Computer-Aided Retrosynthesis for Greener and Optimal Total Synthesis of a Helicase-Primase Inhibitor Active Pharmaceutical Ingredient.

This study leverages and upgrades the capabilities of computer-aided retrosynthesis (CAR) in the systematic development of greener and more efficient total synthetic routes for the active pharmaceutical ingredient (API) IM-204, a helicase-primase inhibitor that demonstrated enhanced efficacy against Herpes simplex virus (HSV) infections. Using various CAR tools, several total synthetic routes were uncovered, evaluated, and experimentally validated, with the goal to maximize selectivity and yield and minimize the environmental impact. The CAR tools revealed several synthetic options under different constraints, which can overperform the patented synthetic route used as a reference.

Single and Multiobjective Shutdown Optimization of a Multistage Continuous Crystallizer.

This study presents the first model-based optimal shutdown procedure of a multistage continuous crystallization process which aims at the maximization of on-spec production and minimization of the shutdown time. The cooling antisolvent crystallization of Aspirin (acetylsalicylic acid) in a three-stage continuous crystallizer was used as a case study. To address the optimal shutdown problem, several single optimization scenarios were considered to assess the impact of the degrees of freedom, discretization schemes, and optimization settings such as the constraints.

Coupling a Simple and Generic Membrane Fouling Model with Biological Dynamics: Application to the Modeling of an Anaerobic Membrane BioReactor (AnMBR).

A simple model is developed for membrane fouling, taking into account two main fouling phenomena: cake formation, due to attached solids on the membrane surface, and pore clogging, due to retained compounds inside the pores. The model is coupled with a simple anaerobic digestion model for describing the dynamics of an anaerobic membrane bioreactor (AnMBR). In simulations, we investigate its qualitative behavior: it is shown that the model exhibits satisfying properties in terms of a flux decrease due to membrane fouling.

Use of Wet Milling Combined with Temperature Cycling to Minimize Crystal Agglomeration in a Sequential Antisolvent-Cooling Crystallization.

The objective of the research was to improve the process design of a combined antisolvent-cooling crystallization to reduce the degree of agglomeration of a real active pharmaceutical ingredient product, which was manufactured using a crystallization stage employing a methanol/water solvent system. Knowledge was gained from the use of process analytical technology (PAT) tools to monitor the process variables, allowing particle size, degree of agglomeration, solute concentration, and supersaturation to be tracked throughout the process. Based on knowledge of the solubility behavior and interpretation of the PAT histories, changes were made to the sequences of antisolvent addition and cooling within the crystallization process to reduce agglomeration in the final product.

Effect of a new variable integration on steady states of a two-step Anaerobic Digestion Model.

This paper deals with a mathematical analysis of two-steps model of anaerobic digestion process, including dynamics of soluble microbial products (SMP). We propose to investigate effects of the new variable SMP on qualitative properties of the process in different generic cases. Equilibria of the model are graphically established considering qualitative properties of the kinetics and, their stability are proved theoretically and/or verified by numerical simulations.

Versatile reconfigurable glass capillary microfluidic devices with Lego® inspired blocks for drop generation and micromixing.

Novel cost effective, versatile, reconfigurable, reusable and easy to assemble glass capillary microfluidic devices were developed and used to generate micro/nano-materials with controlled size and morphology. The devices are composed of coaxial assemblies of glass capillaries held between two interchangeable plastic blocks fabricated from chemically inert polyoxymethylene copolymer using computer numerical control (CNC) machining. Three different blocks were combined and locked together using Lego® inspired stud-and-hole coupling system to achieve different flow configurations.

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles.

L-Asparaginase (ASNase) is a vital component of the first line treatment of acute lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over 53,000 people worldwide by 2020. More recently, ASNase has also been shown to have potential for preventing metastasis from solid tumors. The ASNase treatment is, however, characterized by a plethora of potential side effects, ranging from immune reactions to severe toxicity.

A modelling approach to study the fouling of an anaerobic membrane bioreactor for industrial wastewater treatment.

An Anaerobic Membrane BioReactors (AnMBR) model is presented in this paper based on the combination of a simple fouling model and the Anaerobic Model 2b (AM2b) to describe biological and membrane dynamic responses in an AnMBR. In order to enhance the model calibration and validation, Trans-Membrane Pressure (TMP), Total Suspended Solid (TSS), COD, Volatile Fatty Acid (VFA) and methane production were measured. The model shows a satisfactory description of the experimental data with R≈0.

The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.

Objective: To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders.

Methods: A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed.

End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation.

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients.

JAK2(V617F) is the predominant mutation in myeloproliferative neoplasms (MPN). Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS) cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F), respectively.

Clinical value of negative skin tests to iodinated contrast media.

Background: Several studies have shown that skin tests are useful tools for the diagnosis of iodinated contrast medium (ICM) allergy, but the real number of false negative results is not known.

Objective: To evaluate the negative predictive value of ICM skin tests.

Material And Methods: One hundred and fifty-nine patients tested in our department because of a previous ICM reaction over the last 9 years were called and asked standardized questions about ICM re-exposure.

Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays.

Autism, language delay and mental retardation in a patient with 7q11 duplication.

Chromosomal rearrangements are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.

High prevalence of hypovitaminosis D in Morocco: relationship to lifestyle, physical performance, bone markers, and bone mineral density.

Objectives: We undertook this study to determine the prevalence of hypovitaminosis D, its determinants, and its relationships to physical performance, serum parathyroid hormone (PTH) concentration, bone mineral density, and biochemical markers of bone turnover in healthy, ambulatory, pre- and postmenopausal women.

Methods: The group studied included 415 women aged 24 to 77 years. Between July and September, we assessed calcium intake and measured serum calcium, phosphorus, albumin, alkaline phosphate, 25-hydroxyvitamin D (25(OH)D), PTH, osteocalcin, and C-terminal cross-linking telopeptide of Type I collagen.

Autism, language delay and mental retardation in a patient with 7q11 duplication.

Background: Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer.

Background: The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non-small-cell lung cancer (NSCLC) are not well known.

Objective: To review the clinical and immunological features of patients with PCD, NSCLC and without well-characterised onconeural antibodies.

Methods: The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed.

Arthropathies in factor VII deficiency: a case report.

Unlabelled: Factor VII deficiency (or hypoproconvertinemia) is a rare inherited bleeding disorder that can cause hemarthrosis similar to that seen in hemophilia. We report a case.

Case Report: A 28-year-old woman experienced recurrent spontaneous hemarthrosis in both elbows and one knee starting at 2 years of age.

T cell response to Hu-D peptides in patients with anti-Hu syndrome.

The anti-Hu syndrome is the most common paraneoplastic neurologic syndrome but the exact mechanism of immune mediated neuronal injury remains unknown. Anti-Hu antibodies do not appear to play a pivotal role in the pathogenesis of the disease. To assess cell-mediated immunity, we selected 51 peptides from the Hu-D sequence and tested their ability to bind to six common HLA class I molecules.

Clinical relevance of non-neuronal auto-antibodies in patients with anti-Hu or anti-Yo paraneoplastic diseases.

About half of the patients with paraneoplastic diseases develop an immune response against neuronal antigens expressed by both the tumor and the nervous system. In 31 patients with anti-Hu antibodies and 19 patients with anti-Yo antibodies, we searched for the presence of additional non-neuronal auto-antibodies and further studied whether the presence of such auto-antibodies was correlated with a specific oncological or neurological presentation. Positive antinuclear antibodies (ANA) were found at a titer of 1:40 or above in 48% patients with anti-Hu antibodies, and in 37% patients with anti-Yo antibodies.

Multidrug resistance-associated protein MRP1 expression in human gliomas: chemosensitization to vincristine and etoposide by indomethacin in human glioma cell lines overexpressing MRP1.

The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated.

Paraneoplastic antineuronal antibodies in patients with systemic autoimmune diseases.

Sera from 71 patients with primary Sjögren's syndrome (PSS) and from 102 patients with systemic lupus erythematosus (SLE) were tested by immuno-dot blotting against HuD, Ri, Yo and amphiphysin recombinant proteins. For Ri, Yo and amphiphysin antigens, no immunoreactivity was found in the 173 sera tested. One PSS patient with a clinical picture of subacute sensory neuronopathy had high titers of anti-Hu antibodies.