Systems pharmacology and genome medicine: a future perspective

Genome medicine uses genomic information in the diagnosis of disease and in prescribing treatment. This transdisciplinary field brings together knowledge on the relationships between genetics, pathophysiology and pharmacology. Systems pharmacology aims to understand the actions and adverse effects of drugs by considering targets in the context of the biological networks in which they exist. Genome medicine forms the base on which systems pharmacology can develop. Experimental and computational approaches enable systems pharmacology to obtain holistic, mechanistic information on disease networks and drug responses, and to identify new drug targets and specific drug combinations. Network analyses of interactions involved in pathophysiology and drug response across various scales of organization, from molecular to organismal, will allow the integration of the systems-level understanding of drug action with genome medicine. The interface of the two fields will enable drug discovery for personalized medicine. Here we provide a perspective on the questions and approaches that drive the development of these new interrelated fields

Classification of coffee beans by GC-C-IRMS, GC-MS, and 1H-NMR

In a previous work using 1H-NMR we reported encouraging steps towards the construction of a robust expert system for the discrimination of coffees from Colombia versus nearby countries (Brazil and Peru), to assist the recent protected geographical indication granted to Colombian coffee in 2007.This system relies on fingerprints acquired on a 400MHz magnet and is thus well suited for small scale random screening of samples obtained at resellers or coffee shops. However, this approach cannot easily be implemented at harbour's installations, due to the elevated operational costs of cryogenic magnets. This limitation implies shipping the samples to the NMR laboratory, making the overall approach slower and thereby more expensive and less attractive for large scale screening at harbours. In this work, we report on our attempt to obtain comparable classification results using alternative techniques that have been reported promising as an alternative toNMR: GC-MS andGC-C-IRMS.Although statistically significant information could be obtained by all threemethods, the results showthat the quality of the classifiers dependsmainly on the number of variables included in the analysis; hence NMR provides an advantage since more molecules are detected to obtain a model with better predictions

Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum

A JEDI NMR pulse experiment incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quantitatively two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramolecular phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI experiment that strongly attenuate contributions from the other molecular species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) versus SARS-CoV-2 positive patients (n = 29) (p = 5.2 × 10−8 and 3.7 × 10−8 respectively). Simplification of the sample preparation allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min experiment time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex laboratory environment, thus lowering the barrier to clinical translation of this diagnostic technology

Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum.

A JEDI NMR pulse experiment incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quantitatively two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramolecular phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI experiment that strongly attenuate contributions from the other molecular species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) versus SARS-CoV-2 positive patients (n = 29) (p = 5.2 × 10-8 and 3.7 × 10-8 respectively). Simplification of the sample preparation allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min experiment time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex laboratory environment, thus lowering the barrier to clinical translation of this diagnostic technology

Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation

Extensive studies of the structure–function relationship of antibodies have established that conventional immunoglobulins contain two copies of the antigen-binding fragment (Fab), each of which serves as an autonomous and complete unit for recognizing an antigen. In this paper, we report a previously unidentified mode of antibody–antigen recognition, dubbed “antigen clasping,” where two antigen-binding sites cooperatively clasp one antigen, and the design of a long-neck antibody format that facilitates antigen clasping. Antigen clasping led to recombinant antibodies for histone posttranslational modifications with extraordinarily high specificity, valuable tools for epigenetic research. This study substantially broadens the long-standing paradigm for antibody–antigen recognition

Exploration of human serum lipoprotein supramolecular phospholipids using statistical heterospectroscopy in n-Dimensions (SHY-n): Identification of potential cardiovascular risk biomarkers related to SARS-CoV-2 infection

SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS)

Carmustine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Since 1999, patients presenting with brain metastases (BM) from breast cancer (BC) are treated in our institution with a carmustine (BCNU) - methotrexate (MTX) combination. We report here our clinical experience regarding this combination.</p> <p>Patients and Methods</p> <p>Patients were treated by a combination of BCNU 100 mg/m² on day 1 and MTX 600 mg/m² on day 1 and 15 of a 28 day cycle. Treatment was continued until progression or unacceptable toxicity.</p> <p>Results</p> <p>50 patients were treated between 1999 and 2007. 94% of the patients presented with concomitant extra-cerebral disease. Median number of previous metastatic setting chemotherapy regimens was 2 (0-5). Median number of cycles was 3 (1-20). There were 11 objective responses (23% [95%CI 12-37]) among 48 evaluable patients. Median progression-free survival and overall survival (OS) were 4.2 (95%CI: 2.8-5.3) and 6.9 (4.2-10.7) months respectively, with a one-year OS rate of 32% (20-46). Median Relative Dose Intensity for BCNU and MTX were 0.98 (0.31-1.1) and 0.96 (0.57-1.66) respectively. There were 2 presumed treatment-related deaths. One patient developed febrile neutropenia. Performance status, BS-BM score and presence of liver metastases were associated with OS in univariate analysis.</p> <p>Conclusions</p> <p>This combination appears to be effective and well tolerated in good performance status BC patients presenting with BM.</p

Tumour microvessel density as predictor of chemotherapy response in breast cancer patients

The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer

NMReDATA, a standard to report the NMR assignment and parameters of organic compounds

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Open access articleEven though NMR has found countless applications in the field of small molecule characterization, there is no standard file for the NMR data relevant to structure characterization of small molecules. A file format is introduced to associate the NMR parameters extracted from 1D and 2D spectra of organic compounds to the assigned chemical structure. These NMR parameters, which we shall call NMReDATA, include chemical shift values, signal integrals, intensities, multiplicities, scalar coupling constants, lists of 2D correlations, relaxation times and diffusion rates. The file format is an extension of the existing SDF (Structure Data Format), which is compatible with the commonly used MOL format. The association of an NMReDATA file with the raw and spectral data from which it originates constitutes an NMR record. This format is easily readable by humans and computers and provides a simple and efficient way for disseminating results of structural chemistry investigations, automating the verification of published result, and for assisting the constitution of highly needed open-source structural databases