Polyangiitis Overlap Syndrome: Polyarteritis Nodosa with Leukocytoclastic Vasculitis Associated with Left Ventricular Thrombus and Vocal Cord Palsy: A Case Report.

Polyangiitis overlap syndrome (POS) is a systemic vasculitis characterized by overlapping features of more than one well-defined vasculitic syndrome. We present the case of a 38-year-old Malay man with progressive dyspnea and palpable purpura in his lower limbs. The diagnostic evaluation revealed right-sided segmental pulmonary consolidation with pleural effusion, systolic cardiac dysfunction with the presence of an intracardiac thrombus, and left vocal cord palsy secondary to laryngeal mononeuropathy.

c.1155-3A>G is a pathogenic variant that causes aberrant splicing, disrupted parafibromin expression, and hyperparathyroidism-jaw tumor syndrome.

Germline and somatic pathogenic variants in the gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for -related conditions, including deletion, truncating, missense, and splice site mutations.

Complement and T cell activation in transplantation.

The complement system plays a critical role in modulating adaptive T cell responses. Coordination of the proinflammatory signaling cascade and complement regulators permits efficient T cell priming and survival, while minimizing off-target damage to healthy host cells. In the context of transplantation, anti-donor T cell immunity remains a barrier to long term graft health and complement-targeted therapies have shown the potential to significantly improve patient outcomes.

Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation.

Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear.

Role of complement in humoral immunity.

Purpose Of Review: Antibody-mediated rejection (AMR) after solid organ transplantation remains an unsolved problem and leads to poor early and late patient outcomes. The complement system is a well recognized pathogenic mediator of AMR. Herein, we review the known molecular mechanisms of disease and results from ongoing clinical testing of complement inhibitors after solid organ transplant.

Clinical implications of conflicting variant interpretations in the cancer genetics clinic.

Purpose: The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants.

Methods: Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives.

Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing.

Background: Recent changes in oncology practice guidelines indicate that mutations in cancer susceptibility genes identified on tumor genomic profiling (TGP) should prompt confirmatory germline testing. Our study aimed to determine the proportion of patients with TGP-identified mutations in moderate risk breast and ovarian cancer genes who previously would not have been considered for germline testing.

Methods: From January 2013 to September 2020, 7468 adult Stanford Health Care patients underwent TGP on solid tumor samples and 166 had TGP-identified mutations in moderate risk breast and ovarian cancer susceptibility genes (ATM, BRIP1, CHEK2, PALB2, RAD51C and RAD51D).

Mannan-Binding Lectin Promotes Murine Graft-versus-Host Disease by Amplifying Lipopolysaccharide-Initiated Inflammation.

Conditioning regimens used for hematopoietic stem cell transplantation (HCT) can escalate the severity of acute T cell-mediated graft-versus-host disease (GVHD) by disrupting gastrointestinal integrity and initiating lipopolysaccharide (LPS)-dependent innate immune cell activation. Activation of the complement cascade has been associated with murine GVHD, and previous work has shown that alternative pathway complement activation can amplify T cell immunity. Whether and how mannan-binding lectin (MBL), a component of the complement system that binds mannose as well as oligosaccharide components of LPS and lipoteichoic acid, affects GVHD is unknown.

T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death.

TNF ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by (a) inhibiting RIPK1's death-signaling function and activating NF-κB or (b) causing RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell-dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered.

AMPK mediates regulation of glomerular volume and podocyte survival.

Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS.

Residential proximity to plant nurseries and risk of childhood leukemia.

Background: Pesticides are a potential risk factor for childhood leukemia. Studies evaluating the role of prenatal and/or early life exposure to pesticides in the development of childhood leukemia have produced a range of results. In addition to indoor use of pesticides, higher risks have been reported for children born near agricultural crops.

Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.

Background: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs).

Methods: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA).

Results: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity.

Geographies of insecure water access and the housing-water nexus in US cities.

Safe, reliable, and equitable water access is critical to human health and livelihoods. In the United States, an estimated 471,000 households or 1.1 million individuals lack a piped water connection and 73% of households are located in cities, close to networked supply.

Validation and Characterization of Platelet-Rich Plasma in the Feline: A Prospective Analysis.

To quantitate key parameters of the platelet-rich plasma (PRP) product from a commercially available system in healthy, adult felines. A prospective study was performed from January 2019 to April 2019. 11 adult, healthy cats were used to prospectively analyze a commercially available PRP system.

[Effects of a supportive program on uncertainty, anxiety, and maternal-fetal attachment in women with high-risk pregnancy].

Purpose: The purpose of this study was to identify the effects of a supportive program on uncertainty, anxiety, and maternal-fetal attachment in high-risk pregnant women.

Methods: The participants were 59 high-risk pregnant women admitted to the maternal-fetal intensive care unit. The control group (n=30) received usual treatment and antenatal care, while the experimental group (n=29) received an additional supportive program.

Germline Testing for Patients With Mutations on Somatic Tumor Testing.

Background: The National Comprehensive Cancer Network (NCCN) recommends germline testing for pathogenic mutations identified by somatic tumor sequencing. The aim of this study was to explore whether patients at Stanford with somatic mutations were recommended germline testing in accordance with NCCN guidelines.

Methods: We retrospectively collected all Stanford patients with mutations found by tumor sequencing.

Role of Complement Activation in Allograft Inflammation.

Purpose: Novel paradigms have broadened our understanding of mechanisms through which complement mediates allograft inflammation/injury. Herein we review advances in the field and highlight therapeutic implications.

Recent Findings: Pre-clinical and translational human trials have elucidated complement-dependent mechanisms of post-transplant ischemia-reperfusion (I/R) injury.

Understanding variants of uncertain significance in the era of multigene panels: Through the eyes of the patient.

Variants of uncertain significance (VUSs) are often disclosed to patients despite ambiguous association with disease risk and lack of clinical actionability. It is important to understand how patients understand a VUS result, but few studies have assessed this. Our qualitative study explored patient recall, reaction to, and interpretation of a VUS in the context of multigene panels.