Individualized detection of TMPRSS2-ERG fusion status in prostate cancer: a rank-based qualitative transcriptome signature.

BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.

Matriptase as a potential biomarker and therapeutic target in newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that affects the processing of carbohydrates, proteins, and lipids. In T2DM, metabolic dysregulation occurs through various pathways caused by increased levels of many adipokines and inflammatory chemokines. Impaired insulin-glucose metabolism occurs in tissues. The proteolytic enzyme matriptase is thought to be closely related to glucose metabolism due to its glycolization sites. AIM: Our study aimed to evaluate the correlation between matriptase, a proteolytic enzyme, and metabolic parameters in individuals recently diagnosed with T2DM. We also sought to investigate the potential involvement of matriptase in the development of diabetes. METHODS: We measured all participants' metabolic laboratory parameters, including basic biochemical tests, hemograms, high-sensitivity C-reactive protein (hsCRP), and matriptase levels. RESULTS: Our results showed a significant increase in circulating matriptase levels in individuals with T2DM compared to the control group. Furthermore, individuals with metabolic syndrome had significantly higher matriptase levels than those without in the T2DM and control groups. We also observed that T2DM patients had elevated levels of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), hsCRP, and matriptase, which displayed a positive correlation. CONCLUSION: Our study is the first to report elevated levels of matriptase in individuals with newly diagnosed T2DM and/or metabolic syndrome. Additionally, we found a significant positive correlation between matriptase levels and metabolic and inflammatory parameters, indicating a potential role for matriptase in the pathogenesis of T2DM and glucose metabolism. Further research on matriptase could lead to its recognition as a novel target for investigation.

Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.

BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. RESULTS: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).

Kallikrein-related peptidase-8 (KLK8) aggravated hypoxia-induced right ventricular hypertrophy by targeting P38 MAPK/P53 signaling pathway.

Right ventricular (RV) hypertrophy and further heart failure are major co-morbidities, resulting in the premature death of patients with hypoxic pulmonary hypertension (HPH). The regulatory effects of kallikrein-related peptidase (KLK) family members on cardiac function have been extensively studied. However, to the best of the authors' knowledge, the regulatory effects of KLK8 on RV hypertrophy caused by HPH have yet to be reported. The aim of the present study was to assess KLK8 expression in the RV tissue of HPH-modeled rats, and to further explore the effects and underlying mechanism of KLK8 in regulating the hypertrophy of hypoxia-induced H9c2 cardiomyocytes. In HPH model rats, increases in the right ventricle hypertrophy index, the right ventricular systolic pressure, cardiac output, as well as pulmonary artery wall thickness were observed. Western blot analysis revealed that KLK8 expression and MAPK/p53 signaling activity were enhanced in the RVs of rats in an RV HPH rat model. In hypoxia-induced H9c2 cardiomyocytes, KLK8 overexpression promoted cardiomyocyte hypertrophy, whereas KLK8 silencing showed the opposite results. KLK8 overexpression increased the expression levels of ventricular hypertrophy markers, including atrial natriuretic peptide, brain natriuretic peptide and myosin heavy chain 7, which were blocked upon addition of the p38 MAPK inhibitor, SB202190. Conversely, KLK8 silencing caused a decrease in the expression levels of the ventricular hypertrophy markers, which were further reduced via inhibition of the p38 MAPK/p53 signaling pathway. Taken together, the results of the present study have shown that KLK8 may subtly regulate RV hypertrophy, and therefore KLK8 may be a promising therapeutic target for treating HPH-induced RV hypertrophy.

Potential pharmacological candidates Transmembrane protease, serine 2 inhibitors 2019-ncov treatment / Candidatos potenciales farmacológicos inhibidores de proteasa transmembrana de serina 2 en el tratamiento de 2019-ncov

INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus with characteristic of infecting the respiratory tract, causing severe acute respiratory syndrome. The virus uses the ACE II receptors and the transmembrane protein TMPRSS2 initial step to enter the host cell, this contribution described different types of drug, to perform its inhibition in initial step adhesion. METHODOLOGY: Non-systematic review of articles with the help of preset keywords. RESULTS: In this review we will present drugs that inhibitors of this type of receptor therefore these drugs could be considered potential candidates to mitigate the spread of SARS-CoV-2

INTRODUCCIÓN: La Enfermedad por coronavirus 2019 (COVID-19) causada por el virus SARS-CoV-2, con característica de infectar el tracto respiratorio causando un síndrome respiratorio agudo como paso inicial para ingresar a la célula huésped el virus usa los receptores ACE II y la proteína transmembrana TMPRSS2 para causar la infección, Por lo que se ha descrito diferentes tipos de fármacos para realizar su inhibición en la adhesión del paso inicial. METODOLOGÍA: Revisión no sistemática de artículos con la ayuda de palabras clave preestablecidas. RESULTADOS: En esta revisión presentaremos fármacos que inhiben este tipo de receptor, por lo tanto, estos medicamentos podrían considerarse candidatos potenciales para mitigar la propagación del SARS-CoV-2

Antiviral Activity, Safety, and Pharmacokinetics of AL-794, a Novel Oral Influenza Endonuclease Inhibitor: Results of an Influenza Human Challenge Study.

Background: AL-794 is an orally active prodrug of ALS-033719, which selectively inhibits the endonuclease domain of influenza virus A and B polymerase. Methods: In a phase 1, double-blinded, randomized, placebo-controlled study, healthy subjects were inoculated intranasally with influenza virus (A/Perth/16/2009 H3N2) after confirmation of infection or on day 4. Subjects received 50 mg of AL-794, 150 mg of AL-794, or placebo twice daily for 5 days. Viral load, influenza symptoms, pharmacokinetics, and safety were evaluated. Results: A total of 61 subjects were inoculated. In 42 infected subjects, the mean peak viral load for 50-mg AL-794 recipients, 150-mg AL-794 recipients, and placebo recipients was 3.54, 2.77, and 3.72 log10 50% tissue culture infectious doses (TCID50)/mL, respectively. The mean influenza viral load area under the curve in the corresponding treatment groups was 137, 87.5, and 142 log10 TCID50/mL·h, respectively, and the median time to virus nondetection was 117, 75.3, and 108 hours, respectively. AL-794 was well tolerated, and no viral resistance to ALS-033719 was identified. Conclusion: Following oral administration of AL-794, significant dose-dependent antiviral activity was noted, with a greater decrease in viral load, symptoms, and mucus weight at the 150-mg dose, compared with the 50-mg dose, and no safety concerns for either dose or placebo. Clinical Trials Registration: NCT02588521.

Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register.

BACKGROUND AND AIMS: The International Atherosclerosis Society (IAS) has proposed that patients with "severe" FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC >8.0 mmol/L plus one high-risk feature, or LDLC >5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. METHODS: 2929 definite or possible PFH patients (51% women) aged 20-79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). RESULTS: 1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p < 0.001) more SFH patients had diagnosed CHD at baseline (24.6% vs. 17.5%), were current smokers (21.9% vs 10.2%) and had a BMI > 30 kg/m2 (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184-261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98-203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80-1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. CONCLUSIONS: CHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors.

Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: The CaReHigh Registry.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients. METHODS: The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients. RESULTS: We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (<20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i. CONCLUSIONS: The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

Hypodermin C improves the survival of kidney allografts.

Although immunosuppressive therapies have made organ transplantation a common medical procedure worldwide, chronic toxicity is a major issue of long-term treatment. One method to improve such therapies is the application of immunomodulatory agents from parasites, such as Hypoderma lineatum (Diptera: Oestridae). Hypodermin C (HC) is an enzyme secreted by H. lineatum larvae, and our previous study showed that recombinant HC could degrade guinea pig C3 and inhibit the complement pathway in vitro, suggesting potential activity for inhibiting transplant rejection. However, such properties have not been fully demonstrated in vivo. In this study, we investigated the impact of HC on a fully MHC-mismatched, life-sustaining, murine model of kidney allograft rejection using B6 donors and BABL/c (HC transgenic or wild-type) recipients. Kidney grafts were analyzed by histology, immunohistochemistry and western blotting. The results suggested that HC could effectively inhibit kidney allograft rejection. These findings suggest HC is a promising strategy to improve the survival of human implants.

Advances in the management of dyslipidemia.

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of morbidity and mortality in the United States and therapies aimed at lipid modification are important for the reduction of cardiovascular risk. There have been many exciting advances in lipid management over the recent years. This review discusses these recent advances as well as the direction of future studies. RECENT FINDINGS: Several recent clinical trials support low-density lipoprotein cholesterol (LDL-c) reduction beyond maximal statin therapy for improved cardiovascular outcomes. Ezetimibe reduced LDL-c beyond maximal statin therapy and was associated with improved cardiovascular outcomes for high-risk populations. Further LDL-c reduction may also be achieved with proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibition and a recent trial, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), was the first to show reduction in cardiovascular events for evolocumab. Additional outcome studies of monoclonal antibody and RNA-targeted PCSK9 inhibitors are underway. Quantitative high-density lipoprotein cholesterol (HDL-c) improvements have failed to have clinical impact to date; most recently, cholesteryl ester transfer protein inhibitors and apolipoprotein infusions have demonstrated disappointing results. There are still ongoing trials in both of these areas, but some newer therapies are focusing on HDL functionality and not just the absolute HDL-c levels. There are several ongoing studies in triglyceride reduction including fatty acid therapy, inhibition of apolipoprotein C-3 or ANGTPL3 and peroxisome proliferator-activated receptor-α agonists. SUMMARY: Lipid management continues to evolve and these advances have the potential to change clinical practice in the coming years.

IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy.

IgA nephropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure worldwide. IgAN pathogenesis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is available for IgAN. The absence of IgA1 and CD89 homologs in the mouse has precluded in vivo proof-of-concept studies of specific therapies targeting IgA1. However, the α1KI­CD89Tg mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombinant IgA1 protease (IgA1­P), a bacterial protein that selectively cleaves human IgA1. Mice injected with IgA1­P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease in IgA1-sCD89 complexes. Levels of mesangial IgA1 deposits and the binding partners of these deposits (sCD89, transferrin receptor, and transglutaminase 2) decreased markedly 1 week after treatment, as did the levels of C3 deposition, CD11b(+) infiltrating cells, and fibronectin. Antiprotease antibodies did not significantly alter IgA1­P activity. Moreover, hematuria consistently decreased after treatment. In conclusion, IgA1­P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibrosis, and hematuria in a mouse IgAN model, and therefore may be a plausible treatment for patients with IgAN.

Use and role of monoclonal antibodies and other biologics in preventive cardiology.

Biotechnological advances now enable the design of fully human antibodies to target specific antigens in a growing number of diseases. Monoclonal antibodies (mAbs) differ from traditional small chemical molecules in several ways: (1) biological production ‒ they are grown in and extracted from cell cultures; (2) specificity ‒ they demonstrate high target specificity, with a low risk of drug-drug interactions; (3) administration ‒ they are delivered parenterally (intravenously or subcutaneously); (4) dosage interval ‒ their extended half-lives generally allow for spaced dosing (from weekly to monthly). In cardiology, fully human mAbs directed against proprotein convertase subtilisin / kexin type 9 (PCSK9) have shown to be effective in reducing low-density lipoprotein cholesterol (LDL-C) in phase II clinical trials among patients with familial hypercholesterolaemia (FH). PCSK9 inhibitors have just received approval for the treatment of FH and clinical atherosclerotic disease, and patients not at target under maximally tolerated statin therapy or intolerant to statins. Large-scale phase III trials are currently assessing the role of PCSK9 inhibitors in the secondary prevention setting for patients with acute coronary syndromes (ACS) and poorly controlled LDL-C under evidence-based therapies. Another area currently under investigation for fully human mAbs in secondary prevention is their potential ability to inhibit inflammatory pathways. In this context, canakinumab, a specific mAb inhibiting interleukin-1ß (IL-1ß), has already received approval for the treatment of systemic juvenile idiopathic arthritis. The canakinumab anti-inflammatory thrombosis outcomes trial (CANTOS) is an ongoing trial assessing whether inhibition of IL-1ß could reduce the occurrence of cardiovascular adverse events in 17,200 patients with ACS and with defined persisting inflammation.

An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.

Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice.

PURPOSE: To investigate the influence of complement component C5a inhibition on laser-induced choroidal neovascularization (CNV) in mice using a C5a specific L-aptamer. METHODS: In C57BL/6 J mice CNV was induced by argon-laser, C5a-inhibitor (NOX-D20) was intravitreally injected in three concentrations: 0.3, 3.0, and 30 mg/ml. The unPEGylated derivate (NOX-D20001) was applied at 3.0 mg/ml; the vehicle (5 % glucose) was injected in controls. Vascular leakage was evaluated using fluorescence angiography, CNV area was examined immunohistochemically. Activated immune cells surrounding the CNV lesion and potential cytotoxicity were analyzed. RESULTS: Compared to controls, CNV areas were significantly reduced after NOX-D20 injection at a concentration of 0.3 and 3.0 mg/ml (p = 0.042; p = 0.016). NOX-D20001 significantly decreased CNV leakage but not the area (p = 0.007; p = 0.276). At a concentration of 30 mg/ml, NOX-D20 did not reveal significant effects on vascular leakage or CNV area (p = 0.624; p = 0.121). The amount of CD11b positive cells was significantly reduced after treatment with 0.3 and 3.0 mg/ml NOX-D20 (p = 0.027; p = 0.002). No adverse glial cell proliferation or increased apoptosis were observed at effective dosages. CONCLUSIONS: Our findings demonstrate that the targeted inhibition of complement component C5a reduces vascular leakage and neovascular area in laser-induced CNV in mice. NOX-D20 was proven to be an effective and safe agent that might be considered as a therapeutic candidate for CNV treatment. The deficiency of activated immune cells highlights promising new aspects in the pathology of choroidal neovascularization, and warrants further investigations.