Angiotensinogen M235T gene variants and its association with essential hypertension and plasma renin activity in Malaysian subjects: A case control study

BACKGROUND: Essential hypertension is a major public health concern worldwide where its prevalence accounts for various cerebrovascular diseases. A common molecular variant of angiotensinogen (AGT), the precursor of potent vasoactive hormone angiotensin II, has been incriminated as a marker for genetic predisposition to essential hypertension in some ethnics. This case-control study was designed not only to determine the association of the AGT M235T gene variants with essential hypertension, but also its relationship to Plasma Renin Activity (PRA) in subjects attending the Health Clinic, Kuala Lumpur, Malaysia. METHODS: The study involved 188 subjects, 101 hypertensives and 87 normotensives. Consents were obtained from all the participated subjects. M235T gene variants were investigated using allele specific polymerase chain reaction and PRA was determined by radioimmunoassay. Hypertensinogenic factors such as dietary habits, physical activity, smoking and drinking habits were assessed using a pre-tested questionnaire. RESULTS: The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (χ(2 = )23.184, P < 0.001 and χ(2 )= 21.482, P < 0.001, respectively). The odds ratio for hypertension was 1.36 (95% confidence interval 1.03–1.80) for subjects with homozygous mutated allele TT of the M235T variant compared with other genotypes or 1.98 (95% confidence interval 1.46–2.67) for those carrying T allele compared to those carrying M allele. Plasma Renin Activity is also significantly higher in hypertensive subjects (PRA = 3.8 ± 2.5 ngAI/ml/hr for hypertensives, PRA = 2.6 ± 1.3 ngAI/ml/hr for normotensives, P < 0.001), but was not significantly different between groups of genotypes (P = 0.118). CONCLUSION: The M235T variant of the AGT is significantly associated with essential hypertension whereas the genotype TT or allele T is a possible genetic marker or risk factor for hypertension in Malaysian subjects

Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue

Carbonyl clusters with a capping methylidyne phosphonate ligand - Crystal structure of [Co-3(CO)(9){eta(1)-mu(3)-[CP(O)(OEt)(2)]}]

The bridging methylidyne clusters [Co-3(CO)(9)(eta(1)-mu(3)-[CP(O)(OR)(2)])] 1 (R = Et) and 3 (R = SiMe3) with alpha-phosphoryl substituents have been synthesized by reaction of Cl3C-P(O)(OR)(2) with Co-2(CO)(8), followed by protonation. Cluster 3 was also obtained by the reaction of 1 with Me3SiBr. The structure of 1 has been determined by X-ray crystallography. The donor properties of the P=O function toward Lewis acids such as [Cp2MCl](+) (M = Ti, Zr) were used to assemble early-late metal systems. (C) 1997 Elsevier Science S.A

Unsubstituted 1- and 2-phosphabutadienes: Preparation and spectroscopic characterization

International audienceThe present work is devoted to the preparation of unsubstituted 1- and 2-phosphabutadienes. 2-Phosphadiene 3a is formed by HCl-elimination of the (chloromethyl)vinylphosphine 8 and 1-phosphadienes 1 by 1,4-dehydrochlorination of the corresponding (chloroallyl)phosphine 13a (1a) and by FVT of diallylphosphines 15a,b via a retro-ene reaction (1a,b). All the dehydrohalogenations occurred either in solution at low temperature with a Lewis base or in the gas phase (VGSR). Whichever the method used, only the opened structures 1a,b and 3a have been observed both in solution as well as in the gas-phase. 2-Phosphabutadiene 3a has been unambiguously characterized in solution by 1H and 31P NMR. Adducts of 1a and 3a were isolated when 2-propanethiol was introduced either with the Lewis base and chlorophosphine precursors 8 and 13a or with the condensed products from the VGSR and FVT apparatus (vacuum gas-phase dehydrochlorination of 8 and 13a and thermolysis of the diallylphosphine 15a). Other structural evidence for 1a,b and 3a has been given by coupling the VGSR or FVT apparatus with the IR, MS, and PE spectrometers. In particular, the PE spectra of the opened chains 1a and 3a have been qualitatively estimated (Koopman's approximation and direct calculation (CIPSI)). These results are consistent with the experimental IP values [9.28 eV (πCP - πCP), 9.96 eV (nP), 11.14 eV (πCP + πCP) for 3a, 9.00 eV (πCP - πCP), 10.13 eV (nP), 11.47 eV (πCP + πCP) for 1a]. The possibility of ring closure of 1a and 3a to dihydrophosphetes 2a and 4a is discussed. © 1993 American Chemical Society

Activity of tepotinib in brain metastases (BM): Preclinical models and clinical data from patients (pts) with MET exon 14 (METex14) skipping NSCLC

Abstract 1286P Background BM occur in 20–40% of NSCLC harboring METex14 skipping. We investigated the activity of the MET inhibitor tepotinib in BM in preclinical models and in pts from the VISION study (NCT02864992). Methods Penetration of the blood–brain barrier was assessed in Wistar rats (n=3) at 3.66 mg/kg/h iv tepotinib by determining the unbound brain (fu br)-to-plasma (fu pl) concentration or exposure ratio (Kp u,u). Efficacy was assessed in two lung cancer patient-derived xenografts (PDX) from BM harboring high MET amplification (MET gain in copy number: LU5349 = 11, LU5406 = 24) grown in NOD-SCID mice. Subcutaneous PDX (n=5/group) or PDX orthotopically implanted into the brain (n=10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI. In VISION Cohort A, pts with METex14 skipping NSCLC received tepotinib 500 mg once daily. Systemic objective response, as assessed per RECIST v1.1 by independent review committee (IRC) was a preplanned analysis in pts with baseline brain lesions identified by IRC (BM-IRC) or investigator assessment (BM-INV). Results Preclinical data indicated high binding of tepotinib in the brain, with unbound tepotinib in brain tissue lower than in plasma (fu br = 0.4%, fu pl = 4%). Concentrations of unbound tepotinib in the brain were 25% of plasma (Kp u,u = 0.25).Tepotinib treatment resulted in tumor regression in both PDX models (mean % tumor volume: –84% in LU5349, –63% in LU5406). As of 1 Jan 2020, 22/152 pts enrolled in Cohort A had baseline BM, with similar baseline pt characteristics and comparable systemic response data (Table) as the overall population. Table: 1286P BM-IRC BM-INV Number of patients with BM; n Non-target lesions 14 12 Target lesions 0 1 Objective response rate, % (95% CI) 57.1% (28.9, 82.3) 53.8% (25.1, 80.8) Best overall response; n Partial response 8 7 Stable disease 3 3 Conclusions Tepotinib administration resulted in tumor regression in MET-driven lung cancer BM PDX models. Clinical activity in pts with NSCLC harboring METex14 skipping with baseline BM was consistent with the overall population in VISION. Cohort C aims to assess intracranial response