Search

Background: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49–75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. Methods: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. Results: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00–56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. Conclusions: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

We describe the case of a young woman with Takayasu arteritis with severe stenosis in the main trunk of the left coronary artery. After administration of prednisolone and tocilizumab to control disease activity, coronary artery bypass grafting was performed. Here, we report the successful perioperative management of this cardiac surgery. (Level of Difficulty: Advanced.), Graphical abstract, We describe the case of a young woman with Takayasu arteritis with severe stenosis in the main trunk of the left coronary artery. After administration…

A 71-year-old Japanese woman with a history of rheumatoid arthritis of 50 years’ duration was admitted to our hospital with refractory diarrhea. Endoscopic biopsy revealed AA amyloid deposition in the large intestine. Although the patient had been prescribed 5 tumor necrosis factor inhibitors over the past 10 years, rheumatoid arthritis was poorly controlled, with a Disease Activity Score 28 using C-reactive protein score of 6.52 on admission. Treatment with tocilizumab (8 mg/kg every 2 weeks) was initiated, but this was ineffective. After 3 months, abatacept (cytotoxic T-lymphocyte–associated antigen 4 immunoglobulin) was initiated (750 mg/mo) and the patient’s diarrhea began to improve. After 3 months of abatacept treatment, serum albumin, C-reactive protein, and serum amyloid A levels had all decreased to within normal ranges. After 3 years of abatacept treatment, a repeat biopsy of the large intestine revealed a marked improvement in amyloid deposition. Interleukin 6 is a key factor in AA amyloid formation, but this case suggests that T-cell activation increases the production of cytokines (including interleukin 6) via a mechanism involving cytotoxic T-lymphocyte–associated antigen 4, resulting in a second key factor of AA amyloid formation.

International audience; Background and AimsApolipoprotein A1 (A1) and haptoglobin (HP) serum levels are associated with the spread and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have constructed and validated a multivariable risk calculator (A1HPV6) integrating A1, HP, alpha2-macroglobulin, and gamma glutamyl transferase to improve the performances of virological biomarkers.MethodsIn a prospective observational study of hospitalized patients with nonsevere SARS-CoV-2 infection, A1HPV6 was constructed in 127 patients and validated in 116. The specificity was assessed in 7482 controls representing the general population. The primary diagnostic endpoint was the area under the receiver operating characteristic curve in patients with positive SARS-CoV-2 PCR. The primary prognostic endpoint was the age-and-sex adjusted risk of A1HPV6 to predict patients with WHO-stage > 4 (W > 4) severity. We assessed the kinetics of the A1HPV6 components in a nonhuman primate model (NHP), from baseline to 7 days (D7) after SARS-CoV-2 infection.ResultsThe area under the receiver operating characteristic curve for A1HPV6 was 0.99 (95% CI 0.97–0.99) in the validation subset, which was not significantly different from that in the construction subset, 0.99 (0.99–0.99; P = .80), like for sensitivity 92% (85–96) vs 94% (88–97; P = .29). A1HPV6 was associated with W > 4, with a significant odds ratio of 1.3 (1.1–1.5; 0.002). In NHP, A1 levels decreased (P < .01) at D2 and normalized at D4; HP levels increased at D2 and peaked at D4. In patients, A1 concentration was very low at D2 vs controls (P < .01) and increased at D14 (P < .01) but was still lower than controls; HP increased at D2 and remained elevated at D14.ConclusionThese results validate the diagnostic and prognostic performances of A1HPV6. Similar kinetics of apolipoprotein A1, HP, and alpha-2-macroglobulin were observed in the NHP model. ClinicalTrials.gov number, NCT01927133.

The World Health Organization (WHO) has declared the COVID-19 an international health emergency due to the severity of infection progression, which became more severe due to its continuous spread globally and the unavailability of appropriate therapy and diagnostics systems. Thus, there is a need for efficient devices to detect SARS-CoV-2 infection at an early stage. Nowadays, the reverse transcription polymerase chain reaction (RT-PCR) technique is being applied for detecting this virus around the globe; however, factors such as stringent expertise, long diagnostic times, invasive and painful screening, and high costs have restricted the use of RT-PCR methods for rapid diagnostics. Therefore, the development of cost-effective, portable, sensitive, prompt and selective sensing systems to detect SARS-CoV-2 in biofluids at fM/pM/nM concentrations would be a breakthrough in diagnostics. Immunosensors that show increased specificity and sensitivity are considerably fast and do not imply costly reagents or instruments, reducing the cost for COVID-19 detection. The current developments in immunosensors perhaps signify the most significant opportunity for a rapid assay to detect COVID-19, without the need of highly skilled professionals and specialized tools to interpret results. Artificial intelligence (AI) and the Internet of Medical Things (IoMT) can also be equipped with this immunosensing approach to investigate useful networking through database management, sharing, and analytics to prevent and manage COVID-19. Herein, we represent the collective concepts of biomarker-based immunosensors along with AI and IoMT as smart sensing strategies with bioinformatics approach to monitor non-invasive early stage SARS-CoV-2 development, with fast point-of-care (POC) diagnostics as the crucial goal. This approach should be implemented quickly and verified practicality for clinical samples before being set in the present times for mass-diagnostic research.

Visual Abstract, Highlights • Myocardial infarction leads to recruitment of monocyte/macrophages to the injured myocardium to drive infarct healing. • Activation of formyl peptide receptors (FPR1 and FPR2) present on macrophages contributes to key cellular activities that can potentiate wound healing. • Myocardial infarction was induced in rodents to study the effects of long-term treatment with Compound 43, a small molecule agonist of FPR1 and FPR2. • Main findings: Compound 43 stimulated proresolution macrophage activities, improved left ventricle and infarct structure, and preserved cardiac function post-myocardial infarction. • The results suggest that stimulation of proresolution activities of FPRs can favorably alter post-myocardial infarction pathophysiology that leads to heart failure., Summary Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models. Cmpd43 stimulated FPR1/2-mediated signaling, enhanced proresolution cellular function, and modulated cytokines. Cmpd43 increased LV function and reduced chamber remodeling while increasing proresolution macrophage markers. The findings demonstrate that FPR agonism improves cardiac structure and function post-MI.

Visual Abstract, Highlights • MI leads to ischemic damage of myocardium and activation of inflammatory programs as part of the wound healing response. • Selective activation of FPR2 on macrophages potentiates key cellular activities that enable wound healing. • MI was induced in rodents to study the effects of treatment with BMS-986235, a selective small molecule agonist of FPR2. • BMS-986235 stimulated proresolution macrophage activities, induced neutrophil apoptosis and clearance, improved LV and infarct structure, and preserved cardiac function post MI. • The findings suggest that targeted activation of FPR2 can improve post-MI outcome and may diminish the development of HF., Summary Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.

Background & Aims Identifying new approaches to lessen inflammation, as well as the associated malignant consequences, remains crucial to improving the lives and prognosis of patients diagnosed with inflammatory bowel diseases. Although it previously has been suggested as a suitable biomarker for monitoring disease activity in patients diagnosed with Crohn’s disease, the role of the acute-phase protein serum amyloid A (SAA) in inflammatory bowel disease remains unclear. In this study, we aimed to assess the role of SAA in colitis-associated cancer. Methods We established a model of colitis-associated cancer in wild-type and SAA double-knockout (Saa1/2-/-) mice by following the azoxymethane/dextran sulfate sodium protocol. Disease activity was monitored throughout the study while colon and tumor tissues were harvested for subsequent use in cytokine analyses, Western blot, and immunohistochemistry +experiments. Results We observed attenuated disease activity in mice deficient for Saa1/2 as evidenced by decreased weight loss, increased stool consistency, decreased rectal bleeding, and decreased colitis-associated tissue damage. Macrophage infiltration, including CD206+ M2-like macrophages, also was attenuated in SAA knockout mice, while levels of interleukin 4, interleukin 10, and tumor necrosis factor-ɑ were decreased in the distal colon. Mice deficient for SAA also showed a decreased tumor burden, and tumors were found to have increased apoptotic activity coupled with decreased expression for markers of proliferation. Conclusion Based on these findings, we conclude that SAA has an active role in inflammatory bowel disease and that it could serve as a therapeutic target aimed at decreasing chronic inflammation and the associated risk of developing colitis-associated cancer., Graphical abstract

Graphical abstract, The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.

Pancreatic ductal adenocarcinoma (PDAC) shows remarkable propensity to metastasize. This predilection to escape from the primary tumor is driven by paracrine and autocrine mechanisms that guide cancer cells through a multi-step process concluding with colonization in distant tissues. Although cell-intrinsic features support the metastatic ability of cancer cells, permissive microenvironments within the primary organ and at sites of distant metastasis may be rate-limiting. Identification of cancer cell-extrinsic factors that regulate formation of these environments lend new therapeutic targets for intervening on the metastatic cascade. In addition, the bipolar, yet fundamental, role of the immune system in the metastatic process presents therapeutic opportunities. Herein, we review the current knowledge of the metastatic cascade in PDAC, and propose that genomically stable determinants of metastasis (e.g. the pro-metastatic niche and immune system) are actionable targets for preventing, containing, and treating metastasis in PDAC. Keywords: Inflammation, Cancer, Pancreatic ductal adenocarcinoma, Immunotherapy, Immune evasion, Treatment paradigms, T cells, Macrophages, Neutrophils, Tumor microenvironment, Immunosurveillance, Vaccines, Therapeutic resistance, Metastasis, Clinical trials

Summary A 2-year-old female domestic shorthair cat was referred with a 2 month history of lethargy, weight loss, recurrent hyperthermia and polyarthropathy despite prednisolone. Upon physical examination, the cat showed apathy, hyperthermia, multiple appendicular joint pain and swelling. The CBC showed severe macrocytic normochromic non-regenerative anemia and thrombocytopenia. A population of immature large granular lymphocytes (LGL) was noted on blood smear. Abdominal ultrasonography revealed enlarged mesenteric lymph nodes (LNs), hyper echoic liver and splenomegaly. Cytology of fine needle aspirate of synovial fluid, spleen, liver, enlarged abdominal LNs and bone marrow supported a diagnosis of LGL leukemia with concurrent articular infiltration. A COP-based protocol was initiated with L-asparaginase (400 UI/kg intramuscularly) and prednisolone (1 mg/kg/day orally). However, the cat presented 1 week later with obtundation and paresis, indicating the involvement of the central nervous system (CNS). LGL were also observed on cerebrospinal fluid analysis. Histologic examination noted LGL in the spleen, liver and LNs. Immunohistochemistry (IHC) yielded negative results for both B- and T-cells thus suggesting NK-cells. The diagnosis was LGL leukemia with concurrent articular and CNS involvement. Articular infiltration with LGL is rarely reported in small animals, whereas CNS involvement was previously only suspected in a cat at necropsy.

CVD and associated metabolic diseases are linked to chronic inflammation, which can be modified by diet. The objective of the present study was to determine whether there is a difference in inflammatory markers, blood metabolic and lipid panels and lymphocyte gene expression in response to a high-fat dairy food challenge with or without milk fat globule membrane (MFGM). Participants consumed a dairy product-based meal containing whipping cream (WC) high in saturated fat with or without the addition of MFGM, following a 12 h fasting blood draw. Inflammatory markers including IL-6 and C-reactive protein, lipid and metabolic panels and lymphocyte gene expression fold changes were measured using multiplex assays, clinical laboratory services and TaqMan real-time RT-PCR, respectively. Fold changes in gene expression were determined using the Pfaffl method. Response variables were converted into incremental AUC, tested for differences, and corrected for multiple comparisons. The postprandial insulin response was significantly lower following the meal containing MFGM (P< 0·01). The gene encoding soluble epoxide hydrolase (EPHX2) was shown to be more up-regulated in the absence of MFGM (P= 0·009). Secondary analyses showed that participants with higher baseline cholesterol:HDL-cholesterol ratio (Chol:HDL) had a greater reduction in gene expression of cluster of differentiation 14 (CD14) and lymphotoxinβreceptor (LTBR) with the WC+MFGM meal. The protein and lipid composition of MFGM is thought to be anti-inflammatory. These exploratory analyses suggest that addition of MFGM to a high-saturated fat meal modifies postprandial insulin response and offers a protective role for those individuals with higher baseline Chol:HDL.

Background: Systemic autoinflammatory diseases (SAIDs) are rare debilitating disorders of which there is limited awareness and a significant delay in diagnosis. There is no uniform approach in the diagnosis and treatment of these disorders and the real life state of SAID patient care is poorly characterized. The aim of this study was to obtain data on the epidemiology, state of care and the perception of physicians who are involved in the care of SAID patients. Methods: We performed a questionnaire-based survey and contacted 134 university departments of dermatology, pediatrics, rheumatology and other SAID departments of tertiary care in German-speaking countries. Results: A total of 37 departments participated in the survey. The majority of departments managed both adult and pediatric patients with a variety of monogenic and polygenic/acquired SAIDs. For monogenic SAIDs such as cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF), the diagnostic and treatment strategies were similar among the departments. The diagnostic work-up included inflammatory markers and genetic testing, the first line treatment interleukin-1 (IL-1) blockers for CAPS and colchicine for FMF. For polygenic/acquired SAIDs, we observed a significant heterogeneity in diagnostic and therapeutic approaches. As a major unmet need, diagnostic delay was identified with a median time to diagnosis of 2 (range 1–5) years. The overall state of care for SAID patients was rated to be excellent or good by only 12% of departments, and to be poor or non-sufficient by 40% of departments. Conclusion: This study demonstrates a high need to improve the state of care and to harmonize diagnostic and treatment strategies for SAID patients. Keywords: Autoinflammatory disease, State of care, Survey

Serum amyloid A (SAA) is an acute-phase protein produced primarily in the liver that plays a key role in both the initiation and maintenance of inflammation. Rapidly secreted SAA induces neutrophilia at inflammatory sites, initiating inflammation and inducing the secretion of various cytokines, including TNF-α, IL-6, and IL-17. IL-17 is expressed in several inflammatory cells, including innate immune cells such as γδT cells, ILC3 cells, and neutrophils. Increased IL-17 levels exacerbate various inflammatory diseases. Among other roles, IL-17 induces bone loss by increasing receptor activator of nuclear factor-κB ligand (RANKL) secretion, which stimulates osteoclast differentiation. Several studies have demonstrated that chronic inflammation induces bone loss, suggesting a role for SAA in bone health. To test this possibility, we observed an increase in IL-17-producing innate immune cells, neutrophils, and γδT cells in these mice. In 6-month-old animals, we detected increased osteoclast-related gene expression and IL-17 expression in bone lysates. We also observed an increase in neutrophils that secreted RANKL in the bone marrow of TG mice. Finally, we demonstrated decreased bone mineral density in these transgenic (TG) mice. Our results revealed that the TG mice have increased populations of IL-17-producing innate immune cells, γδT cells, and neutrophils in TG mice. We additionally detected increased RANKL and IL-17 expression in the bone marrow of 6-month-old TG mice. Furthermore, we confirmed significant increases in RANKL-expressing neutrophils in TG mice and decreased bone mineral density. Our results provide evidence that chronic inflammation induced by SAA1 causes bone loss via IL-17-secreting innate immune cells.

Increased myeloperoxidase (MPO) expression and activity are associated with atherosclerotic disease in patients with chronic kidney disease (CKD). However, the causal relationship between MPO and the development and progression of atherosclerosis in patients with CKD is unknown. Eight-week-old male low-density-lipoprotein-receptor–deficient mice were subjected to 5/6 nephrectomy, irradiated, and transplanted with bone marrow from MPO-deficient mice to induce bone marrow MPO deletion (CKD-bMPOKO) or bone marrow from WT mice as a control to maintain preserved bone marrow MPO(CKD-bMPOWT). The mice were maintained on a high-fat/high-cholesterol diet for 16 weeks. As anticipated, both groups of mice exhibited all features of moderate CKD, including elevated plasma creatinine, lower hematocrit, and increased intact parathyroid hormone but did not demonstrate any differences between the groups. Irradiation and bone marrow transplantation did not further affect body weight, blood pressure, creatinine, or hematocrit in either group. The absence of MPO expression in the bone marrow and atherosclerotic lesions of the aorta in the CKD-bMPOKO mice was confirmed by immunoblot and immunohistochemistry, respectively. Decreased MPO activity was substantiated by the absence of 3-chlorotyrosine, a specific by-product of MPO, in aortic atherosclerotic lesions as determined by both immunohistochemistry and highly sensitive LC-MS. Quantification of the aortic lesional area stained with oil red O revealed that CKD-bMPOKO mice had significantly decreased aortic plaque area as compared with CKD-bMPOWT mice. This study demonstrates the reduction of atherosclerosis in CKD mice with the deletion of MPO in bone marrow cells, strongly implicating bone-marrow-derived MPO in the pathogenesis of CKD atherosclerosis.

Crystalline cellulose nanocrystals (CNCs) have emerged as novel materials for a wide variety of important applications such as nanofillers, nanocomposites, surface coatings, regenerative medicine and potential drug delivery. CNCs have a needle-like structure with sizes in the range of 100–200 nm long and 5–20 nm wide and a mean aspect ratio 10–100. Despite the great potential applicability of CNCs, very little is known about their potential immunogenicity. Needle-like materials have been known to evoke an immune response in particular to activate the (NOD-like receptor, pyrin domain-containing 3)-inflammasome/IL-1β (Interleukin 1β) pathway. In this study we evaluated the capacity of unmodified CNC and its cationic derivatives CNC-AEM (aminoethylmethacrylate)1, CNC-AEM2, CNC-AEMA(aminoethylmethacrylamide)1 and CNC-AEMA2 to stimulate NLRP3-inflammasome/IL-1β pathway and enhance the production of mitochondrial reactive oxygen species (ROS). Mouse macrophage cell line (J774A.1) was stimulated for 24 h with 50 µg/mL with unmodified CNC and its cationic derivatives. Alternatively, J774A1 or PBMCs (peripheral blood mononuclear cells) were stimulated with CNC-AEMA2 in presence or absence of LPS (lipopolysaccharide). IL-1β secretion was analyzed by ELISA, mitochondrial function by JC-1 staining and ATP content. Intracellular and mitochondrial reactive oxygen species (ROS) were assessed by DCF-DA (2′,7′-dichlorodihydrofluorescein diacetate) and MitoSOX, respectively. Mitochondrial ROS and extracellular ATP were significantly increased in cells treated with CNC-AEMA2, which correlates with the strongest effects on IL-1β secretion in non-primed cells. CNC-AEMA2 also induced IL-1βsecretion in LPS-primed and non-primed PBMCs. Our data suggest that the increases in mitochondrial ROS and ATP release induced by CNC-AEMA2 may be associated with its capability to evoke immune response. We demonstrate the first evidence that newly synthesized cationic cellulose nanocrystal derivative, CNC-AEMA2, has immunogenic properties, which may lead to the development of a potential non-toxic and safe nanomaterial to be used as a novel adjuvant for vaccines., Highlights • Immunogenicity of CNC derivatives was studied on the NLRP3 inflammasome pathway. • Only CNC-AEMA2 induced IL-1β secretion in non-primed and primed macrophages. • IL-1β secretion caused by CNC-AEMA2 involves mitochondrial ROS and ATP release.