Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting the EGFR signaling pathway in cancer therapy

Introduction: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review. Expert opinion: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.
Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)–Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed. Areas covered: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B. Expert opinion: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach.
Hydrogen sulfide as a therapeutic target for inflammation

Introduction: The view of hydrogen sulfide has changed from a toxic by-product to a crucial signaling molecule, with enormous potential as a pharmacological target for diseases ranging from heart disease to sepsis. Despite this progression of ideas, there is still a large amount that is unknown about this gaseous signaling molecule. Hydrogen sulfide has been implicated as a tissue protectant in many pathological conditions, the mechanisms of tissue protection is a point of controversy, particularly distinguishing the direct actions from the indirect downstream effects of hydrogen sulfide. This point of controversy is particularly pertinent in inflammation research. Areas covered: Current research into the pathways in which hydrogen sulfide can act as a pro-inflammatory molecule and as an anti-inflammatory molecule. Expert opinion: How controversies regarding hydrogen sulfide may have occurred is discussed. Addressed are the direct and indirect pathways of hydrogen sulfide on inflammation, the effects of different concentrations of hydrogen sulfide and how the effects of hydrogen sulfide on the immune system vary with different delivery mechanisms. Furthermore, there is a discussion on what key gaps exist in current knowledge and must be addressed before hydrogen sulfide can be considered a valid pharmacological target.
Review of the Series “Disease of the Year 2011: Toxoplasmosis” Pathophysiology of Toxoplasmosis

Toxoplasma gondii is a major cause of chronic parasitic infection in the world. This protozoan can cause retino-choroiditis in newborns and in adults, both immunocompetent and immunodeficient. This disease tends to be recurrent and can lead to severe visual impairment. The authors review current knowledge on the role of parasite genetics in influencing susceptibility to ocular toxoplasmosis and on the immuno-pathogenesis of this disease.
Targeting chemokines in proteinuria-induced renal disease

Introduction: Proteinuria is a common finding in glomerular diseases that contributes to the progression of chronic kidney injury. Tubular cells reabsorb the excess of albumin and other plasma proteins from the tubular lumen, triggering several pathophysiologic responses, such as overexpression of fibrogenic mediators and inflammatory chemokines. Chemokines are implicated both in the recruitment of inflammatory infiltrate and in a number of physiological and pathological processes related to protein overload. Areas covered: In recent years, the specific chemokines and their receptors and the intracellular signaling pathways involved in proteinuria-induced renal damage have been identified. This review provides an overview of the role of chemokines and their receptors in proteinuria-related renal disease and summarizes novel therapeutic approaches to restrain the progression of renal damage. Expert opinion: Inhibition of chemokine-induced biological activities is a promising therapeutic strategy in proteinuric disorders. Neutralizing antibodies and small organic molecules targeting chemokines and chemokine receptors have been proven to prevent inflammation and renal damage in experimental models of protein overload. Some of these compounds are currently being tested in human clinical trials.
LSD1 inhibition: a therapeutic strategy in cancer?

Introduction: The role of epigenetic dysfunction in cancer is increasingly appreciated. This has raised the question as to whether enzymes that regulate the structure and function of chromatin might represent novel therapeutic targets. The histone demethylase LSD1 is one such candidate and novel, potent inhibitors are under development. Areas covered: The literature on LSD1 (also known as KDM1A, AOF2, BHC110 or KIAA0601) was identified in Pubmed and is herein discussed. Areas covered include the structure and enzymatic activity of LSD1, its role in chromatin regulatory complexes, its functional roles in normal and malignant tissue, pharmacological inhibitors of its activity and their putative therapeutic roles. Expert opinion: Pre-clinical data supporting a therapeutic role for LSD1 inhibitors are most encouraging in acute myeloid leukaemia, although optimal dosing strategies and beneficial combinations with other agents remain unclear. Studies making use of potent, selective LSD1 inhibitors active in the nanomolar range are required to establish therapeutic indications in other subtypes of haematological malignancy, and in solid tumours.
Tumor endothelial markers as a target in cancer

Introduction: Several anti-angiogenic agents have been developed and some of them have been clinically applied in the tumor therapy. Anti-angiogenic therapy faces some hurdles: inherent or acquired resistance, increased invasiveness, and lack of biomarkers. Characterization of tumor endothelial markers may help to target endothelium and to identify potential predictive factors of response to anti-angiogenic therapies. Numerous surrogates, angiogenic and endothelium markers have emerged from recent pre-clinical studies, including physiological and soluble molecules in plasma and from platelets, circulating cells, tumor tissue factors and imaging markers. However, no wholly validated biomarkers currently exist to predict the success or the failure of the anti-angiogenic therapy of cancer. Therefore, the research of suitable and validate biomarkers is currently ongoing. Areas covered: This review provides an overview of the status of our knowledge concerning tumor endothelial markers, therapeutics targeting, possible resistance mechanisms and predictive value of these biomarkers and discuss future strategies to use and identify them in the anti-angiogenic therapy. Expert opinion: Anti-angiogenesis is a milestone to improve the treatment of several types of cancer and predictive biomarkers for a response to anti-endothelium therapy are one of the most important challenges for anti-angiogenesis research.
Oxysterol receptors and their therapeutic applications in cancer conditions

Introduction: Oxysterols are implicated in various cellular processes. Among their target proteins, liver X receptors (LXRs) α and β modulate the cell cycle in a large range of cancer cell lines. Besides their role as cholesterol sensors, LXRs are also involved in the proliferation/apoptosis balance regulation in various types of cancers. Areas covered: This review covers oxysterols and derivatives of cholesterol as well as synthetic or natural ligands (agonist/antagonist) of LXRs. Most tumor cell lines are sensitive to LXR activation. Indeed various cancers are concerned such as prostate, breast, glioblastoma, colorectal, and ovary tumors, and leukemia. Expert opinion: Developing the use of LXR ligands in human health, especially in the field of cancer, represents a novel and promising strategy. Despite a wide spectrum of applications, numerous adverse effects of LXR activation need to be solved before genuine clinical trials in humans. Future directions will be based on the engineering of selective LXRs modulators (SLiMs) as already done for nuclear steroid receptors.
Review for Disease of the Year: Epidemiology of Juvenile Idiopathic Arthritis and its Associated Uveitis: The Probable Risk Factors

Abstract Juvenile idiopathic arthritis (JIA) is the most common systemic disease associated with uveitis in childhood. The frequency of JIA-associated uveitis (JIAU) varies geographically, and between ethnicities. Uveitis risk is high in JIA associated with oligoarthritis, young age at arthritis onset and ANA positivity. Gender alters risk for the incidence of JIA and the severity of JIAU. Familial cases support the possible role of genetic influences in the pathogenesis. Arthritis typically precedes the uveitis, but uveitis may occur up to seven years following the arthritis onset. Although complications still occur, the frequency of bilateral blindness has dropped, probably by both improved screening of high-risk patients with JIA, and the increased use of early immunosuppression. However, there is still continuing persistence of JIAU into adulthood. For improvement of epidemiological knowledge of this complicated disease, large, well-defined, long-term population-based registries are needed with the application of universally agreed case definitions and outcome measures.
MmpL3 a potential new target for development of novel anti-tuberculosis drugs

Introduction: Tuberculosis (TB) is still a leading cause of mortality in the developing world and there is an unmet clinical need for new drugs with novel mechanism of action. Targeting the complex and unique cell wall of TB-causing pathogen Mycobacterium tuberculosis (Mtb) has been a mainstay of TB drug discovery. Though, the composition of the cell wall of Mtb is well understood, little is known about the assembly process of the cell wall such as the transport of mycolic acids across the cell wall. Areas covered: Recent research demonstrating MmpL3 protein as a transmembrane transporter of mycolic acids is discussed. In addition, MmpL3 has also been implicated in heme transport. Research describing several diverse chemical inhibitors that inhibit MmpL3 is reviewed. Expert opinion: Evidence so far suggests MmpL3 is a transporter of mycolic acids. It has emerged as a novel therapeutic target for Mtb that is essential and for which several small molecule inhibitors have been identified. Identifying the interacting partners, understanding the substrate specificity and the mechanism of transport by MmpL3 are some of the gaps in knowledge that need to be addressed.
Targeting CD28 to prevent transplant rejection

Introduction: The pivotal role of costimulatory pathways in regulating T-cell activation versus tolerance has stimulated tremendous interest in their manipulation for therapeutic purposes. Of these, the CD28–B7 pathway is arguably the most important and best studied. Therapeutic targets of CD28 are currently used in the treatment of melanoma, autoimmune diseases and in transplantation. Areas covered: In this review, we summarize our current knowledge of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling, and review the current state and challenges of harnessing them to promote transplant tolerance. Expert opinion: Despite the success of belatacept, a first-in-class CTLA-4 fusion protein now clinically used in transplantation, it is apparent that we have only scratched the surface in understanding the complexities of how costimulatory pathways modulate the immune system. Our initial assumption that positive costimulators activate effector T cells and prevent tolerance, while negative costimulators inhibit effector T cells and promote tolerance, is clearly an oversimplified view. Indeed, belatacept is not only capable of blocking deleterious CD28–B7 interactions that promote effector T-cell responses but can also have undesired effects on tolerogenic regulatory T-cell populations.
Can we change the way we look at BCG vaccine?

differences is cultural denial of smoking in our community, especially among females. This is supported by epidemiological studies of smoking conducted in communities similar to ours, using questionnaires; these studies showed wide variation in prevalence and concluded that social, cultural and religious inhibitions may have prevented smokers from providing accurate information about their smoking habits. [6] We therefore consider that the actual number of smokers among the population we studied is much higher. Nevertheless, the percentage of smokers among patients with CAD and COPD comorbidity is higher than among patients with CAD comorbidity alone, indicting that smoking may have been a risk factor for CAD and COPD comorbidity. There are, however, 2 further alternative explanations for the low prevalence of smoking among the present study population that we ought to consider. Firstly, we have not assessed the role of passive smoking, which increases the risk of both ischemic heart disease and COPD. [7] Hence we cannot rule out the possible contribution of passive smoking to causing COPD and CAD in our subjects. Secondly, it is possible that nonsmoking-related COPD and risk factors other than smoking for CAD were important etiological factors in this study population.
In Vitro Immunomodulatory Effects of Human Corneal Stromal Cells on Human Th17 Cells*

Abstract Purpose: To investigate the immunomodulatory effects of human corneal stromal cells on the function of Th17 cells, in vitro. Methods: Th17 cells were co-cultured with corneal stromal cells with or without 1-methyltryptophan, 1400w dihydrochloride, interleukin (IL)-10 inhibitor, or transforming growth factor-beta (TGF-β) inhibitor. The secretion of IL-17A by Th17 cells and the upregulation of T regulatory (Treg) cell frequencies were evaluated. Transwell assays were conducted to evaluate whether the immunomodulatory effects of stromal cells were dependent on cell-to-cell contact. Results: Corneal stromal cells suppressed the secretive function of Th17 cells and upregulated Treg cell frequencies, enhancing TGF-β. Tranwell assays showed similar immunomodulatory effects of the stromal cells on the function of Th17 cells. TGF-β inhibitors attenuated the suppressive effects of the stromal cells on the function of Th17 cells, whereas other inhibitors didn't. Conclusion: It which indicates that human corneal stromal cells suppress the function of Th17 cells through a TGF-β-dependent pathway.
Therapeutic potential of STAT4 in autoimmunity

Introduction: STAT4, which acts as the major signaling transducing STATs in response to IL-12, is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. Areas covered: This review summarizes that STAT4 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, mast cells, dendritic cells and T helper cells. In addition, STAT4-mediated signaling promoted the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis. Expert opinion: Due to its crucial roles in inflammation and autoimmunity, STAT4 may have promise as an effective therapeutic target for autoimmune diseases. Understanding the molecular mechanisms driving STAT4, together with knowledge on the ability of current immunosuppressive treatment to target this process, may open an avenue to novel therapeutic options.
New frontiers of target therapy in oncology: acute promyelocytic leukemia

SUMMARY By introduction of all-trans retinoic acid (ATRA) in de novo acute promyelocytic leukemia (APL) an revolution in therapy of this disease has been made. The rate of molecular complete remissions (CR) have been doubled compared to conventional chemotherapy with anthracyclines ranging from 90% to 95%. Consolidation therapy is required in order to reduce the risk of early relapse. Maintenance therapy is recommended as it further reduces the risk of relapse, especially in high-risk patients. The relapse rate in APL is relatively high, about 30% and is the most common within three years of starting the treatment. Another agent, arsenic trioxide (ATO) is the optimal drug that achieves high CR rate in relapsed, approximately 80% and hematopoietic stem cell transplantation (HSCT) may prolong the overall survival in patients with APL. ATRA and ATO have become a paradigm of targeted therapy, and APL is a paradigm of curable disease, at least in comparison to other forms of acute myeloid leukemia (AML). Sažetak Uvođenjem all-trans retinoične kiseline (ATRA) u de novo akutnoj promijelocitnoj leukemiji (APL) napravljena je revolucija u terapiji ove bolesti. Stopa molekularnih kompletnih remisija (CR) udvostručila se u odnosu na konvencionalnu hemioterapiju antraciklinima i kreće se 90-95%. Konsolidaciona terapija je obavezna radi redukcije rizika od ranog relapsa bolesti. Terapija održavanja je preporučena jer dodatno redukuje rizik od relapsa, pogotovo kod visoko rizičnih bolesnika. Stopa relapsa APL je relativno visoka, oko 30%, i najčešća je unutar tri godine od početka lečenja. Drugi agens, arsen trioksid (ATO) je optimalni medikament koji postiže visoke stope CR u relapsu, oko 80%, a transplantacija matičnih ćelija hematopoeze (TMĆH) može produžiti ukupno preživljavanje bolesnika sa APL. ATRA i ATO su postali paradigma target terapije, a APL paradigma kurabilne maligne bolesti, bar u odnosu na druge forme akutnih mijeloidnih leukemija (AML).
Mechanobiology of bone cells

Summary Bone mass, morphology and properties of the bone material are regulated by the functions of osteoblasts, osteocytes, and osteoclasts. These cells respond directly or indirectly to mechanical forces from the environment with the expression of differentiation markers, proliferation or release of bioactive factors. Osteocytes appear to be an important regulator for the adaptation of bone to changes in the mechanical environment. Mesenchymal stem cells which are located in bone marrow can be mechanically stimulated to differentiate into osteoblasts and chondrocytes but not to adipocytes. Integrin receptors are the principal mediators of mechanical forces and induce a signal transduction. The conversion of mechanical signals into biochemical signals is facilitated by unfolding of proteins to expose binding sites. Implant materials offer the opportunity to control the mechanical stimulation of cells by modifying the rigidity, geometry of adhesion sites, and the 3D-environment.
Venous thromboembolism prophylaxis: Solutions are in our hands

V thromboembol i sm (VTE) i s a spectrum of diseases involving deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Without prophylaxis, the probable incidence of confirmed hospital acquired DVT is approximately 10 to 40% of medical or surgical patients and 40 to 60% followings major orthopedic surgery. [1] Venous thromboembolism carries signifi cant hospital morbidities and mortalities. It has been estimated that 10% of hospital deaths are due to pulmonary embolism (PE). [1] Therefore, VTE is considered the number one cause of preventable death among hospitalized patients.
Effect of Exercise on Total and Intraabdominal Body Fat in Postmenopausal Women: A Randomized, Controlled Trial

The investigators reviewed data from the Physical Activity for Total Health Study to learn the effects of a year-long exercise intervention program on body fat stores. The randomized, controlled trial, carried out in 1997-2001, enrolled 173 sedentary postmenopausal women 50 to 75 years of age who were overweight with a body mass index of 24 to 25 and more than 33% body fat. Eighty-seven women were assigned to a facility where they exercised at moderate intensity for at least 45 minutes 5 days a week for 12 months. Activities included treadmill walking, stationary cycling, and strength training. In addition, walking, aerobic activity, and bicycling at home were encouraged. The remaining 86 women served as a control group by attending weekly stretching sessions. Participants were given individual attention in the facility classes, exercised in groups, attended classes in behavioral change, received weekly phone calls, and had individual meetings every 3 months in an attempt to promote adherence to the program. The women who exercised regularly lost an average of 1.3 kg after 12 months, whereas women in the control group gained 0.1 kg on average. Exercisers lost an average of 8.5 gm/cm 2 of intraabdominal body fat, as estimated by CT scanning, whereas control subjects gained 0.1 gm/cm 2 . Both body weight and hip circumference differed significantly after 12 months. Group differences in body weight and body fat changes were not a function of age or body mass index. Highly active women (who exercised more than 195 minutes per week) lost 4.2% of total body fat, compared with 2.4% for intermediate-level exercisers, 0.6% for women exercising at a low level (135 minutes or less per week), and 0.4% for control subjects. A similar trend was evident for change in intraabdominal fat, with highly active women losing 6.9%. Loss of intraabdominal fat correlated with increased cardiorespiratory fitness. Sedentary older women who are overweight should be encouraged to exercise regularly at a moderately intense level. A decline in body fat, particularly intraabdominal fat, can be expected.