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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.

Functional changes in spatial genome organization during human development are poorly understood. Here we report a comprehensive profile of nuclear dynamics during human cardiogenesis from pluripotent stem cells by integrating Hi-C, RNA-seq and ATAC-seq. While chromatin accessibility and gene expression show complex on/off dynamics, large-scale genome architecture changes are mostly unidirectional. Many large cardiac genes transition from a repressive to an active compartment during differentiation, coincident with upregulation. We identify a network of such gene loci that increase their association inter-chromosomally, and are targets of the muscle-specific splicing factor RBM20. Genome editing studies show that TTN pre-mRNA, the main RBM20-regulated transcript in the heart, nucleates RBM20 foci that drive spatial proximity between the TTN locus and other inter-chromosomal RBM20 targets such as CACNA1C and CAMK2D . This mechanism promotes RBM20-dependent alternative splicing of the resulting transcripts, indicating the existence of a cardiac-specific trans -interacting chromatin domain (TID) functioning as a splicing factory. The spatial organization of the genome plays an important but unclearly defined role in gene regulation. Here, the authors integrate Hi-C, RNA-seq and ATAC-seq data to map cardiogenesis from pluripotent stem cells and describe an RBM20-dependent splicing factory assembling the TTN locus with other RBM20 targets.

Background The study objectives were to assess the prognostic value of quantitative PET and to test whether combining baseline metabolic tumour burden with early PET response could improve predictive power in DLBCL. Methods A total of 147 patients with DLBCL underwent FDG-PET/CT scans before and after two cycles of RCHOP. Quantitative parameters including metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were measured, as well as the percentage change in these parameters. Cox regression analysis was used to test the relationship between progression-free survival (PFS) and the study variables. Receiver operator characteristics (ROC) analysis determined the optimal cut-off for quantitative variables, and Kaplan–Meier survival analysis was performed. Results The median follow-up was 3.8 years. As MTV and TLG measures correlated strongly, only MTV measures were used for multivariate analysis (MVA). Baseline MTV (MTV-0) was the only statistically significant predictor of PFS on MVA. The optimal cut-off for MTV-0 was 396 cm 3 . A model combing MTV-0 and Deauville score (DS) separated the population into three distinct prognostic groups: good (MTV-0 < 400; 5-year PFS > 90 %), intermediate (MTV-0 ≥ 400+ DS1-3; 5-year PFS 58.5 %) and poor (MTV-0 ≥ 400+ DS4-5; 5-year PFS 29.7 %) Conclusions MTV-0 is an important prognostic factor in DLBCL. Combining MTV-0 and early PET/CT response improves the predictive power of interim PET and defines a poor-prognosis group in whom most of the events occur.

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, factors such as thymic selection and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCRβ variable region of 426 healthy individuals, we find that, on average, fewer than 1% of TCRβ clones are shared between individuals, consistent with largely private TCRβ repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCRβ clones, with each additional shared HLA allele contributing to an increase in ~0.01% of the total shared TCRβ clones, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCRβ clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCRβ clone sharing, indicating that the pattern of private TCRβ clonal expansion is a general feature of the T-cell response to other infectious antigens as well. However, increased age also correlates with increased sharing among the lowest frequency clones, consistent with decreased repertoire diversity in older individuals. Together, all of these factors contribute to shaping the TCRβ repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

Hyperspectral imaging is built with the aggregation of imaging, spectroscopy and radiometric techniques. This technique observes the sample behaviour when it is exposed to light and interprets the properties of the biological samples. As hyperspectral imaging helps in interpreting the sample at the molecular level, it can distinguish very minute changes in the sample composition from its scatter properties. Hyperspectral data collection depends on several parameters such as electromagnetic spectrum wavelength range, imaging mode and imaging system. Spectral data acquired using a hyperspectral imaging system contain variations due to external factors and imaging components. Moreover, food samples are complex matrices with conditions of surface and internal heterogeneities, which may lead to variations in acquired data. Hence, before extracting information, these variations and noises must be reduced from the data using reference-dependent or reference-independent spectral pre-processing techniques. Using of the entire hyperspectral data for information extraction is tedious and time-consuming. In order to overcome this, exploratory data analysis techniques are used to select crucial wavelengths from the excessive hyperspectral data. Using appropriate chemometric techniques (supervised or unsupervised learning techniques) on this pre-processed hyperspectral data, qualitative or quantitative information from sample can be obtained. Qualitative information for analysing of the chemical composition, detecting of the defects and determining the purity of the food product can be extracted using discriminant analysis techniques. Quantitative information including variation in chemical constituents and contamination levels in food and agricultural sample can be extracted using categorical regression techniques. In combination with appropriate spectra pre-processing and chemometric technique, hyperspectral imaging stands out as an advanced quality evaluation system for food and agricultural products.

The Ad26.COV2.S vaccine 1 – 3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies 1 . However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I–IIa clinical trial 2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. Analysis of the immunogenicity of the Ad26.COV2.S vaccine against the B1.351 and P.1 SARS-CoV-2 variants of concern shows reduced neutralization antibody titres, but comparable T cell responses and antibody-dependent effector functions.

The current management of lymphoma requires accurate diagnosis and subtyping of de novo lymphoma and of relapsed or refractory lymphoma in known cases. The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the clinical management of lymphomas is unclear. To investigate the use of EBUS-TBNA in the diagnosis of de novo and relapsed mediastinal lymphomas. A total of 2,256 consecutive patients who underwent EBUS-TBNA in a tertiary center between February 2008 and April 2013 were prospectively evaluated. The diagnostic accuracy and clinical use of EBUS-TBNA in 100 cases of de novo or suspected relapsed mediastinal lymphoma was investigated by comparing EBUS-TBNA diagnosis with the final diagnosis. De novo mediastinal lymphoma was correctly diagnosed by EBUS-TBNA in 45 (88%) of 51 and relapsed lymphoma in 15 (100%) of 15 lymphoma cases. EBUS-TBNA accurately established a diagnosis other than lymphoma in 32 (97%) of 33 patients with suspected lymphoma relapse. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in the diagnosis of mediastinal lymphoma were 89%, 97%, 98%, 83%, and 91%, respectively. Sensitivity of EBUS-TBNA in subtyping lymphomas into high-grade non-Hodgkin lymphoma, low-grade non-Hodgkin lymphoma, and Hodgkin lymphoma was 90%, 100%, and 79%, respectively. EBUS-TBNA diagnosis was adequate for clinical management in 84 (84%) of 100 cases. Multimodality evaluation of EBUS-TBNA can be successful in the diagnosis of de novo mediastinal lymphomas and is ideally suited in distinguishing lymphoma relapse from alternative pathologies; it is least sensitive in subtyping Hodgkin lymphoma.

BackgroundSeveral routes of fecal microbiota transplantation (FMT) administration are available for treating recurrent Clostridioides difficile infections (CDI), the most recent of which are capsules.AimTo assess the efficacy of colonoscopy, capsule, enema, and nasogastric tube (NGT) FMT for the treatment of recurrent CDI.MethodsWe reported clinical outcomes of colonoscopy, capsule, enema, and NGT FMT for the treatment of recurrent CDI according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. During January 2000 to January 2018, three databases were searched: PubMed, EMBASE, and CINAHL. Primary outcome was overall cure rate which was assessed using a random effects model; secondary outcomes included adverse effects as well as subgroup analyses comparing donor relationship, sample preparation, and study design.ResultsTwenty-six studies (1309 patients) were included in the study. FMT was administered using colonoscopy in 16 studies (483 patients), NGT in five studies (149 patients), enema in four studies (360 patients), and capsules in four studies (301 patients). The random effects of pooled FMT cure rates were colonoscopy 94.8% (CI 92.4–96.8%; I2 15.6%), capsule 92.1% (CI 88.6–95.0%; I2 7.1%), enema 87.2% (CI 83.4–90.5%; I2 0%), and NGT/NDT 78.1% (CI 71.6–84.1%; I2 0%). On subgroup analysis of colonoscopy FMT, sample preparation methods had comparable cure rates: fresh 94.9% compared to 94.5%. Similarly, cure rates were unaffected by donor relationship: mixed 94.5% compared to unrelated donor 95.7%.ConclusionCDI cure rates with FMT performed with colonoscopy are superior to enema and NGT FMT, while those with FMT with colonoscopy and capsule are comparable.

The histone H2A variant H2A.Z is essential for embryonic development and for proper control of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions of amino acid sequence of H2A.Z likely determine its functional specialization compared to core histone H2A. For example, H2A.Z contains three divergent residues in the essential C-terminal acidic patch that reside on the surface of the histone octamer as an uninterrupted acidic patch domain; however, we know little about how these residues contribute to chromatin structure and function. Here, we show that the divergent amino acids Gly92, Asp97, and Ser98 in the H2A.Z C-terminal acidic patch (H2A.Z(AP3)) are critical for lineage commitment during ESC differentiation. H2A.Z is enriched at most H3K4me3 promoters in ESCs including poised, bivalent promoters that harbor both activating and repressive marks, H3K4me3 and H3K27me3 respectively. We found that while H2A.Z(AP3) interacted with its deposition complex and displayed a highly similar distribution pattern compared to wild-type H2A.Z, its enrichment levels were reduced at target promoters. Further analysis revealed that H2A.Z(AP3) was less tightly associated with chromatin, suggesting that the mutant is more dynamic. Notably, bivalent genes in H2A.Z(AP3) ESCs displayed significant changes in expression compared to active genes. Moreover, bivalent genes in H2A.Z(AP3) ESCs gained H3.3, a variant associated with higher nucleosome turnover, compared to wild-type H2A.Z. We next performed single cell imaging to measure H2A.Z dynamics. We found that H2A.Z(AP3) displayed higher mobility in chromatin compared to wild-type H2A.Z by fluorescent recovery after photobleaching (FRAP). Moreover, ESCs treated with the transcriptional inhibitor flavopiridol resulted in a decrease in the H2A.Z(AP3) mobile fraction and an increase in its occupancy at target genes indicating that the mutant can be properly incorporated into chromatin. Collectively, our work suggests that the divergent residues in the H2A.Z acidic patch comprise a unique domain that couples control of chromatin dynamics to the regulation of developmental gene expression patterns during lineage commitment.

Responses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection. DRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4 and CD8 DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients. In patients with an abnormal biopsy, the majority of CD8 DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8 DRTC were more abundant pre- and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples. The findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection.