Differences In Pathobiology Research Articles

Viral Determinants of Childhood Asthma Exacerbation Severity and Treatment Response

Although respiratory viruses are common triggers of asthma exacerbations, the influence of viral infection characteristics on exacerbation presentation and treatment response in the pediatric emergency department (ED) is unclear. To assess viral infection characteristics of children experiencing ED asthma exacerbations and to test their associations with severity and treatment response. This is a prospective study of children, aged 4 to 18 years, who received standard ED asthma exacerbation treatment with inhaled bronchodilators and systemic corticosteroids. Nasal swabs collected for viral metagenomic analyses determined virus presence, load, and species. Outcomes included exacerbation severity (Pediatric Asthma Severity [PAS] score, clinician impression, and vital signs) and treatment response (discharge home without needing additional asthma therapies). Of 107 children, 47% had moderate/severe exacerbations by PAS and 64% demonstrated treatment response. Viral metagenomic analysis on nasal swabs from 73 children detected virus in 86%, with 10 different species identified, primarily rhinovirus A (RV-A), RV-C, and enterovirus D68. Exacerbations involving RV-A were milder (odds ratio [OR]= 0.25; 95% confidence interval [CI]= 0.07-0.83) and tended to be more responsive to treatment than non-RV-A infections, whereas exacerbations involving enterovirus D68 were more severe (OR= 8.3; 95% CI= 1.3-164.7) and had no treatment response association. Viral load was not associated with treatment response but exhibited a strong linear relationship with heart rate (rpartial= 0.48), respiratory rate (rpartial= 0.25), and oxygen saturation (rpartial= -0.25), indicative of severity. The majority of ED asthma exacerbations are triggered by respiratory viruses. Viral species are associated with severity and treatment response, suggesting that early pathogen detection could inform ED treatment decisions. Additional studies are needed to identify differences in pathobiology underlying exacerbations triggered by different viral species, and how to effectively treat these heterogeneous exacerbations.

Clinical and genomic features of Mycobacterium avium complex: a multi-national European study

BackgroundThe Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.MethodsWhole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.ResultsOverall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p < 0.001 and OR 0.11 95% CI 0.02–0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).ConclusionsThis study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

Treatment Outcomes and Prognostic Factors with Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (ASCT) in African American (AA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Determination Phase 3 Trial

Background AA pts with NDMM have equal or longer overall survival (OS) vs White pts when treatment access is equal (Fillmore, Blood 2019; Dong, Blood Cancer J 2022). DETERMINATION included one of the largest cohorts of AA pts in prospective NDMM trials (n=132/722, 18.3%). The overall progression-free survival (PFS) difference (RVd-alone vs RVd+ASCT; median 46.2 vs 67.5 months [mos]; hazard ratio [HR] 1.53) was not seen in AA pts (HR 1.07; Richardson, N Engl J Med 2022). Multivariable PFS analyses, overall and by arm, showed that prognostic factors may vary according to treatment received, potentially indicating differences in MM pathobiology; PFS in AA vs White pts was longer with RVd-alone (HR 0.58) but similar with RVd+ASCT (HR 0.95) (Hassoun, EBMT 2023). We build upon this prior work with new analyses to explore outcomes with RVd-alone vs RVd+ASCT in AA and White pts. Methods Pts aged 18-65 y received RVd (3 cycles), stem cell mobilization, then 5 more RVd cycles (RVd-alone: n=357; 66 AA, 268 White) or ASCT and 2 more RVd cycles (RVd+ASCT: n=365; 66 AA, 272 White), and then R maintenance. We analyzed PFS (primary endpoint) by race, with exploration of potentially confounding effects of body mass index (BMI) and sex. Treatment exposure, response, event-free survival (EFS; events: progressive disease [PD], death, non-protocol therapy [NPT]), OS, and safety by race were evaluated. Exploratory genomic analyses in a subset of pts assessed frequency of Duffy-null genotype, a common variant in AA pts associated with lower circulating neutrophil count without increased infection risk that may have a key role in cytokine homeostasis (Jinna, Cells 2022). Results AA pts were younger and more commonly female than White pts, as seen in the GRIFFIN study (Nooka, Blood Cancer J 2022), with higher rates of ECOG PS &amp;gt;0, BMI ≥30, LDH &amp;gt;ULN, and low hemoglobin (panel A). Of 153 samples tested to date, 13 (8.5%) were Duffy-null: 11/17 (64.7%) AA and 2/136 (1.5%) non-AA pts. Median treatment duration from randomization (cycle 2) in AA and White pts, respectively, was 27.5 and 28.7 mos (RVd-alone) vs 36.1 and 36.2 mos (RVd+ASCT); 16% of AA and 13% of White pts discontinued within the first 3 RVd cycles due to adverse events (AEs; 5%/3% of AA/White pts), pt/investigator decision (5%/6%), PD (3%/3%), death (2%/&amp;lt;1%), or other reasons (2%/1%). In the 79%/86% of AA/White pts (RVd+ASCT) who underwent ASCT on study, transplant parameters were similar. 77%/83% of AA/White pts on the RVd-alone arm and 74%/80% on RVd+ASCT started R maintenance; median duration was 43.3/35.8 mos and 45.2/40.4 mos, respectively. In AA/White pts, median % of cycles with mean R dose &amp;gt;10 mg was 78%/88% (RVd-alone) and 83%/58% (RVd+ASCT). At data cut-off, of pts who started maintenance, 35%/25% of AA/White pts on the RVd-alone arm and 35%/29% on the RVd+ASCT arm were ongoing, and 65%/75% and 65%/71% had discontinued (including 37%/57% and 33%/37% due to PD), respectively. AE data are shown in panel B. Odds of achieving ≥CR were greater with RVd-alone vs RVd+ASCT in AA pts and were lower for AA vs White pts on the RVd+ASCT arm (panel B). Median PFS (RVd-alone vs RVd+ASCT) was not reached (NR) vs 61.4 mos (HR 1.07) in AA pts and 44.3 vs 67.2 mos (HR 1.67) in White pts. PFS with RVd-alone vs RVd+ASCT was longer in AA pts with BMI ≥30 (median NR vs 58.6 mos, HR 0.74), but shorter in AA pts with BMI &amp;lt;30 (66.4 mos vs NR, HR 1.86) and White pts with BMI &amp;lt;30 (45.3 vs 82.3 mos, HR 1.78) or ≥30 (41.1 vs 64.4 mos, HR 1.58). The PFS with RVd-alone vs RVd+ASCT was similar in male (HR 1.28) and female (HR 0.90) AA pts but shorter in male (HR 1.47) and female (HR 1.85) White pts. With RVd-alone vs RVd+ASCT, median EFS was 47.7 vs 48.2 mos (HR 0.99) in AA pts and 31.7 vs 46.7 mos (HR 1.30) in White pts; 5-y OS was 83.2% vs 78.7% (HR 0.99) in AA pts and 77.1% vs 80.3% (HR 1.08) in White pts. Among AA/White pts off study treatment, 64%/77% had received NPT; 27%/28% (RVd-alone arm) had received ASCT as NPT. Conclusions Our analyses suggest that PFS, EFS, and OS were similar with RVd-alone and RVd+ASCT in AA pts on this study. Importantly, while outcomes with RVd+ASCT were similar in AA and White pts, exploratory analyses suggest AA pts with high BMI and female AA pts may derive more PFS benefit from RVd-alone. Rates of starting maintenance/NPT use were lower in AA vs White pts, but maintenance duration proved longer in AA pts, with similar rates of grade ≥3 hematologic AEs, including neutropenia; analyses of outcomes by Duffy status are ongoing and will be presented.

Inadequate therapeutic responses to glucocorticoid treatment in bronchial asthma.

Bronchial asthma (BA) is a heterogeneous disease. Some patients benefit greatly from glucocorticoid (GC) treatment, whereas others are non-responders. This could be attributable to differences in pathobiology. Thus, predicting the responses to GC treatment in patients with BA is necessary to increase the success rates of GC therapy and avoid adverse effects. The sustained inflammation in BA decreases glucocorticoid receptor (GR, NR3C1) function. Meanwhile, GRβ overexpression might contribute to GC resistance. Important factors in decreased GR function include p38 mitogen-activated protein kinase-dependent GR phosphorylated at Ser226, reduced expression of histone deacetylase 2 following activation of the phosphatidylinositol 3-kinase-δ signaling pathway, and increased nuclear factor-kappa B activity. MicroRNAs, which are involved in GC sensitivity, are considered biomarkers of the response to inhaled GCs. Some studies revealed that inflammatory phenotypes and disease-related modifiable factors, including infections, the airway microbiome, mental stress, smoking, and obesity, regulate individual sensitivity to GCs. Therefore, future investigations are warranted to improve treatment outcomes.

Topological data analysis identifies molecular phenotypes of idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a debilitating, progressive disease with a median survival time of 3–5 years. Diagnosis remains challenging and disease progression varies greatly, suggesting the possibility of distinct...

Evolution, Transmission, and Pathogenicity of High Pathogenicity Avian Influenza Virus A (H5N8) Clade 2.3.4.4, South Korea, 2014-2016.

During 2014–2016, clade 2.3.4.4 H5N8 high pathogenicity avian influenza virus (HPAIV) caused the largest known avian influenza epidemic in South Korea. Based on data from earlier H5N8 outbreaks, primitive H5N8 virus in South Korea was classified into five subgroups: C1, C2, C3, C4, and C5. The present study investigated the pathogenic and molecular epidemiologic characteristics of H5N8 viruses obtained from 388 cases of poultry farms and 85 cases of wild bird infections in South Korea during 2014–2016. Representative viruses of subgroups C1, C2, and C4 showed significant pathobiological differences in specific pathogen-free (SPF) chickens, with the H1731 (C1) virus showing substantially lower infectivity, transmissibility, and pathogenicity than the H2102 (C2) and H1924 (C4) viruses. Full genome sequence analysis showed the number of mutations that significantly increased in domestic duck-origin H5N8 HPAIVs compared to the viruses from gallinaceous poultry. These differences may have been due to the long-term circulation of viruses in domestic duck farms. The same mutations, at positions 219 and 757 of PB1, independently evolving in the C0, C1, and C2 subgroups may have been positively selected, resulting in convergent evolution at the amino acid level. Bayesian discrete trait phylodynamic analysis (DTA) indicated multiple introductions of H5N8 HPAIV from wild birds into domestic poultry in various regions in South Korea. Following initial viral introduction into domestic duck farms in the western part of Korea, domestic ducks played a major role in viral transmission and maintenance. These findings highlight the need for continued genomic surveillance and pathobiological characterization of HPAIV in birds. Enhanced biosecurity in poultry farms should be implemented to prevent the introduction, maintenance, and spread of HPAIV.

Immunohistochemical Expression of Choline Acetyltransferase and Catecholamine-Synthesizing Enzymes in Head-and-Neck and Thoracoabdominal Paragangliomas and Pheochromocytomas.

Paragangliomas (PGLs) are neural-crest-derived, non-epithelial neuroendocrine tumors distributed along the parasympathetic and sympathetic nerves. Head-and-neck PGLs (HNPGLs) have been recognized as nonchromaffin, nonfunctional, parasympathetic tumors. By contrast, thoracoabdominal paragangliomas and pheochromocytomas (PPGLs) are chromaffin, functional, sympathetic tumors. Although HNPGLs and PPGLs have the same histological structure, the zellballen pattern, composed of chief and sustentacular cells surrounded by abundant capillaries, the pathobiological differences between these types of PGLs remain unclarified. To determine the phenotypic features of these PGLs, we performed an immunohistochemical study using specific antibodies against choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, and enzymes for the catecholamine-synthesis, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH), in 34 HNPGLs from 31 patients, 12 thoracoabdominal PGLs from 12 patients, and 26 pheochromocytomas from 22 patients. The expression of ChAT, TH, and DBH was 100%, 23%, and 10% in the HNPGLs; 12%, 100%, and 100% in the pheochromocytomas; and 25%, 67%, and 100% in the thoracoabdominal PGLs, respectively. These results designate HNPGLs as acetylcholine-producing parasympathetic tumors, in contrast to PPGLs being catecholamine-producing tumors. The other most frequently used neuroendocrine markers are synaptophysin and chromogranin A expressed 100% and 80%, respectively, and synaptophysin was superior to chromogranin A in HNPGLs. This is the first report of HNPGLs being acetylcholine-producing tumors. Immunohistochemistry of ChAT could be greatly useful for pathologic diagnosis of HNPGL. Whether measurement of acetylcholine levels in the blood or urine could be a tumor marker of HNPGLs should be investigated soon.

Estrogen pendulum in schizophrenia and Alzheimer’s disease: Review of therapeutic benefits and outstanding questions

Although produced largely in the periphery, gonadal steroids play a key role in regulating the development and functions of the central nervous system and have been implicated in several chronic neuropsychiatric disorders, with schizophrenia and Alzheimer’s disease (AD) most prominent. Despite major differences in pathobiology and clinical manifestations, in both conditions, estrogen transpires primarily with protective effects, buffering the onset and progression of diseases at various levels. As a result, estrogen replacement therapy (ERT) emerges as one of the most widely discussed adjuvant interventions. In this review, we revisit evidence supporting the protective role of estrogen in schizophrenia and AD and consider putative cellular and molecular mechanisms. We explore the underlying functional processes relevant to the manifestation of these devastating conditions, with a focus on synaptic transmission and plasticity mechanisms. We discuss specific effects of estrogen deficit on neurotransmitter systems such as cholinergic, dopaminergic, serotoninergic, and glutamatergic. While the evidence from both, preclinical and clinical reports, in general, are supportive of the protective effects of estrogen from cognitive decline to synaptic pathology, numerous questions remain, calling for further research.

Caucasians with acral lentiginous melanoma have the same outcome as patients with stage- and limb-matched superficial spreading melanoma

PurposeAcral lentiginous melanoma (ALM), a relatively rare subtype of cutaneous melanoma, has been reported to have a worse prognosis than other melanomas. We aimed to assess clinical findings in Caucasian ALM patients and compare the data with a matched cohort of superficial spreading melanoma (SSM) patients.MethodsWe studied 63 patients with ALM and 63 randomly stage- and limb-matched patients with SSM (non-ALM). In both cohorts, guideline-adjusted diagnosis, treatment and follow-up were performed.ResultsWe did not observe differences in prognostic factors (e.g., tumor thickness, ulceration) between the two cohorts. Both in ALM and non-ALM patients positive sentinel lymph node was a significant independent predictor for disease relapse and melanoma-specific death. However, disease relapse and melanoma-specific death rates did not significantly differ between ALM and non-ALM patients. An overall 5-year melanoma-specific survival of 82.5% and 81% was observed in ALM and non-ALM patients, respectively.ConclusionsOur data confirm that patients with ALM have no worse outcome than non-ALM patients when correcting for significant prognostic factors. Hence, the reportedly high rates of fatal ALM cases should not be ascribed to pathobiological differences between ALM and non-ALM but are most likely are a consequence of a delay in diagnosis and thus advanced stage of ALM.

Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes

Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine.

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can progress into nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Western diets, high in fats, sugars, and cholesterol, are linked to NAFLD development. Murine models are often used to study NAFLD; however, there remains debate on which diet-induced model best mimics both human disease progression and pathogenesis. In this study, we performed a side-by-side comparison of two popular diet models of murine NAFLD/NASH and associated HCC, a high-fat diet supplemented with 30% fructose water (HFHF) and a Western diet high in cholesterol (WDHC), and these were compared with a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, and WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumor burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. This study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC is a reliable method to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.

Coronary Artery Disease in patients with End‐Stage Kidney Disease; Current perspective and gaps of knowledge

Coronary artery disease (CAD) is very common in dialysis patients. One third have preexisting CAD and another one third have significant occult disease at the time of starting dialysis. Symptoms are often absent or are atypical, emphasizing the need for vigorous screening, specifically in patients awaiting transplant. The lesions tend to be heavily calcified, diffuse, and involve multiple vessels, consequently, percutaneous coronary interventions are more complicated to perform, and are less successful in achieving and maintaining short- and long-term patency. Dialysis patients have been excluded from the randomized controlled trials on which the current standards for managing CAD have been established. Due to differences in pathobiology and risks and benefits, it is uncertain that the results of these clinical trials extrapolate to patients with advanced chronic kidney disease(CKD). Here we review the data from observational studies and identify special considerations concerning the diagnosis and management of CAD in dialysis patients, including the use of noninvasive functional testing vs anatomical testing, the management of acute coronary syndromes and of stable coronary artery disease, the role for percutaneousrevascularization vs coronary artery bypass grafting, and of platelet inhibitor therapy after coronary stenting. We review the preliminary results of the recently published ISCHEMIA-CKD trial, the only trial to date to involve large numbers of dialysis patients. This is the first of, hopefully, many trials in the pipeline that will examine therapies for CAD specifically in patients with advanced CKD, a growing population that is at particularly high risk for poor outcomes.

Sex-specific Alterations in the Urinary and Tissue Microbiome in Therapy-naïve Urothelial Bladder Cancer Patients

Comprehensive characterization of the urinary and urothelium-bound microbiomes in bladder cancer (BCa) and healthy state is essential to understand how these local microbiomes may play a role in BCa tumorigenesis and response to therapy, as well as to explain sex-based differences in BCa pathobiology. Performing 16 s rDNA microbiome analysis on 166 samples (urine and paired bladder tissues) from therapy-naïve BCa patients undergoing radical cystectomy and healthy controls, we defined (1) sex-specific microbiome differences in the urine and bladder tissue, and (2) representativeness of the tissue microenvironment by the voided urinary microbiome. The genus Klebsiella was more common in the urine of female BCa patients versus healthy controls, while no clinically relevant bacteria were found differently enriched in men. In tissues, the genus Burkholderia was more abundant in the neoplastic versus the non-neoplastic tissue in both sexes, suggesting a potential role in BCa pathobiology. Lastly, we found that the urinary microbiome shares >80% of the bacterial families present in the paired bladder tissue, making the urinary microbiome a fair proxy of the tissue bacterial environment. Patient summaryWe identified specific bacteria present in the urine and tissues of male and female bladder cancer patients. These novel data represent a first step toward understanding the influence of the bladder microbiome on the development of bladder cancer and on the response to intravesical and systemic therapies.

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.

BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.

MicroRNA Expression Profiles in External Cervical Resorption

IntroductionExternal cervical resorption (ECR) has been challenging for its diagnosis, prevention, and treatment. Its etiology and pathogenesis are largely unknown. This study characterized microRNA (miRNA) expression patterns of human tissues from ECR lesions and identified potential messenger RNA targets and pathways. MethodsGranulomatous tissues from ECR (n = 5) and their adjacent nonaffected asymptomatic gingival connective tissues (n = 5) were collected. Similarly, chronic periodontitis (CP) and control samples were collected (n = 3). Quantitative reverse transcription polymerase chain reaction array analysis compared the expression profiles of 88 miRNAs between diseases. Differentially expressed miRNAs were identified using the Student t test. Bioinformatics for messenger RNA (miRWalk) and KEGG pathway analyses were performed to identify predicted target genes and biological/cellular functions and signaling pathways. ResultsThree miRNAs (miR-20a-5p, miR-210-3p, and miR-99a-4p) were significantly down-regulated and 1 miRNA (miR-122-5p) was significantly up-regulated in ECR (P < .05). One up-regulated and 1 down-regulated miRNA reached the significance threshold in CP. A comparison of miRNA expression in ECR and CP identified 3 differentially expressed miRNAs, indicating differences in disease pathobiology. Inflammation-associated Wnt, PI3K-Akt, mitogen-activated protein kinases signaling, and bone formation–associated transforming growth factor beta pathways were identified and predicted to be modulated by differentially expressed miRNAs in both ECR and CP. Biological processes unique to each disease entity were identified, such as T- and B-cell receptor signaling pathways, osteoclast differentiation, and extracellular matrix–receptor interaction for CP. Glycosaminoglycan biosynthesis, mineral absorption, and insulin signaling pathways for ECR were identified. ConclusionsThis proof-of-principle in vivo study indicated that ECR has both common and unique miRNA expression profiles in comparison with CP, which are predicted to target genes regulating inflammation, immunity, and metabolism of mineralized tissues.

The right ventricle has more resident immune cells than the left ventricle

The right ventricle (RV) pumps deoxygenated blood from the systemic circulation to the lungs for reoxygenation. Diseases such as pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease are associated with hypoxia that leads to an increase in pulmonary vascular resistance (PVR), resulting in RV hypertrophy and dysfunction. The RV may differ from the left ventricle (LV) in the pathobiology in response to increases in afterload and no specific therapy exists for RV dysfunction. In order to gain insight into the biology of the RV compared to the LV, and perhaps uncover potentially novel therapeutic approaches for RV dysfunction, we performed RNA‐sequencing on RV and LV tissue from rats in normal ambient conditions or subjected to hypoxia (10% O2) for two weeks. Gene ontology and pathway analysis of the RV compared to the LV revealed multiple transcriptomic differences under ambient conditions and in particular, increased expression in the RV of genes related to immune function. Immune cell profiling by flow cytometry of rat cardiac digests, analyzed as the percentage of CD45+/CD11b/c+ cells in the cell population, revealed that in both ambient conditions and hypoxia, the RV had a significantly greater percentage of double‐positive cells compared to the LV (normoxia: average % ± SEM, 8.55 ± 1.71 RV vs. 2.04 ± 0.62 LV and hypoxia: 6.59 ± 2.71 vs. 1.55 ± 0.4; P &lt;0.005, two‐way ANOVA, n=4 rats/group). Hypoxia had no significant effect on these values (P&gt;0.05). These data reveal that the RV has a greater number of resident immune cells compared to the LV, possibly contributing to differences in pathobiology. Further investigation may reveal immune‐related therapeutic strategies for RV disease.Support or Funding InformationSupported by Department of Defense (W81XWH‐14‐1‐0372)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance.

We have previously shown significant pathology in the heart and kidney of murine hematopoietic-acute radiation syndrome (H-ARS) survivors of 8.7-9.0 Gy total-body irradiation (TBI). The goal of this study was to determine temporal relationships in the development of vasculopathy and the progression of renal and cardiovascular delayed effects of acute radiation exposure (DEARE) at TBI doses less than 9 Gy and to elucidate the potential roles of senescence, inflammation and oxidative stress. Our results show significant loss of endothelial cells in coronary arteries by 4 months post-TBI (8.53 or 8.72 Gy of gamma radiation). This loss precedes renal dysfunction and interstitial fibrosis and progresses to abnormalities in the arterial media and adventitia and loss of coronary arterioles. Major differences in radiation-induced pathobiology exist between the heart and kidney in terms of vasculopathy progression and also in indices of inflammation, senescence and oxidative imbalance. The results of this work suggest a need for different medical countermeasures for multiple targets in different organs and at various times after acute radiation injury to prevent the progression of DEARE.

Distinct plasma gradients of microRNA-204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension.

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06–0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups (P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 (P = 0.0004), and a converse increase of extracellular miR-204 (P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

Interleukin-23: The Common Link Between the Joint, the Gut, and the Skin?

Prof McGonagle introduced the symposium and briefly described the aims of the meeting. Dr Behrens first discussed how findings from relevant psoriasis and psoriatic arthritis (PsA) registries can be applied to improve daily practice, and reflected on the real-life effectiveness of biologic therapies in the treatment of PsA. Prof McGonagle then followed with a discussion describing the key immunological pathways involved in psoriasis and PsA, evaluating the key similarities and differences in tissue and cytokine pathobiology in both conditions. Prof Danese then concluded the symposium by presenting on the pathophysiology of the interleukin (IL)-23 pathway in inflammatory bowel disease (IBD), reviewing the latest data for IL-23 inhibitors in treating IBD.

Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies.

Chronic inflammatory arthropathies, such as rheumatoid arthritis (RA), spondyloarthritis, including psoriatic arthritis (PsA), ankylosing spondyloarthritis (AS), osteoarthritis (OA), and intervertebral disc degenerative disease (DDD) constitute major public health problems that are anticipated to grow significantly as the human population ages. However, many aspects concerning the molecular mechanisms underlying their onset and progression remain unclear. This narrative review critically analyzes the molecular mechanisms underlying the inflammation-associated pathogenesis of the aforementioned joint diseases. This includes, in particular, the major role played by several key soluble factors (such as cytokines and the associated signaling pathways, designated as "fragile nodes") produced by local cells and recruited to the joints' immune cells, whose elimination by specific drugs has dramatically improved the diseases' symptomatology and outcome in human clinical trials or in rodent arthritis models. We hypothesize that the pathogenesis of chronic inflammatory arthropathies is governed by hierarchical, imbalanced pro-inflammatory cytokine networks (HIPICNs) (comprising a combination of fragile nodes) that are created during the development of both autoimmune (RA, PsA, and AS) and non-autoimmune (OA and DDD) disorders. The main aim of this review is to provide evidence that despite substantial pathobiological differences between these arthropathies, the HIPICNs created are quite common, thus justifying the merging of these disorders mechanistically and suggesting that these common mechanisms exist in the onset and progression of different joint diseases.