A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder impacting various organs, notably prevalent in women of reproductive age. This review explores the involvement of a disintegrin and metalloproteinases (ADAMs) in SLE pathogenesis. Despite advancements in understanding SLE through genome and transcriptome studies, the role of ADAMs in post-translational regulations remains insufficiently explored. ADAMs, transmembrane proteins with diverse functions, impact cell adhesion, migration, and inflammation by shedding cell surface proteins, growth factors, and receptors. Notably, ADAM9 is implicated in Th17 cell differentiation, which is crucial in SLE pathology. ADAM10 and ADAM17 play pivotal roles in T-cell biology, influencing immune cell development and differentiation. Elevated soluble ADAM substrates in SLE patients serve as potential biomarkers correlating with disease activity. Targeting ADAMs or their substrates offers promising therapeutic avenues for SLE management and treatment enhancement.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Complement activation and increased expression of Syk, mucin-1 and CaMK4 in kidneys of patients with COVID-19.

Acute and chronic kidney failure is common in hospitalized patients with COVID-19, yet the mechanism of injury and predisposing factors remain poorly understood. We investigated the role of complement activation by determining the levels of deposited complement components (C1q, C3, FH, C5b-9) and immunoglobulin along with the expression levels of the injury-associated molecules spleen tyrosine kinase (Syk), mucin-1 (MUC1) and calcium/calmodulin-dependent protein kinase IV (CaMK4) in the kidney tissues of people who succumbed to COVID-19. We report increased deposition of C1q, C3, C5b-9, total immunoglobulin, and high expression levels of Syk, MUC1 and CaMK4 in the kidneys of COVID-19 patients. Our study provides strong rationale for the expansion of trials involving the use of inhibitors of these molecules, in particular C1q, C3, Syk, MUC1 and CaMK4 to treat patients with COVID-19.

Activation of classical and alternative complement pathways in the pathogenesis of lung injury in COVID-19.

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.

Estimation of the relationship between the sacral hiatus and other dorsal sacral parameters using principle component analysis.

PURPOSE: Correct localization of the sacral hiatus is essential for administering a successful caudal epidural block. The purpose of this study is to create a statistical model of sacral hiatus from dorsal sacral parameters to improve the location of the hiatus and thus, reduce the failure rate. The aim of this investigation was to examine the relationship of sacral hiatus morphology and dimension with sacral curvature. This study further examines the dorsal sacral parameters that could affect the sacral hiatus dimension. METHODS: Adult, human, dry sacra and three-dimensionally reconstructed sacra from computed tomography imaging of normal subjects were included in the study and measured using digital Vernier calipers of 0.01 mm accuracy and Geomagic freeform plus software, respectively. RESULT: The most frequent shape of the sacral hiatus was an inverted V (48%) followed by inverted U shape (32%), an irregular shape (12.3%), an M shape (4.7) and an A shape (2.8%). The data were represented by mean and standard deviation. Sacra with M-shaped hiatus had the lowest hiatal length (14.21 ± 5.44 mm), whereas sacra with an inverted V-shaped hiatus had the highest length (25.41 ± 11.3 mm). The anteroposterior diameter of the sacral hiatus at the base in males and females was found to be 3.46 ± 1.48 mm and 2.79 ± 0.83 mm, respectively (P < 0.001). The distance between the caudal end of the median sacral crest and the apex of the sacral hiatus (7.90 ± 6.74 mm, 4.4 ± 5.86 mm) also revealed sexual dimorphism (P < 0.001). CONCLUSION: The correlations between most of the dorsal sacral parameters and length of the sacral hiatus are significant. The intercornual distance is also moderately correlated with the distance between right and left lateral sacral crest S1 level. Dorsal sacral parameters predicts variance of the sacral hiatus dimension from 40 to 73% and this could be utilized for statistical model of the sacral hiatus.

Prevalence of anomalous or ectopic insertion of pectoralis minor: a systematic review and meta-analysis of 4146 shoulders.

INTRODUCTION: The proximal insertion beyond coracoid process of pectoralis minor is considered as hidden culprit of rotator cuff disorders. The ectopic insertion is also associated with thoracic outlet syndrome. The current review was conducted to provide a comprehensive evidence-based assessment of the anatomical characteristics of ectopic insertion of pectoralis minor. MATERIALS AND METHODS: A through systematic search was conducted on the major electronic database, PubMed, EMBASE, Google Scholar and Journals of Anatomy, orthopedics, plastic surgery, sports medicine. The primary outcome was to measure the prevalence of ectopic insertion of pectoralis minor tendons. The data extraction was conducted for pooled estimation and metanalysis. RESULTS: A total of 25 studies were included for systematic review. The overall pooled estimate of ectopic insertion of Pectoralis Minor was 19.27% (95% CI 15-24%). The prevalence rate in dissected specimen was 21% (CI 15-28%) and in arthroscopic evaluation was 22% (95% CI 5-59%) which was marginally higher with wide confidence interval due small sample size. The prevalence rate in MRI and USG were 15 and 12%, because MRI and USG have almost similar sensitivity in the detection of anomalous insertion of Pectoralis Minor. The distribution of subtypes of anomalous or ectopic insertion based on Le Double classification was 34% for type I, 42 and 9% for Type III. The incidence of ectopic insertion of pectoralis minor was highest in Japanese population. The female and left side have slightly higher incidence at insignificant level. CONCLUSION: The preoperative MRI or at least USG evaluation of shoulder joint must be conducted for appropriate surgical planning, because the prevalence of ectopic insertion is around 20%. The preoperative detection of anomalous insertion of pectoralis minor can be crucial in minimizing the incidences of iatrogenic injuries of tendon or post-operative complications.

Cell derived extracellular matrix-rich biomimetic substrate supports podocyte proliferation, differentiation and maintenance of native phenotype.

Current technologies and available scaffold materials do not support long-term cell viability, differentiation and maintenance of podocytes, the ultra-specialized kidney resident cells that are responsible for the filtration of the blood. We developed a new platform which imitates the native kidney microenvironment by decellularizing fibroblasts grown on surfaces with macromolecular crowding. Human immortalized podocytes cultured on this platform displayed superior viability and metabolic activity up to 28 days compared to podocytes cultured on tissue culture plastic surfaces. The new platform displayed a softer surface and an abundance of growth factors and associated molecules. More importantly it enabled podocytes to display molecules responsible for their structure and function and a superior development of intercellular connections/interdigitations, consistent with maturation. The new platform can be used to study podocyte biology, test drug toxicity and determine whether sera from patients with podocytopathies are involved in the expression of glomerular pathology.

Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia.

Intestinal ischemia followed by reperfusion leads to local and remote organ injury attributed to inflammatory response during the reperfusion phase. The extent to which ischemia contributes to ischemia/reperfusion injury has not been thoroughly studied. After careful evaluation of intestinal tissue following 30 min of ischemia, we noticed significant local mucosal injury in wild-type mice. This injury was drastically reduced in C3-deficient mice, suggesting C3 involvement. Depletion of circulating complement with cobra venom factor eliminated, as expected, injury recorded at the end of the reperfusion phase but failed to eliminate injury that occurred during the ischemic phase. Immunohistochemical studies showed that tissue damage during ischemia was associated with increased expression of C3/C3 fragments primarily in the intestinal epithelial cells, suggesting local involvement of complement. In vitro studies using Caco2 intestinal epithelial cells showed that in the presence of LPS or exposure to hypoxic conditions the cells produce higher C3 mRNA as well as C3a fragment. Caco2 cells were also noted to produce cathepsins B and L, and inhibition of cathepsins suppressed the release of C3a. Finally, we found that mice treated with a cathepsin inhibitor and cathepsin B-deficient mice suffer limited intestinal injury during the ischemic phase. To our knowledge, our findings demonstrate for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. Modulation of cathepsin activity may prevent injury of organs exposed to ischemia.

Three-dimensional morphometric and volumetric analysis of maxillary sinuses.

BACKGROUND: The maxillary sinus is a pyramid-shaped cavity with varying shapes, sizes, and capacities. Its dimensions grow gradually and develop until early adulthood. Anatomical knowledge of the maxillary sinus is essential to understanding sinonasal disorders, planning surgical procedures and preventing complications. Awareness of the sinus's proximity to critical structures helps avoid injuries during surgery. The European, Korean, and Sri Lankan population study parameters show varying results and do not necessarily apply to the Indian population. The standard morphometric data of the maxillary sinus is scanty in the Indian population. The study aimed to determine the volume and morphometry of the maxillary sinus along with gender differences in the Eastern population of the Indian. MATERIALS AND METHODS: A retrospective cross-sectional study was conducted using cone beam computed tomography data of maxillary sinuses of 100 normal individuals. The data were analysed after the three-dimensional reconstruction of digital imaging and communications in medicine (DICOM) images with the help of DICOM to print and Geomagic freeform software in the Anatomy department. The different linear morphometric variables and volume of the maxillary sinus were studied. SPSS version 27.0. was utilised for statistical analyses. RESULTS: The mean values of Antero-posterior diameter, Transverse diameter, Craniocaudal diameters, the height of ostium from the floor and volume of the maxillary sinus in males on the right side are 36.61 mm, 20.7 mm, 40.31 mm, 26.02 mm and 16055.24 mm³ and on the left side are 37.17 mm, 20.17 mm, 40.73 mm, 26.91 mm and 15712.66 mm³ whereas in females the values on the right side are 38.10 mm, 21.56 mm, 38.96 mm, 25.81 mm and 14687.78 mm³ and on left side are 38.23 mm, 21.53 mm, 38.48 mm, 25.28 mm and 14203.13 mm3 respectively. The side-to-side parameter differences were non-significant within the male and female groups, respectively. The females had significantly (p < 0.05) larger transverse diameters than males in both the right and left maxillary sinuses. The males tend to have a slightly larger mean craniocaudal diameter than females, but the difference was found statistically significant (p < 0.05) only in the left maxillary sinus. The gender differentiation based on the measured parameters of bilateral maxillary sinus accuracy rate was 89.4% in males and 61.8% in females. CONCLUSIONS: These parameters serve as a standard or reference point, allowing radiologists and surgeons to compare individual patient scans to population averages and aid in better clinical outcomes. The mean values of different parameters of the maxillary sinus may be utilised to differentiate various suspected sinus pathologies, which is helpful for functional endoscopic sinus surgery. Gender differentiation can be done more accurately by forensic experts using Maxillary sinus transverse diameter bilaterally, followed by craniocaudal diameter of the left side sinus for predicting the gender of an unknown maxilla.

Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.

Intertwined pathways of complement activation command the pathogenesis of lupus nephritis.

The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus. However, more recent studies have shown the contribution of factors B and D which implies the involvement of the alternative pathway. While there is evidence on the role of the lectin pathway in systemic lupus erythematosus, it is yet to be demonstrated whether this pathway is protective or harmful in lupus nephritis. Complement is being explored for the development of disease biomarkers and therapeutic targeting. In the current review we discuss the involvement of complement in lupus nephritis.

CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.

Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.

An imbalance in oxidant/antioxidant dynamics: correlation with therapeutic response in patients with carcinoma of posterior one third of the tongue.

The objective was to study the alterations in circulating pro-/antioxidants in patients with cancer of the posterior one third of the tongue, before and after concomitant chemoradiation, and to assess variation in their levels to therapeutic response. Sixty patients with newly diagnosed squamous cell carcinoma of the posterior one third of the tongue and 60 healthy controls were enrolled. Blood samples were collected before and after chemoradiation and after 3 months of follow-up. Pro-/antioxidant levels were estimated using standard methods. Response to therapy was assessed during and after therapy and after 3 months of followup. Pretreatment levels of lipid peroxide were significantly elevated while antioxidant levels were lowered in cancer patients compared to controls. After chemotherapy, lipid peroxidation showed a significant decline, while antioxidants showed a significant rise in complete responders, compared with partial/nonresponders, and remained highly significant after therapy and during follow-up. Pretreatment levels of antioxidant-oxidant parameters and the extent of their change during treatment can predict the therapeutic response to concomitant chemoradiation in carcinoma tongue.

CYFRA 21-1: a potential molecular marker for noninvasive differential diagnosis of urothelial carcinoma of bladder.

Establishing CYFRA 21-1 detection for noninvasive differential diagnosis of urothelial carcinoma (UC) of bladder would help to improve assessment and follow-up of patients, as well as to improve screening of high-risk groups. The study group comprised of 147 subjects including 72 patients with UC of bladder, 75 controls and 17 follow-up cases. The levels of CYFRA 21-1 in serum, urine and urinary cell lysate were estimated by high sensitivity ELISA. Our results indicate that urinary CYFRA 21-1 provides a high value of overall sensitivity for UC of bladder and is also useful even for detection of low grade tumors that might indicate possible earlier detection and treatment administration.

Oxidant/anti-oxidant dynamics in patients with advanced cervical cancer: correlation with treatment response.

Cervical cancer is the most common cancer in Indian women. Oxidative stress is potentially harmful to cells and ROS are involved in multistage carcinogenesis, in initiation and promotion. The aim was to study the alterations in the circulating pro-/anti-oxidants in advanced cervical cancer patients, before and after neoadjuvant chemoradiation and to assess the relevance of the variation in the levels to therapeutic response. 90 patients with advanced cancer cervix (FIGO IIIa-IVa) and 90 healthy controls were enrolled. Blood samples were collected: before and after chemotherapy, after radiation and after 1 year on follow-up. Pro-/anti-oxidant levels were estimated using standard methods. Response to therapy was assessed during and after therapy and after 1 year of follow-up. The pre-treatment levels of plasma lipid peroxide were significantly elevated; while antioxidant levels were lowered in cancer patients; when compared to controls. After chemotherapy, lipid peroxidation showed a significant decline in complete responders, as compared with partial/non-responders and remained highly significant after therapy and during follow-up. Anti-oxidant enzymes showed a mild increase (P < 0.05), after chemotherapy in complete responders, as compared with partial/non-responders and remained highly significant after therapy and on follow-up. This important finding suggests that pre-treatment levels of antioxidant-oxidant parameters and the extent of their change during treatment can predict the therapeutic response to neoadjuvant chemoradiation in advanced cancer cervix. Oxidant-antioxidant profile merits investigation as markers of response, survival, and recurrence in larger prospective studies, which might throw light on their possible use as predictors of chemoradiosensitivity of cervical tumors.

Complement Deposition on the Surface of RBC After Trauma Serves a Biomarker of Moderate Trauma Severity: A Prospective Study.

BACKGROUND: Activation of the complement system and complement deposition on red blood cells (RBCs) contribute to organ damage in trauma. We conducted a prospective study in subjects with traumatic injuries to determine the pattern of complement deposition on RBC and whether they are associated with clinical outcomes. METHOD: A total of 124 trauma patients and 42 healthy controls were enrolled in this prospective study. RBC and sera were collected at 0, 6, 24, and 72 h from trauma patients and healthy controls during a single draw. Presence of C4d, C3d, C5b-9, phosphorylation of band 3 and production of nitric oxide were analyzed by flow cytometry. RESULTS: RBC from trauma patients at all time points up to 24 h displayed significantly higher deposition of C4d on their RBC membrane as compared with healthy donors. Incubation of normal RBC with sera from trauma patients resulted in significant increase of C4d deposition (at 0, 6, 24, and 72 h), C5b-9 deposition (at 0 and 6 h), phosphorylation of band 3 (at 0 and 24 h), and nitric oxide production up to 24 h compared with sera from healthy subjects. Deposition of C4d and C5b-9 in patients with an Injury Severity Score (ISS) of 9 and above remained elevated up to 72 h. CONCLUSIONS: Our study demonstrates that the presence of C4d, C3d, and C5b-9 on the surface of RBC is linked to increased phosphorylation of band 3 and increased production of nitric oxide. Deposition of C4d and C5b-9 decreased faster over course of 3-day study in subjects with ISS less than 9.

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic.

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury.

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.