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B7 homolog 3 (B7-H3; CD276 ), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA 0 ) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA 0 with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA 0 rate 1 year postprostatectomy was 66% (95% confidence interval 47–81%). The use of B7-H3–targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180. In a single-arm phase 2 study, enoblituzumab (a humanized, Fc-engineered, B7-H3-targeting antibody) was found to be safe and showed preliminary evidence of potential clinical activity in men with high-risk localized prostate cancer.

Spaceflight can change metabolic, immunological, and biological homeostasis and cause skin rashes and irritation, yet the molecular basis remains unclear. To investigate the impact of short-duration spaceflight on the skin, we conducted skin biopsies on the Inspiration4 crew members before (L-44) and after (R + 1) flight. Leveraging multi-omics assays including GeoMx™ Digital Spatial Profiler, single-cell RNA/ATAC-seq, and metagenomics/metatranscriptomics, we assessed spatial gene expressions and associated microbial and immune changes across 95 skin regions in four compartments: outer epidermis, inner epidermis, outer dermis, and vasculature. Post-flight samples showed significant up-regulation of genes related to inflammation and KRAS signaling across all skin regions. These spaceflight-associated changes mapped to specific cellular responses, including altered interferon responses, DNA damage, epithelial barrier disruptions, T-cell migration, and hindered regeneration were located primarily in outer tissue compartments. We also linked epithelial disruption to microbial shifts in skin swab and immune cell activity to PBMC single-cell data from the same crew and timepoints. Our findings present the inaugural collection and examination of astronaut skin, offering insights for future space missions and response countermeasures. Here the authors profile skin microenvironment changes in response to spaceflight by performing a multi omics analysis using skin punch biopsies from the crew members of SpaceX Inspiration4 mission comparing before, post launch and one day after return 91 of the 3-day mission.

The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment. The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors.

Background Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling ( n  = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments ( q -values) were applied to account for multiple hypothesis testing. Results In patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR] FOXA1 (high)  = 1.04, 95% CI = 0.61–1.76, HR FOXA1 (low)  = 0.30, 95% CI = 0.14–0.67, q interaction  = 0.0013), and a resembling trend was observed for AR (HR AR (high)  = 1.15, 95% CI = 0.60–2.20, HR AR (low)  = 0.42, 95% CI = 0.24–0.75, q interaction  = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HR RFi ESR1 (high)  = 0.76, 95% CI = 0.43–1.35, HR RFi, ESR1 (low)  = 0.56, 95% CI = 0.29–1.06, q interaction  = 0.37). Irrespective of molecular subtype, higher levels of ESR1 , Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HR ESR1  = 0.80, 95% CI = 0.69–0.92, q  = 0.005; HR Mast cells  = 0.74, 95% CI = 0.65–0.85, q  < 0.0001; and HR PGR  = 0.78, 95% CI = 0.68–0.89, q  = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HR BCproliferation  = 1.54, 95% CI = 1.33–1.79, q  < 0.0001; HR Hypoxia  = 1.38, 95% CI = 1.20–1.58, q  < 0.0001). The results were similar for OS. Conclusions Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR , ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .

PurposePatients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR.Experimental designPatients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles.ResultsFifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR.ConclusionNeoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.Trial registration: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.

PurposeTo empirically verify whether patient hospital satisfaction ratings on social media such as Yelp provide similar information as the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys.Design/methodology/approachOLS and ordinal regressions performed on secondary data obtained from Yelp.com and 2016 Hospital Compare database disclosed by CMS.FindingsResults show that the patient hospital satisfaction ratings from Yelp can predict the patient experience of care domain scores obtained through the annual HCAHPS surveys and are also positively and significantly correlated to the overall hospital quality performance scores given by CMS.Research limitations/implicationsStudy suggests that social media patient review information could be used to supplement the information obtained from HCAHPS surveys, thereby providing hospitals more accurate information about their patient experiences.Practical implicationsHospital leaders need not wait an entire year to receive their HCHAPS scores to know about the issues related to their patient experience that need improvement and can periodically refer to free Yelp patient review scores on Yelp.com to obtain similar information.Originality/valueTo the best of knowledge, this research is the first to empirically demonstrate that patient reviews freely obtained from social media sites like Yelp can provide similar information as obtained from HCAHPS surveys and can thus be used to supplement HCAHPS.

Background The characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited. Molecular and spatial characterization of HER2+ TME of primary, recurrent, and metastatic breast tumors has the potential to identify immune mediated mechanisms and biomarker targets that could be used to guide selection of therapies. Methods We examined 15 specimens from eight patients with HER2+ breast cancer: 10 primary breast tumors (PBT), two soft tissue, one lung, and two brain metastases (BM). Using molecular profiling by bulk gene expression TME signatures, including the Tumor Inflammation Signature (TIS) and PAM50 subtyping, as well as spatial characterization of immune hot, warm, and cold regions in the stroma and tumor epithelium using 64 protein targets on the GeoMx Digital Spatial Profiler. Results PBT had higher infiltration of immune cells relative to metastatic sites and higher protein and gene expression of immune activation markers when compared to metastatic sites. TIS scores were lower in metastases, particularly in BM. BM also had less immune infiltration overall, but in the stromal compartment with the highest density of immune infiltration had similar levels of T cells that were less activated than PBT stromal regions suggesting immune exclusion in the tumor epithelium. Conclusions Our findings show stromal and tumor localized immune cells in the TME are more active in primary versus metastatic disease. This suggests patients with early HER2+ breast cancer could have more benefit from immune-targeting therapies than patients with advanced disease.

As eCommerce has become widespread, the challenge of successfully navigating the returns process has grown perilous. The product returns issue is even more difficult for microenterprises that sell unique or custom products with fewer resources. The authors examined the impact of the antecedents of return policy leniency, specifically economic and social success factors. Using a web crawler over a 24-week period, the authors collected and analyzed data for a sample of 781 shops from Etsy, an eCommerce platform. Results indicate that the well-studied factor of sales, in addition to a new social factor – community dialogue – impacts an Etsy shop's return policy leniency.

Organophosphate (OP) insecticides are used to eliminate agricultural threats posed by insects, through inhibition of the neurotransmitter acetylcholinesterase (AChE). These potent neurotoxins are extremely efficacious in insect elimination, and as such, are the preferred agricultural insecticides worldwide. Despite their efficacy, however, estimates indicate that only 0.1% of organophosphates reach their desired target. Moreover, multiple studies have shown that OP exposure in both humans and animals can lead to aberrations in embryonic development, defects in childhood neurocognition, and substantial contribution to neurodegenerative diseases such as Alzheimer’s and Motor Neurone Disease. Here, we review the current state of knowledge pertaining to organophosphate exposure on both embryonic development and/or subsequent neurological consequences on behaviour, paying particular attention to data gleaned using an excellent animal model, the zebrafish (Danio rerio).

Case summary A 15-year-old male castrated domestic shorthair cat originally presented to its primary care veterinarian with a chief complaint of a multi-month history of decreased appetite, weight loss and mild weight-bearing lameness. On physical examination, over the right scapula there was mild-to-moderate muscle wasting and a palpable firm, bony mass measuring approximately 3.5 cm × 3 cm. A complete blood count, chemistry panel, urinalysis, urine culture and baseline thyroxine were clinically unremarkable. Further diagnostics included CT, which revealed a large, expansile, irregularly mineralized mass centered over the caudoventral scapula at the site of attachment of the infraspinatus muscle. Following wide surgical excision by means of complete scapulectomy the patient regained function of the limb and has been free of disease since. The clinical institution’s pathology service examined the resected scapula with associated mass and diagnosed an intraosseous lipoma. Relevance and novel information Intraosseous lipoma is a rare form of bone neoplasia that has only been reported once in the small animal veterinary literature. Histopathology, clinical signs and radiographic changes were consistent with what is described in human literature. It is hypothesized that these tumors occur because of invasively growing adipose tissue within the medullary canal following trauma. Considering the rarity of primary bone tumors in cats, intraosseous lipomas should be considered as a differential diagnosis in future cases with similar signs and history.