Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.

The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer.

Interplay between CD28 and PD-1 in T cell immunotherapy.

Immune checkpoint therapy targeting the PD-1/PD-L1 axis has revolutionised the treatment of solid tumors. However, T cell exhaustion underpins resistance to current anti-PD-1 therapies, resulting in lower response rates in cancer patients. CD28 is a T cell costimulatory receptor that can influence the PD-1 signalling pathway (and vice versa).

Inflammation of adenohypophysis is commonly associated with headache in surgically managed Rathke's cleft cysts.

Purpose: Rathke's cleft cysts (RCC) are present in up to 20% of autopsy studies but only a minority necessitate surgical treatment. Inflammation of RCC is thought to be significant in three processes: the development of classical symptoms, a predisposition to rupture or apoplexy, and increasing the rate of RCC recurrence. We aim to characterize clinical presentation, histological and radiological findings in patients with surgically managed RCC.

A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling.

Background: TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.

Methods: This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type.

Determinants of Liraglutide Treatment Discontinuation in Type 1 Diabetes: A Post Hoc Analysis of ADJUNCT ONE and ADJUNCT TWO Randomized Placebo-Controlled Clinical Studies.

Introduction: Two phase 3 randomized controlled studies (ADJUNCT ONE (Clinicaltrials.gov: NCT01836523), ADJUNCT TWO (Clinicaltrials.gov: NCT02098395)) evaluated liraglutide (1.

Hypoglycaemia following physical exercise in a patient with novel SLC16A1 variant.

Rare defects in the promoter region of SLC16A1, the gene encoding monocarboxylate transporter 1 (MCT-1), result in exercise-induced hyperinsulinism. In this disorder, inappropriate insulin secretion is triggered by anaerobic exercise with consequent hypoglycaemia. We describe the case of a 41-year-old man presenting with a generalised tonic-clonic seizure and severe hypoglycaemia following strenuous exercise.

A mixed-methods assessment of the Australasian Society of Genetic Counselors (ASGC) Mentor Program.

Purpose: In Australia and New Zealand, one third of genetic counselors have less than 5 years' experience. Sharing experienced practitioners' professional knowledge is needed as the profession grows. Formal mentoring is an important facilitator of career progression and shared knowledge.

Genetic counseling workforce diversity, inclusion, and capacity in Australia and New Zealand.

Purpose: To understand diversity, inclusion, and capacity of genetic counselors (GCs) in Australasia (Australia and New Zealand).

Methods: Individuals with or working toward a GC qualification in Australasia were invited to complete an online survey, between November 2022 and March 2023. Quantitative data were analyzed using descriptive statistics, 1-sample proportion -tests, 2-sample -tests, and χ tests.

Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation.

Evolocumab in metastatic castration-resistant prostate cancer: study protocol for a single-arm, phase II trial, and initial experience with use of a validated lipid biomarker to direct therapy.

Background: Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), primary and secondary resistance to current therapies remains. Elevated circulating sphingolipids are associated with poor outcomes in patients with mCRPC, including therapeutic resistance and shorter overall survival. PCPro is a clinically accessible, regulatory compliant plasma lipid biomarker of poor prognosis in mCRPC, which incorporates prognostic sphingolipids.

The design and evaluation of a bone health teaching module for secondary school students in NSW, Australia.

Issue Addressed: The growing prevalence of osteoporosis requires preventative management starting from an early age as peak bone mass is typically reached by age 30. However, current Australian adolescents are not adequately addressing key osteoprotective factors. Alarmingly, around 17% have insufficient vitamin D levels, 55% consume insufficient dietary calcium, and 79% are insufficiently active.

Designing and Validating a Hereditary Spastic Paraplegia-Specific Quality of Life Rating Scale (HSPQoL).

Patients with Hereditary Spastic Paraplegia (HSP) report reduced quality of life (QoL) compared to the general population. Generic QoL measures do not address disease-specific aspects such as spasticity, access to specialty HSP clinics, and bladder symptoms. We designed and validated a HSP-specific QoL scale (HSPQoL), intended for use in standard clinical settings and clinical trials.

Case Series of Cerebellar Ataxia with Tremor Due to Heterozygous STUB1 Variants (SCA48) without TBP Expansions: Further Evidence for SCA48 as a Monogenic Disease.

Clinically-relevant variants in the STUB1 gene have been associated with an autosomal dominant spinocerebellar ataxia 48 (SCA48), a recently described inherited neurodegenerative condition that is characterised by cognitive and psychiatric changes. To describe the clinical phenotype and genetic findings of three new Australian probands with STUB1 to expand the current understanding of the spectrum of clinical presentation and natural history of SCA48. Clinical and genetic review of patients diagnosed with SCA48 ataxia drawn from our centres.

Current status of research on the mechanisms of tumor-associated macrophages in esophageal cancer progression.

Esophageal carcinoma (EC) is one of the most common tumors in China and seriously affects patient survival and quality of life. In recent years, increasing studies have shown that the tumor microenvironment is crucial in promoting tumor progression and metastasis. Tumor-associated macrophages (TAM) are key components of the tumor immune microenvironment and promote both tumor growth and antitumor immunity.

Consultation informs strategies to improve functional evidence use in variant classification.

To determine if a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Experimental assay data can provide strong functional evidence for or against pathogenicity in variant classification, but appears to be underutilised. We surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice.

Noninvasive assessment of hydroquinidine effect in Brugada syndrome (QUIET BrS).

Background: Hydroquinidine reduces arrhythmic events in patients with Brugada syndrome (BrS). The mechanism by which it exerts antiarrhythmic benefit and its electrophysiological effects on BrS substrate remain incompletely understood.

Objective: This study aimed to determine the effect of hydroquinidine on ventricular depolarization and repolarization in patients with BrS in vivo.

Increased frequency of germline pathogenic variants among individuals with dermatofibrosarcoma protuberans.

Purpose: To identify candidate susceptibility genes for dermatofibrosarcoma protuberans (DFSP).

Methods: All individuals with DFSP from the International Sarcoma Kindred Study ( = 3767 individuals with sarcoma diagnoses from Australia, Europe, New Zealand, and United States) and cohorts that were not ascertained based on sarcoma status or other phenotypes (Geisinger MyCode,  = 170,503 individuals, United States; UK Biobank,  = 469,789 individuals, United Kingdom) were evaluated for germline pathogenic or likely pathogenic (P/LP) variants in 156 cancer genes.

Results: There were 92 unrelated individuals with DFSP across the 3 cohorts.

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship.

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD).

Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS.

Cytokines reprogram airway sensory neurons in asthma.

Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential environmental dangers. However, this function can be detrimental during allergic reactions, as vagal nociceptors contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer.

Background: Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα ().

Methods: In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib.