure reduction as an indicator of therapeutic efficacy induced by GSR biofeedback, we used meta-analytic methods to summarize extant findings. We also compare and contrast study design with relevance to the interpretation of outcomes. Results: Out of 21 articles retrieved for GSR/EDA/Skin conductance biofeedback, four studies were identified as interventional trials, involving 99 patients with drug-resistant epilepsy in total. Three of these studies included a control group and a positive therapeutic effect of biofeedback was reported in each of these. The difference in seizure frequency percentage (Biofeedback—Control) was between −54.4 and −74.0% with an overall weighted mean difference of −64.3% (95% CI: −85.4 to −43.2%). The response rates (proportion of patients manifesting >50% reduction in seizure frequency) varied from 45 to 66% across studies. Significance: This timely evaluation highlights the potential value of GSR biofeedback therapy, and informs the optimal study design of larger scale studies that are now required to more definitively establish the utility of this non-invasive, non-pharmacological interventional approach for drug-resistant epilepsy. [ABSTRACT FROM AUTHOR]