Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder - recommendations from ECTRIMS and the EBMT.

Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing-remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD).

Assessing whether providing regular, free HIV self-testing kits reduces the time to HIV diagnosis: an internet-based, randomised controlled trial in men who have sex with men.

Background: The risk of onwards HIV transmission is strongly influenced by the interval between HIV infection and its diagnosis. The SELPHI trial examined whether this interval could be reduced by offering free HIV self-testing kits to men-who-have-sex with-men (MSM).

Setting: Internet-based RCT of MSM aged ≥16 years, resident in England/Wales, recruited via sexual and social networking sites.

Macrophage to neuron communication via extracellular vesicles in neuropathic pain conditions.

Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons.

Ultrasensitive ctDNA detection for preoperative disease stratification in early-stage lung adenocarcinoma.

Circulating tumor DNA (ctDNA) detection can predict clinical risk in early-stage tumors. However, clinical applications are constrained by the sensitivity of clinically validated ctDNA detection approaches. NeXT Personal is a whole-genome-based, tumor-informed platform that has been analytically validated for ultrasensitive ctDNA detection at 1-3 ppm of ctDNA with 99.

Symptom Evolution in Individuals with Ongoing Symptomatic COVID-19 and Post COVID-19 Syndrome After SARS-CoV-2 Vaccination Versus Influenza Vaccination.

Background: COVID-19 symptoms may persist beyond acute SARS-CoV-2 infection, as ongoing symptomatic COVID-19 [OSC] (symptom duration 4-12 weeks) and post-COVID syndrome [PCS] (symptom duration ≥12 weeks). Vaccination against SARS-CoV-2 decreases OSC/PCS in individuals subsequently infected with SARS-CoV-2 post-vaccination. Whether vaccination against SARS-CoV-2, or any other vaccinations (such as against influenza) affects symptoms in individuals already experiencing OSC/PCS, more than natural symptom evolution, is unknown.

Using an inferior decoy alternative to nudge COVID-19 vaccination.

Optimizing vaccine uptake is a public health challenge that requires the implementation of effective strategies. The asymmetric dominance (or decoy) effect describes the increasing likelihood of selecting an option when a clearly inferior alternative is offered. Therefore, we aimed to test the impact of offering decoy alternatives-less convenient vaccination appointments-on vaccination intentions.

The Last Decade in Cardiac Amyloidosis: Advances in Understanding Pathophysiology, Diagnosis and Quantification, Prognosis, Treatment Strategies, and Monitoring Response.

Cardiac amyloidosis represents a unique disease process characterized by amyloid fibril deposition within the myocardial extracellular space. Advances in multimodality cardiac imaging enable accurate diagnosis and facilitate prompt initiation of disease-modifying therapies. Furthermore, rapid advances in multimodality imaging have enriched understanding of the underlying pathogenesis, enhanced prognostication, and resulted in the development of imaging-based markers that reflect the amyloid burden, which is of increasing importance when assessing the response to treatment.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up.

Unidirectional and bidirectional causation between smoking and blood DNA methylation: evidence from twin-based Mendelian randomisation.

Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects.

Harmonization of alcohol use data and mortality across a multi-national HIV cohort collaboration.

Background: Alcohol use is measured in diverse ways across settings. Harmonization of measures is necessary to assess effects of alcohol use in multi-cohort collaborations, such as studies of people with HIV (PWH).

Methods: Data were combined from 14 HIV cohort studies (nine European, five North American) participating in the Antiretroviral Therapy Cohort Collaboration.

Contrastive learning of T cell receptor representations.

Computational prediction of the interaction of T cell receptors (TCRs) and their ligands is a grand challenge in immunology. Despite advances in high-throughput assays, specificity-labeled TCR data remain sparse. In other domains, the pre-training of language models on unlabeled data has been successfully used to address data bottlenecks.

Neurophysiological Insights into the Pathophysiology of Stiff-Person Spectrum Disorders.

Background: Stiff Person Spectrum Disorders (SPSD) are classically defined by the presence of muscle stiffness, spasms and hyperactivity of the central nervous system. There is a notable correlation between neurophysiological features and the clinical hallmark of SPSD, which has greatly encouraged the use of these techniques for diagnostic purposes. Besides, electrophysiological techniques allow for a functional evaluation of the 'hyperactivity of the CNS', thus offering the opportunity to clarify the mechanisms underlying this disorder.

Incorporating immune checkpoint inhibitors in epithelial ovarian cancer.

Objective: Therapeutic interventions for epithelial ovarian cancer (EOC) have increased greatly over the last decade but improvements outside of biomarker selected therapies have been limited. There remains a pressing need for more effective treatment options that can prolong survival and enhance the quality of life of patients with EOC. In contrast to the significant benefits of immunotherapy with immune checkpoint inhibitors (CPI) seen in many solid tumors, initial experience in EOC suggests limited efficacy of CPIs monotherapy.

10 years of BiTE immunotherapy: an overview with a focus on pancreatic cancer.

Various therapeutic strategies have been developed to treat Pancreatic Cancer (PaCa). Unfortunately, most efforts have proved unfruitful, as the poor prognosis observed in this disease has only attained little improvement in the past 40 years. Recently, deeper understanding of the immune system and its interaction with malignant tumors have allowed significant advances in immunotherapy.

Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer.

CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data.

Beta papillomaviruses: From foe to friend in skin cancer immunity.

In this issue of Cancer Cell, Son et al. highlight an unexpected role for skin β-papillomaviruses in the protection against skin carcinogenesis. T cell immunity to skin papillomaviruses blocks the expansion of p53 mutant clones in ultraviolet (UV) radiation-damaged skin, preventing the development of skin cancer.

Vascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer's disease: A putative biomarker of amyloid-induced vascular damage.

We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance.

Initial antigen encounter determines robust T-cell immunity against SARS-CoV-2 BA.2.86 variant three years later.

Objectives: We aimed to evaluate the adaptive immune responses cross-recognition of the hypermutated SARS-CoV-2 BA.2.86 variant and identify the determinants influencing this recognition.

General practice chlamydia testing: qualitative study of staff approaches using behavioural change theory.

Background: Chlamydia is the most diagnosed bacterial sexually transmitted infection in England, but opportunistic testing remains low in general practice despite high prevalence among young people. Attempts to increase testing have been met with little success; therefore, there is a need to explore why rates remain low and how this may be improved.

Aim: To explore general practice staff perceptions of opportunistic chlamydia testing, including barriers, facilitators, interventions, and policies, using the Behaviour Change Wheel (BCW).

TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.