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ID PMID Title PublicationDate abstract
34842044 Studies on the synergistic action of methylglyoxal and peroxynitrite on structure and func 2021 Nov 28 Albumin, an important serum protein, is continuously exposed to various oxidizing/nitrating and glycating agents. Depending upon the nature/concentration of reactive species present, the protein may be glycated, oxidized/nitroxidized or glyco-nitro-oxidized. Peroxynitrite is a powerful nitroxidant and has been reported to damage a wide array of macromolecules. On the other hand, methylglyoxal is a very strong reactive dicarbonyl and a potent precursor for the formation of advanced glycation end products under pathological conditions. In certain pathological conditions albumin may be modified by peroxynitrite and methylglyoxal simultaneously. There is dearth of literature suggests that structural/conformational and functional alteration in albumin upon glycation and oxidation/nitroxidation, however the alterations produced by glyco-nitro-oxidation has not yet been explored. Therefore, in this study, simultaneous effect of glycation and nitroxidation on the structure and conformation, vis-a-vis function of albumin was explored. Glyco-nitro-oxidized albumin showed decreased free amino acid content together with decreased affinity of albumin towards cobalt. Molecular docking model and molecular dynamic simulations showed close interaction and formation of stable complexes between methylglyoxal, peroxynitrite and albumin. Formation of carboxymethyl lysine and 3-nitrotyrosine in glyco-nitro-oxidized albumin were confirmed by MALDI-TOF MS and UP-LC MS. Aggregate formation in glyco-nitro-oxidized albumin was visualized by transmission electron microscopy. On the basis of these results, it may be speculated that, albumin modified with endogenously generated methylglyoxal and peroxynitrite might be a driving factor in the progression of heightened inflammatory autoimmune responses. The work presents a ground to study the role of glyco-nitro-oxidized albumin in the pathogenesis and progression of various autoimmune diseases including rheumatoid arthritis.Communicated by Ramaswamy H. Sarma.
34829303 Clinical Manifestations, Pathogenesis, Diagnosis and Treatment of Peripheral Neuropathies 2021 Oct 21 PURPOSE OF REVIEW: To discuss and summarize recent findings in peripheral neuropathy (PN) related to connective tissue diseases (CTD) including its prevalence, clinical manifestations, pathogenesis, diagnosis and treatment. RECENT FINDINGS: Although PN is a common complication in CTD and has been well studied, recent research has shown that PN is more diverse and frequent in different subtypes of CTD than was expected. The incidence of PN in Sjögren's syndrome and rheumatoid arthritis (RA) varies according to different disease subtypes, and the pathogenesis of neuropathic pain in different subtypes of eosinophilic granulomatosis with polyangiitis (EGPA) may also differ. Neurogenic inflammation, autoantibody-mediated changes, ischemia of the vascular wall and metabolic mechanisms have been shown to contribute to the pathogenesis of PN in CTD. Moreover, allergic inflammation has been recently identified as a possible new mechanism producing peripheral neuropathic pain associated with MPO-ANCA negative EGPA patients. Glucocorticoids are routinely used to relieve pain caused by PN. However, these steroids may cause hyperalgesia, exacerbate neuropathic pain, and activate the early phase of pain induction and produce hyperalgesia. Recently, neuroactive steroids, such as progesterone, tetrahydroprogesterone and testosterone, have been shown to exert protective effects for several PN symptoms, and in particular neuropathic pain. Neuroactive steroids will be an interesting topic for future research into PN in CTD. SUMMARY: It is essential for the diagnosis and treatment of PN in CTD to be updated. Timely diagnosis, appropriate treatments, and multidisciplinary care are essential to minimize morbidity and decrease the risk of permanent neurologic deficits. Further studies are needed to guide diagnosis and treatment.
34791576 Hypoxia modulates human mast cell adhesion to hyaluronic acid. 2022 Apr Hypoxia is an inherent factor in the inflammatory process and is important in the regulation of some immune cell functions, including the expression of mast cell pro- and anti-inflammatory mediators. Hypoxia also influences cell adhesion to the extracellular matrix (ECM). Hyaluronic acid is one of the major components of the ECM that is involved in inflammatory and tissue regeneration processes in which mast cells play a prominent role. This prompted us to investigate the effects of hypoxia on the expression of hyaluronic acid receptors in mast cells and mast cell adhesion to this ECM component. We found that human LAD2 mast cells spontaneously adhered to hyaluronic acid in a CD44-dependent manner and that reduced oxygen concentrations inhibited or even completely abolished this adhesion process. The mechanism of hypoxia downregulation of mast cell adhesion to hyaluronic acid did not involve a decrease in CD44 expression and hyaluronidase-mediated degradation of adhesion substrates but rather conformational changes in the avidity of CD44 to hyaluronic acid. Hypoxia-mediated regulation of mast cell adhesion to extracellular matrix components might be involved in the pathogenic accumulation of mast cells observed in the course of certain diseases including rheumatoid arthritis and cancer.
34722065 Prevalence of Thyroid Dysfunction in Patients With Hepatitis C. 2021 Sep INTRODUCTION: Hepatitis C has been linked to a multitude of autoimmune disorders, including rheumatoid arthritis, thyroid disease, cryoglobulinemia, immune thrombocytopenic purpura, systemic lupus erythematosus, and Sjögren's syndrome. In this study, efforts were made to draw a parallel between hepatitis C and thyroid dysfunction. METHODS: This case-control study was conducted between June 2020 and March 2021 in the gastroenterology ward of a tertiary care hospital. We enrolled 300 hepatitis C-positive patients in this study through consecutive convenient non-probability sampling. In addition, 300 patients without hepatitis C were signed up as a control group. Blood sampling for thyroid function tests was conducted via phlebotomy from the cubital vein and the samples were dispatched to the laboratory for further study. RESULTS: The control group had more euthyroid patients as compared to patients with hepatitis C (74.6% vs. 89.6%; p-value: <0.01). Hepatitis C patients had more cases of primary hypothyroidism compared to the control group (10.6% vs. 4.6%; p-value: 0.005). Similarly, patients with hepatitis C had a higher prevalence of subclinical hypothyroidism compared to the control group (6.0% vs. 1.3%; p-value: 0.002). CONCLUSION: Hepatitis C patients have a high frequency of thyroid dysfunction, particularly primary hypothyroidism and subclinical hypothyroidism. Therefore, it is important to ensure regular screening for early prognosis and avoid treatment modalities that are known to cause thyroid abnormalities.
34666637 Airborne pollutants as potential triggers of systemic autoimmune rheumatic diseases: a nar 2021 Oct 19 The pathogenesis of systemic autoimmune rheumatic diseases (SARDs) is complex and remains insufficiently understood. It is commonly accepted that both intrinsic and extrinsic environmental factors interact to induce a self-reactive immune response. Case reports and observational studies have revealed an association between SARDs and specific airborne environmental factors, but the heterogeneity of the published studies hampers clear conclusions. The aim of this review is to provide an overview of the available epidemiological evidence on the relationship between airborne pollutants and SARDs. We performed a narrative review using the PubMed database. Observational studies have shown significant associations between airborne pollutants and SARDs. Cigarette smoking is strongly associated with the development of rheumatoid arthritis (RA) while the association between cigarette smoke and the development of other SARDs remains controversial. For decades, silica exposure has been linked to systemic sclerosis (SSc), RA and systemic lupus erythematosus (SLE). There is also strong evidence for a link between solvents and SSc. Recent observations even suggest that ambient air pollution is associated with the development of SARDs. Some studies have shown associations between asbestos, organic dust, metals and pesticides and SARDs, but more studies are needed to confirm these findings. Increasing evidence has linked airborne pollutants to SARDs. Although more studies are needed to understand the potential mechanisms by which these environmental agents contribute to disease pathogenesis, awareness of the link between environmental agents and SARDs is important to recognize and prevent work-related and environmentally induced diseases.
34302262 Delay differential equations based models in NONMEM. 2021 Dec Delay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time. Two of them are based on algorithms already applied elsewhere, while others are extensions of existing ordinary differential equations (ODEs) solvers. The purpose of this tutorial is to introduce basic concepts underlying DDE based models and to show how they can be developed using NONMEM. The examples include previously published DDE models such as logistic growth, tumor growth inhibition, indirect response with precursor pool, rheumatoid arthritis, and erythropoiesis-stimulating agents. We evaluated the accuracy of NONMEM DDE solvers, their ability to handle stiff problems, and their performance in parameter estimation using both first-order conditional estimation (FOCE) and the expectation-maximization (EM) method. NONMEM control streams and excerpts from datasets are provided for all discussed examples. All DDE solvers provide accurate and precise solutions with the number of significant digits controlled by the error tolerance parameters. For estimation of population parameters, the EM method is more stable than FOCE regardless of the DDE solver.
34270526 Psychosocial and economic impact of uveitis in Mexico. 2021 OBJECTIVE: To determine the psychosocial and economic impact suffered by patients diagnosed with uveitis in Mexico. METHODS: Survey in uveitis-diagnosed patients. Demographic data and socioeconomic level were recorded. Symptoms, time to diagnosis, type of treatment, behavior, attitudes and feelings towards the disease were identified. RESULTS: One hundred surveys were conducted in patients with uveitis, who had a mean age of 45 ± 17.08 years, and socioeconomic level ≤ D; 54 were females. Diagnostic delay was 1.87 ± 2.73 years. Annually, patients attend 2.1 ± 2.14 appointments per month, and are admitted once to the emergency department and remain hospitalized for 3.7 days. Patients use systemic treatment with steroidal anti-inflammatory drugs (53 %), immunosuppressant agents (31 %), biological therapy (7 %), topical treatment with lubricants (44 %) or steroids (26 %) and undergo surgery (39 %). Observed comorbidities include hypertension, diabetes mellitus, rheumatoid arthritis (18 %), Sjögren's syndrome, systemic lupus erythematosus, and nonspecific chronic ulcerative colitis. Complications: visual impairment, cataracts and blindness. Uveitis affects their life in 83 % of cases, in 41 % does it daily, and 49 % need care from another person. Seventy-nine percent receive private care and 43 % have social security, with $ 3,590 ± $ 2,730.65 pesos being spent monthly on medicines, transportation, medical appointments and studies. Annually, work absenteeism is 8.5 ± 14.56 days, plus 7.0 days of disability or hospitalization; 51% refer lack of support to learn about the disease. CONCLUSIONS: This is the first national study to portray the condition of patients with uveitis and the shortcomings they go through, including the economic and biopsychosocial fields.
34152447 GABAergic signaling by cells of the immune system: more the rule than the exception. 2021 Aug Gamma-aminobutyric acid (GABA) is best known as an essential neurotransmitter in the evolved central nervous system (CNS) of vertebrates. However, GABA antedates the development of the CNS as a bioactive molecule in metabolism and stress-coupled responses of prokaryotes, invertebrates and plants. Here, we focus on the emerging findings of GABA signaling in the mammalian immune system. Recent reports show that mononuclear phagocytes and lymphocytes, for instance dendritic cells, microglia, T cells and NK cells, express a GABAergic signaling machinery. Mounting evidence shows that GABA receptor signaling impacts central immune functions, such as cell migration, cytokine secretion, immune cell activation and cytotoxic responses. Furthermore, the GABAergic signaling machinery of leukocytes is implicated in responses to microbial infection and is co-opted by protozoan parasites for colonization of the host. Peripheral GABA signaling is also implicated in inflammatory conditions and diseases, such as type 1 diabetes, rheumatoid arthritis and cancer cell metastasis. Adding to its role in neurotransmission, growing evidence shows that the non-proteinogenic amino acid GABA acts as an intercellular signaling molecule in the immune system and, as an interspecies signaling molecule in host-microbe interactions. Altogether, the data raise the assumption of conserved GABA signaling in a broad range of mammalian cells and diversification of function in the immune system.
34054828 The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19? 2021 IL-36 is a member of the interleukin 1 cytokine family, which is currently experiencing a renaissance due to the growing understanding of its context-dependent roles and advances in our understanding of the inflammatory response. The immunological role of IL-36 has revealed its profound and indispensable functional roles in psoriasis, as well as in several inflammatory diseases, including inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis (RA) and cancer. More recently, an increasing body of evidence suggests that IL-36 plays a crucial role in viral, bacterial and fungal infections. There is a growing interest as to whether IL-36 contributes to host protective immune responses against infection as well as the potential implications of IL-36 for the development of new therapeutic strategies. In this review, we summarize the recent progress in understanding cellular expression, regulatory mechanisms and biological roles of IL-36 in infectious diseases, which suggest more specific strategies to maneuver IL-36 as a diagnostic or therapeutic target, especially in COVID-19.
34041953 Capnocytophaga gingivalis Bacteremia After Upper Gastrointestinal Bleeding in Immunocompro 2021 Jan Odontogenic bacteremia, most commonly involving gram-positive oral flora, can result from daily self-care practices or professional dental procedures. Though usually transient and quickly cleared by the immune system, the presence of periodontal disease increases the frequency of exposure and risk of persistence of oral-systemic infections. Comorbidities such as asplenia, alcoholism, and immunocompromise increase the risk of complications of hematogenous spread and severe systemic illness. Capnocytophaga is a genus of anaerobic fastidious gram-negative bacilli, which is a common member of human oral flora, and its density is proportional to mass of dental plaques and periodontal diseases. Capnocytophaga spp that colonize humans are less virulent and are uncommon causes of bacteremia when compared with the Capnocytophaga typical of canines. C gingivalis has been rarely reported as a cause of disease in immunocompromised or immunocompetent hosts. In this article, we present a case of an immunocompromised 70-year-old man with poor oral hygiene, on methotrexate and prednisone for rheumatoid arthritis and sarcoidosis, who was admitted for chronic obstructive pulmonary disease exacerbation and developed C gingivalis bacteremia and septic shock after an episode of upper gastrointestinal bleeding. Poor oral hygiene in our patient is believed to have increased his risk as an immunocompromised patient to developing C gingivalis bacteremia. This case highlights the importance of oral care in immunocompromised patients especially while hospitalized, and those about to receive transplant, chemotherapy, or on immune modulators.
33365072 Icariin enhances cell survival in lipopolysaccharide-induced synoviocytes by suppressing f 2021 Jan The mechanism of action of synovitis, as the vital pathological process of rheumatoid arthritis and osteoarthritis, remains to be elucidated. The effects and the mechanism of icariin (ICA), which is a promising therapeutic agent in synovitis, was investigated in the present study. In addition, ferroptosis, a vital cell process involved in several diseases, was also studied in synovitis for the first time. Lipopolysaccharide (LPS)-induced synoviocytes served as a synovitis cell model. The cells were divided into control, LPS and experimental groups and were treated with different concentrations of ICA. Cell viability was determined by Cell Counting Kit-8 assay and cell death was determined by flow cytometry. The expression levels of proteins (GPX4, SLC7A11, SLC3A2L, TRF, Nrf2 and NCOA4) were measured by western blotting. Quantification of malondialdehyde (MDA), iron and glutathione peroxidase 4 (GPX4) activity levels were performed via using corresponding assay kits. Cell death was increased, and cell viability was decreased in LPS-induced synoviocytes. Furthermore, MDA levels and iron content were elevated and GPX levels was reduced in LPS-induced synoviocytes. Transferrin receptor protein 1 and nuclear receptor coactivator 4 were upregulated and proteins of the Xc-/GPX4 axis, as well as nuclear factor erythroid 2-related factor 2, were decreased by LPS treatment. All aforementioned LPS affects were alleviated by ICA via a concentration-dependent manner. ICA counteracted the effects of RSL3, a ferroptosis activator, on cell viability, lipid peroxidation, iron content and relative protein expression of ferroptosis in synoviocytes. ICA protects the cells from death in synoviocytes induced by LPS, via the inhibition of ferroptosis by activating the Xc-/GPX4 axis, which can be exploited as a new therapeutic strategy for synovitis.
33930803 Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibit 2021 Aug 5 Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC(50) values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.
33710502 Delay of endoscopic submucosal dissection-induced gastric ulcer healing by methotrexate. 2021 Jun We report a case of methotrexate (MTX) delaying the healing of an endoscopic submucosal dissection (ESD)-induced gastric ulcer. The patient, who had been taking MTX for rheumatoid arthritis, underwent ESD for early gastric carcinoma. Despite taking vonoprazan after ESD, abdominal pain and anorexia continued, and the gastric ulcer did not heal after the ESD. After discontinuing MTX, the patient's symptoms improved and the ulcer healed. Patients taking MTX require careful follow-up after ESD, considering that ulcers can be difficult to heal. Discontinuation of MTX should be considered if delayed healing of an ulcer is observed.
33645046 [Research progress of effect of Rhei Radix et Rhizoma and its anthraquinone in treatment o 2021 Jan Rhei Radix et Rhizoma was first recorded in Shennong Ben Cao Jing, with a wide range of pharmacological activities. Autoimmune disease is a kind of disease that damages the tissue structure and function of immune cells and their components due to the impairment of immune tolerance function, including atherosclerosis, multiple sclerosis, gout, rheumatoid arthritis, autoimmune thyroiditis, ulcerative colitis, type 1 diabetes and IgA nephropathy. In recent years, clinical and experimental studies show that Rhei Radix et Rhizoma has potential therapeutic effects on autoimmune diseases. Under the guidance of the theory of traditional Chinese medicine, this paper reviews therapeutic and intervening effects of Rhei Radix et Rhizoma and its main active ingredient anthraquinone on autoimmune diseases. It also puts forward new study directions in view of the existing problems in studies of rhubarb and its anthraquinone, with the aim to provide reference for clinical treatment and scientific studies of effect of Rhei Radix et Rhizomaon autoimmune diseases.
33619316 Genetically predicted education attainment in relation to somatic and mental health. 2021 Feb 22 A deeper understanding of the causal links from education level to health outcomes may shed a light for disease prevention. In the present Mendelian randomization study, we found that genetically higher education level was associated with lower risk of major mental disorders and most somatic diseases, independent of intelligence. Higher education level adjusted for intelligence was associated with lower risk of suicide attempts, insomnia, major depressive disorder, heart failure, stroke, coronary artery disease, lung cancer, breast cancer, type 2 diabetes and rheumatoid arthritis but with higher risk of obsessive-compulsive disorder, anorexia nervosa, anxiety, bipolar disorder and prostate cancer. Higher education level was associated with reduced obesity and smoking, which mediated quite an extent of the associations between education level and health outcomes. These findings emphasize the importance of education to reduce the burden of common diseases.
33555010 Capillary Blood Levels of Hydroxychloroquine and Methotrexate Are Stable for up to 5 Years 2021 Jul 7 BACKGROUND: Hydroxychloroquine (HCQ) and methotrexate (MTX) are common antirheumatic drugs used chronically by patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (1, 2). Therapeutic drug monitoring (TDM) of HCQ and MTX provides critical compliance information, but typically requires venipuncture and shipment of refrigerated blood samples to the clinical laboratory. Capillary blood collection by finger prick offers a convenient alternative to venipuncture. The long-term stability of capillary blood HCQ and MTX collected using volumetric absorptive microsamplers (VAMS) has not previously been evaluated. In this study, we evaluated the stability of capillary MTX and HCQ levels when stored on VAMS for up to 5 years. METHODS: Samples of patients with RA and SLE were collected for HCQ or MTX monitoring as part of 2 clinical studies in 2015 (HCQ: n = 24 | MTX: n = 61) and 2017 (HCQ: n = 126). Venous and capillary blood samples were shipped to Exagen Inc.'s clinical laboratory. HCQ and MTXPG3 were measured using separate LC-MS/MS methodologies. Baseline venous blood levels of HCQ and MTXPG3 were determined within 1 week of draw and compared to capillary blood levels determined following 3 or 5 years of storage. RESULTS: Venous blood HCQ and capillary blood MTXPG3 determinations made at baseline were significantly different from capillary blood determinations performed following 5 years of storage at -80 °C. However, these differences were within the specified limits of agreement [HCQ: Avg % change after storage (CI 95%) = -7.1% (-12.6, -1.6%), pt-test = 0.0205, interclass correlation coefficient (ICC) = 0.96 | MTXPG3: Avg % change after storage (CI 95%) = 13.3% (7.1, 19.4%), pt-test = 0.0001, ICC = 0.90]. CONCLUSION: Dried capillary blood HCQ and MTXPG3 levels collected on VAMS are stable for up to 5 years.
33548305 Tonsillectomy and the subsequent risk of psoriasis: A nationwide population-based cohort s 2021 Dec BACKGROUND: Tonsillectomy has been suggested as an intervention to resolve psoriasis. OBJECTIVE: This study aimed to investigate the subsequent risk of psoriasis in patients who received tonsillectomy. METHODS: We used data from the Taiwan National Health Insurance Research Database. The tonsillectomy group (case group) and the tonsillectomy-free group (comparison group) were matched at a ratio of 1:4 by demographic data, comorbidities, medical confounders, and the index date. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 2021 patients as the case group and matched 8084 individuals as the comparison group. The adjusted HR (aHR) of psoriasis was 0.43 (95% CI, 0.22-0.87; P < .05). The study population is composed of a mainly male (65%) and young population (mostly younger than 50 years). Notably, patients with rheumatoid arthritis increased the risk of psoriasis (aHR, 3.97; 95% CI, 1.17-13.48; P < .05). In our stratification analysis, the risk of psoriasis decreased in almost all subgroups. LIMITATION: Our database did not include information on genome and the subtypes of psoriasis. CONCLUSION: Our study showed a decreased risk of psoriasis in the tonsillectomy group after adjustment for baseline characteristics, comorbidities, and medical confounders compared with the reference group.
32681397 Use of tocilizumab in amyloid a nephropathy associated with Sweet syndrome: a case report 2021 Feb Amyloid A nephropathy is a possible complication of chronic inflammatory disease. Proteinuria and kidney failure are the main features of the disease. Tocilizumab (TCZ), an IL6-R antibody approved for rheumatoid arthritis, is a promising choice for histologically demonstrated nephropathy. We describe a case of kidney amyloid associated with Sweet syndrome treated with TCZ. The patient was affected by Sweet syndrome associated with proteinuria. Kidney biopsy showed amyloid deposits. During the follow-up, cutaneous and renal findings were refractory to many immunosuppressive regimen (cyclophosphamide, leflunomide, interferon and steroid). After few years, the patient developed rapidly progressive nephropathy associated with nephrotic syndrome (proteinuria up to 6 g/die). A second kidney biopsy was performed and it showed worsening of amyloid nephropathy. Thus, TCZ was administrated (8 mg/kg once a month) and it stabilized kidney function and induced partial remission of the nephrotic syndrome in the following 2 years.
35201489 The gold complex auranofin: new perspectives for cancer therapy. 2021 Oct 20 Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin-proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.
35172428 Ultra-short cementless anatomical stem for intracapsular femoral neck fractures in patient 2021 Dec The aim of this study was to present the midterm results of total hip arthroplasty with ultra-short anatomical cementless stem in the primary treatment of displaced intracapsular femoral neck fractures in patients younger 60 years. From 2006 to 2015, 17 hip arthroplasties (with the Proxima stem) were performed in group of 17 patients for the treatment of acute femoral neck fractures Garden type III and IV. The mean follow-up period was 112.7 (range: 64-148) months. Patients were evaluated retrospectively - clinically and radiographically, using the Harris hip scoring system during the year 2020. Seven males and ten females (mean age: 45.0 years) were included in the study. Each of them had one or more risk factors (time delay, comminution of the femoral neck, corticosteroids usage, the presence of coxarthrosis, rheumatoid arthritis, alcohol abuse, etc…), because of which the osteosynthesis was not performed. Harris hip scores were 6.3 preoperatively and 82.9 at the final follow-up. Three patients (17.6%) had complications: luxation, aseptic stem loosening (migration with subsidence - "varisation" and thigh pain) and deep infection. One patient (5.9%) with infection was revised. In carefully selected younger patients with displaced intracapsular femoral neck fracture, where the osteosynthesis as first treatment option should be associated with high risk of complication (avascular femoral head necrosis, non-union) due to the presence of risk factors, the primary total hip arthroplasty could be performed. The ultra-short cementless stem offers promising results in these rare cases in the midterm.