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Resting-state functional magnetic resonance imaging (rs-fMRI), which measures the spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal, is increasingly utilized for the investigation of the brain’s physiological and pathological functional activity. Rodents, as a typical animal model in neuroscience, play an important role in the studies that examine the neuronal processes that underpin the spontaneous fluctuations in the BOLD signal and the functional connectivity that results. Translating this knowledge from rodents to humans requires a basic knowledge of the similarities and differences across species in terms of both the BOLD signal fluctuations and the resulting functional connectivity. This review begins by examining similarities and differences in anatomical features, acquisition parameters, and preprocessing techniques, as factors that contribute to functional connectivity. Homologous functional networks are compared across species, and aspects of the BOLD fluctuations such as the topography of the global signal and the relationship between structural and functional connectivity are examined. Time-varying features of functional connectivity, obtained by sliding windowed approaches, quasi-periodic patterns, and coactivation patterns, are compared across species. Applications demonstrating the use of rs-fMRI as a translational tool for cross-species analysis are discussed, with an emphasis on neurological and psychiatric disorders. Finally, open questions are presented to encapsulate the future direction of the field.

Diabetes mellitus (DM) is one of the most common and costly disorders that affect humans around the world. Recently, clinicians and scientists have focused their studies on the effects of glycemic variability (GV), which is especially associated with cardiovascular diseases. In healthy subjects, glycemia is a very stable parameter, while in poorly controlled DM patients, it oscillates greatly throughout the day and between days. Clinically, GV could be measured by different parameters, but there are no guidelines on standardized assessment. Nonetheless, DM patients with high GV experience worse cardiovascular disease outcomes. In vitro and in vivo studies showed that high GV causes several detrimental effects, such as increased oxidative stress, inflammation, and apoptosis linked to endothelial dysfunction. However, the evidence that treating GV is beneficial is still scanty. Clinical trials aiming to improve the diagnostic and prognostic accuracy of GV measurements correlated with cardiovascular outcomes are needed. The present review aims to evaluate the clinical link between high GV and cardiovascular diseases, taking into account the underlined biological mechanisms. A clear view of this challenge may be useful to standardize the clinical evaluation and to better identify treatments and strategies to counteract this DM aspect.

Animal models are a significant component of biomedical research and play an important role in translational studies. Traditionally, rodent models have been the mainstay and principal choice of researchers but in recent years, there have been significant changes in the landscape of animal modeling. For example, newer techniques have greatly expanded the use and successful application of large animal models such as pigs for translational studies. The evolving types and species of animal models can influence the research landscape in terms of facilities, expertise, reproducibility and funding streams, which creates new challenges for research studies. It is also important that investigators are prepared to address the necessity of their animal model research and capable to educate the public regarding its value.

Animal models have been instrumental in elucidating key biochemical and physiologic processes of cancer onset and propagation in a living organism. Most importantly, they have served as a surrogate for patients in the evaluation of novel diagnostic and therapeutic anticancer drugs, including radiopharmaceuticals. Experimental tumors raised in rodents constitute the major preclinical tool of new-agent screening before clinical testing. Such models for oncologic applications today include solid tumors raised in syngeneic fully immunocompetent hosts and human xenografts induced in immunodeficient mouse strains, and tumors spontaneously growing in genetically engineered mice represent the newest front-line experimental modality. The power of these models to predict clinical efficacy is a matter of dispute, as each model presents inherent strengths and weaknesses in faithfully mirroring the extremely complex process of human carcinogenesis. Differences in size and physiology, as well as variations in the homology of targets between mice and humans, may lead to translational limitations. Other factors affecting the predictive power of preclinical models may be animal handling during experimentation and suboptimal compilation and interpretation of preclinical data. However, animal models will remain a unique source of in vivo information and the irreplaceable link between in vitro studies and our patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. It is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture and immune responses. Innate pro-inflammatory cytokines (e.g., IL-1β, and TNF-α); mediators of activated T helper (Th)1 and Th17 cells (e.g., IFN-γ, and IL-17); and effector mechanisms of neutrophilic granulocytes, macrophages, and plasma cells are involved. On the other hand, HS lesions contain anti-inflammatory mediators (e.g., IL-10) and show limited activity of Th22 cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction, and scarring. HS pathogenesis is still enigmatic, and a valid animal model for HS is currently not available. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. Available treatments are limited, mostly off-label, and surgical interventions are often required to achieve remission. In this paper, we provide an overview of the current knowledge surrounding HS, including the diagnosis, pathogenesis, treatments, and existing translational studies.

This report presents the proceedings from a workshop titled “Microbiome, Metabolism and Immunoregulation of Asthma” that was held virtually May 13 and 14, 2021. The workshop was jointly sponsored by the American Thoracic Society (Assembly on Allergy, Immunology, and Inflammation) and the National Institute of Allergy and Infectious Diseases. It convened an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research. The main purpose was to identify key scientific gaps and needs to further advance research on microbial and metabolic mechanisms that may contribute to variable immune responses and disease heterogeneity in asthma. Discussions were structured around several topics, including 1) immune and microbial mechanisms of asthma pathogenesis in murine models, 2) the role of microbes in pediatric asthma exacerbations, 3) dysregulated metabolic pathways in asthma associated with obesity, 4) metabolism effects on macrophage function in adipose tissue and the lungs, 5) computational approaches to dissect microbiome–metabolite links, and 6) potential confounders of microbiome–disease associations in human studies. This report summarizes the major points of discussion, which included identification of specific knowledge gaps, challenges, and suggested directions for future research. These include questions surrounding mechanisms by which microbiota and metabolites shape host health versus an allergic or asthmatic state; direct and indirect influences of other biological factors, exposures, and comorbidities on these interactions; and ongoing technical and analytical gaps for clinical translation.

A major hypothesis in addiction research is that alcohol induces neuroadaptations in the mesolimbic dopamine (DA) system and that these neuroadaptations represent a key neurochemical event in compulsive drug use and relapse. Whether these neuroadaptations lead to a hypo- or hyperdopaminergic state during abstinence is a long-standing, unresolved debate among addiction researchers. The answer is of critical importance for understanding the neurobiological mechanism of addictive behavior. Here we set out to study systematically the neuroadaptive changes in the DA system during the addiction cycle in alcohol-dependent patients and rats. In postmortem brain samples from human alcoholics we found a strong down-regulation of the D1 receptor- and DA transporter (DAT)-binding sites, but D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations, we compared the human data with that from alcohol-dependent rats at several time points during abstinence. We found a dynamic regulation of D1 and DAT during 3 wk of abstinence. After the third week the rat data mirrored our human data. This time point was characterized by elevated extracellular DA levels, lack of synaptic response to D1 stimulation, and augmented motor activity. Further functional evidence is given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of alcohol-dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes in the striatal DA system; in this model a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.

Chronic inflammatory arthritis of childhood, known as juvenile idiopathic arthritis (JIA), exhibits distinct and shared features with adult-onset disease. Recent advances in minimally invasive synovial biopsy, high resolution imaging and sequencing technologies have enabled detailed characterisation of the inflamed synovium in JIA, facilitating insights into the underlying immunopathology. In this review we draw on these findings to consider how the developing immunological and structural context of the joint impacts the presentation and consequence of inflammatory joint disease in children and young adults.

Background Subcutaneous adalimumab is the preferred treatment for most children with juvenile idiopathic arthritis (JIA) and non-infectious uveitis, usually administered every other week. Some patients do not respond or lose responsiveness over time, leading to dose escalation to weekly administration. This study evaluated the efficacy and pharmacokinetics of weekly subcutaneous adalimumab in children with JIA and idiopathic uveitis. Methods This is a retrospective study on clinical and pharmacokinetic characteristics of patients treated with subcutaneous adalimumab for psoriatic arthritis or non-infectious uveitis (idiopathic or JIA-associated) who did not respond or ceased to respond to biweekly administration. Results Four patients were enrolled: three females and one male, with a median age of 15 years (range 7–18; IQR 6). One had juvenile psoriatic arthritis, two had idiopathic uveitis, and one had JIA-related uveitis. They all presented a poor control of the disease on biweekly administrations, while it was successfully controlled on weekly administrations. None of them presented adverse events. Pharmacokinetic analyses identified two groups of patients: those with high clearance and those with low clearance. In both groups, weekly dosing increased the predicted drug concentrations, and in patients with high clearance only weekly administration provided the predicted concentration exceeding the therapeutic cut-off of 9.6 mg/L. Conclusions Weekly adalimumab administrations were safe and effective in controlling both articular and ocular inflammation. In cases where the disease is poorly controlled with regular biweekly administrations, we encourage escalating adalimumab treatment to weekly administration before adding other therapies or switching to different biologics.

Purpose Recent studies have investigated intraperitoneal paclitaxel (IP PTX) combined with systemic chemotherapy for the treatment of gastric cancer peritoneal metastases (GCPM). This clinical trial integrated translational study was conducted to identify biomarkers that can predict patient responses to IP PTX plus systemic systemic S-1 plus oxaliplatin (SOX) chemotherapy. Materials and methods Patients from the PIPS-GC phase Ib/II clinical trial, enrolled at the Korea University Guro Hospital, were included in analyses. Whole exome and transcriptome sequencing were performed on formalin-fixed, paraffin-embedded gastric tumor, normal gastric, and peritoneal tumor tissues. A metastatic tumor-specific gene set was analyzed using The Cancer Genome Atlas (TCGA) gastric cancer data and publicly available single-cell RNA sequencing (scRNA-seq) datasets. Spatial transcriptomic analysis of primary and peritoneal tumors from a non-responder was performed to validate candidate biomarkers. Results Nine patients with gastric cancer were enrolled; six in the response group and three in the non-response group. Candidate genes for predicting IP PTX plus systemic SOX chemotherapy response were identified and compared with TCGA-GC and scRNA-seq datasets. Spatial transcriptomics revealed higher expression of thrombospondin type 1 domain-containing protein 4 (THSD4) in peritoneal tumors, which was associated with chemotherapy resistance via midkine and epithelial–mesenchymal transition pathways. Conclusion This PIPS-GC clinical trial identified THSD4 as a potential biomarker for predicting IP PTX plus systemic SOX response in gastric cancer peritoneal metastasis. Further research is required to elucidate the mechanism of action by which THSD4 affects GCPM and validate its clinical utility as a predictive biomarker for IP PTX response.