Diagnostic tests in canine andrology - What do they really tell us about fertility?

Dog breeders often require breeding soundness evaluations which include andrological examinations of the genital organs, hormone measurements, and semen analyses. During the past decades, a considerable number of research results have been published, allowing diagnoses of specific andrological conditions and fertility assessment. For specific examinations, however, no standard procedures have been defined and for some parameters different reference ranges have been published. Therefore, examination results from different facilities are difficult to compare and profound conclusions regarding health and fertility of a male dog are not always possible. Conventional semen examination, however, is still useful in identifying deviations or no deviations from normality, especially if confounding factors are taken into account and if the exam is repeated in case of inconclusive findings. A standardization of examination procedures and reference ranges would help to harmonize the exchange of examination results and interpretation of the findings

Evaluation of the Temporal Muscle Thickness as an Independent Prognostic Biomarker in Patients with Primary Central Nervous System Lymphoma.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient's frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2-097-4.848, p < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608-3.911, p < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Diagnostic tests in canine andrology - What do they really tell us about fertility?

Dog breeders often require breeding soundness evaluations which include andrological examinations of the genital organs, hormone measurements, and semen analyses. During the past decades, a considerable number of research results have been published, allowing diagnoses of specific andrological conditions and fertility assessment. For specific examinations, however, no standard procedures have been defined and for some parameters different reference ranges have been published. Therefore, examination results from different facilities are difficult to compare and profound conclusions regarding health and fertility of a male dog are not always possible. Conventional semen examination, however, is still useful in identifying deviations or no deviations from normality, especially if confounding factors are taken into account and if the exam is repeated in case of inconclusive findings. A standardization of examination procedures and reference ranges would help to harmonize the exchange of examination results and interpretation of the findings

Incremental value of high-frequency QRS analysis for diagnosis and prognosis in suspected exercise-induced myocardial ischaemia.

AIM Exercise stress testing is used to detect myocardial ischaemia, but is limited by low sensitivity and specificity. The authors investigated the value of the analysis of high-frequency QRS components as a marker of abnormal depolarization in addition to standard ST-deviations as a marker of abnormal repolarization to improve the diagnostic accuracy. METHODS AND RESULTS Consecutive patients undergoing bicycle exercise stress nuclear myocardial perfusion imaging were prospectively enrolled. Presence of myocardial ischaemia, the primary diagnostic endpoint, was adjudicated using MPI and coronary angiography. Automated high-frequency QRS analysis was performed in a blinded fashion. The prognostic endpoint was major adverse cardiac events (MACEs) during two years of follow-up. Exercise-induced ischaemia was detected in 147/662 patients (22%). The sensitivity of high-frequency QRS was similar to ST-deviations (46% vs. 43%, p=0.59), while the specificity was lower (75% vs. 87%, p<0.001). The combined use of high-frequency QRS and ST-deviations classified 59% of patients as 'rule-out' (both negative), 9% as 'rule-in' (both positive) and 32% in an intermediate zone (one test positive). The sensitivity for 'rule-out' and the specificity for 'rule-in' improved to 63% and 97% compared with ST-deviation analysis alone (both p<0.001). MACE-free survival was 90%, 80% and 42% in patients in the 'rule-out', intermediate and 'rule-in' groups ( p<0.001). After adjustment for age, gender, ST-deviations and clinical post-test probability of ischaemia, high-frequency QRS remained an independent predictor for the occurrence of MACEs. CONCLUSION The use of high-frequency QRS analysis in addition to ST-deviation analysis improves the diagnostic accuracy during exercise stress testing and adds independent prognostic information

Development of anti-CD32b antibodies with enhanced Fc function for the treatment of B and plasma cell malignancies

The sole inhibitory Fcg receptor CD32b (Fcg RIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of Fcg RIIIa on immune effector cells. The NVS32b mAbs selectively target CD32bþ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32bþ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc–binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32bþ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32bþ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32bþ malignant cells

Development of anti-CD32b antibodies with enhanced Fc function for the treatment of B and plasma cell malignancies

The sole inhibitory Fcγ receptor CD32b (FcγR2b) is expressed throughout B and plasma cell development and on their malignant counterparts with the highest expression found on multiple myeloma. Additionally, CD32b expression on tumor cells is known to sequester IgG Fc whereby providing a mechanism of resistance to therapeutic monoclonal antibodies (mAb) with Fc dependent activity. Taken together, CD32b represents an attractive tumor antigen for targeting with a mAb. To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. The complementarity-determining regions (CDRs) of these antibodies bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcR on immune effector cells. NVS32b mAbs selectively depletes CD32b+ healthy and malignant B cells but spares myeloid cells and CD32a+ cells. These antibodies mediate potent killing of opsonized cells via antibody dependent cellular cytotoxicity and phagocytosis (ADCC & ADCP), as well as complement dependent cytotoxicity (CDC). Additionally, NVS32b CDRs block the CD32b Fc binding domain, thereby minimizing CD32b mediated resistance to therapeutic mAbs with Fc dependent activity, including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b positive xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor microenvironment and enhancement of DC maturation in response to immune-complexes. The activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed on samples from CLL and MM patients. NVS32b mAbs demonstrated great therapeutic potential, as a single agent or in combination with other mAb therapeutics

Development of Anti-CD32b Antibodies with Enhanced Fc Function for the Treatment of B and Plasma Cell Malignancies

The sole inhibitory Fcγ receptor CD32b (FcγR2b) is expressed throughout B and plasma cell development and on their malignant counterparts with the highest expression found on multiple myeloma. Additionally, CD32b expression on tumor cells is known to sequester IgG Fc whereby providing a mechanism of resistance to therapeutic monoclonal antibodies (mAb) with Fc dependent activity. Taken together, CD32b represents an attractive tumor antigen for targeting with a mAb. To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. The complementarity-determining regions (CDRs) of these antibodies bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcR on immune effector cells. NVS32b mAbs selectively depletes CD32b+ healthy and malignant B cells but spares myeloid cells and CD32a+ cells. These antibodies mediate potent killing of opsonized cells via antibody dependent cellular cytotoxicity and phagocytosis (ADCC & ADCP), as well as complement dependent cytotoxicity (CDC). Additionally, NVS32b CDRs block the CD32b Fc binding domain, thereby minimizing CD32b mediated resistance to therapeutic mAbs with Fc dependent activity, including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b positive xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor microenvironment and enhancement of DC maturation in response to immune-complexes. The activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed on samples from CLL and MM patients. NVS32b mAbs demonstrated great therapeutic potential, as a single agent or in combination with other mAb therapeutics