Effect of Antisolvent Additives in Aqueous Zinc Sulfate Electrolytes for Zinc Metal Anodes: The Case of Acetonitrile.

Aqueous zinc-ion batteries (ZIBs) employing zinc metal anodes are gaining traction as batteries for moderate to long duration energy storage at scale. However, corrosion of the zinc metal anode through reaction with water limits battery efficiency. Much research in the past few years has focused on additives that decrease hydrogen evolution, but the precise mechanisms by which this takes place are often understudied and remain unclear. In this work, we study the role of an acetonitrile antisolvent additive in improving the performance of aqueous ZnSO4 electrolytes using experimental and computational techniques. We demonstrate that acetonitrile actively modifies the interfacial chemistry during Zn metal plating, which results in improved performance of acetonitrile-containing electrolytes. Collectively, this work demonstrates the effectiveness of solvent additive systems in battery performance and durability and provides a new framework for future efforts to optimize ion transport and performance in ZIBs.

Prognostic value of preoperative inflammatory ratios in early glottic cancer treated with transoral laser surgery.

BACKGROUND: There is growing evidence regarding the prognostic utility of ratios such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammatory index (SIII) in head and neck squamous cell carcinoma (HNSCC). However, most studies to date include heterogeneous series with different treatments or tumor subsites. METHODS: We collected data from 201 patients with stage I-II glottic squamous cell carcinoma treated with transoral laser surgery. NLR, PLR, and SIII were calculated from preoperative cell blood count, cut-off points were obtained by ROC curve analysis, and survival rates were calculated. RESULTS: High NLR (p = 0.012) and SIII (p = 0.037), but not PLR (p = 0.48), were associated with worse disease-specific survival (DSS). A similar trend was observed with overall survival (OS), although it did not reach statistical significance. On multivariable analyses, both high NLR (HR = 3.8, 95% CI = 1.5-9.9, p = 0.006) and high SIII (HR = 2.77, 95% CI = 1.1-6.9, p = 0.03) were significantly associated with shortened DSS. CONCLUSIONS: Preoperative NLR and SIII emerge as independent prognostic biomarkers for early-stage surgically treated glottic tumors and could guide individualized follow-up.

Structural and evolutionary analysis unveil functional adaptations in the promiscuous behavior of serum albumins.

Promiscuous activities have been related to the capacity to catalyze reactions different from those a protein has evolved to sustain. In this work, we rethought the serum albumin's promiscuous behavior using evolutionary and structural analysis. We found that the cross aldol condensation of acetone and p-formylbenzonitrile is a promiscuous reaction conserved in humans serum albumin and in closely related albumins from other mammals. Evolutionary analysis indicates that the residues involved in this promiscuous reaction are evolving under positive selection, an evolutionary pattern indicating a putative functional adaptation. Also, key residues are located in an evolutionary conserved cavity connected with the protein surface with an also conserved tunnel and mutations involving these residues are described in human diseases. Overall, our results suggest that albumin could have evolved to sustain a still unknown biological function among the many others it maintains. Our results could contribute to better characterize the serum albumin family and raise questions about the evolution of protein promiscuity and function.

Microfluidics-Enabled Multimaterial Maskless Stereolithographic Bioprinting.

A stereolithography-based bioprinting platform for multimaterial fabrication of heterogeneous hydrogel constructs is presented. Dynamic patterning by a digital micromirror device, synchronized by a moving stage and a microfluidic device containing four on/off pneumatic valves, is used to create 3D constructs. The novel microfluidic device is capable of fast switching between different (cell-loaded) hydrogel bioinks, to achieve layer-by-layer multimaterial bioprinting. Compared to conventional stereolithography-based bioprinters, the system provides the unique advantage of multimaterial fabrication capability at high spatial resolution. To demonstrate the multimaterial capacity of this system, a variety of hydrogel constructs are generated, including those based on poly(ethylene glycol) diacrylate (PEGDA) and gelatin methacryloyl (GelMA). The biocompatibility of this system is validated by introducing cell-laden GelMA into the microfluidic device and fabricating cellularized constructs. A pattern of a PEGDA frame and three different concentrations of GelMA, loaded with vascular endothelial growth factor, are further assessed for its neovascularization potential in a rat model. The proposed system provides a robust platform for bioprinting of high-fidelity multimaterial microstructures on demand for applications in tissue engineering, regenerative medicine, and biosensing, which are otherwise not readily achievable at high speed with conventional stereolithographic biofabrication platforms.

An enzymatic alternative for the synthesis of nucleoside 5'-monophosphates.

A new procedure was carried out for the synthesis of nucleoside 5'-monophosphates, involving the use of two enzymes. The first step applied phospholipase D from Streptomyces netropsis and phosphatidylcholine as phosphatidyl donor, to give 5'-(3-sn-phosphatidyl) nucleosides (C, U, A, I). These were selectively hydrolysed in the second step by the action of phospholipase C from Bacillus cereus to produce the respective 5'-nucleotides. Application of this methodology on a preparative scale conducted to 5'-adenosine monophosphate in 63% overall yield from adenosine. The regioselectivity of these enzymes avoids protection steps, the overall synthesis is performed under mild reaction conditions and product isolation is easily achieved.

Large scale analysis of protein conformational transitions from aqueous to non-aqueous media.

BACKGROUND: Biocatalysis in organic solvents is nowadays a common practice with a large potential in Biotechnology. Several studies report that proteins which are co-crystallized or soaked in organic solvents preserve their fold integrity showing almost identical arrangements when compared to their aqueous forms. However, it is well established that the catalytic activity of proteins in organic solvents is much lower than in water. In order to explain this diminished activity and to further characterize the behaviour of proteins in non-aqueous environments, we performed a large-scale analysis (1737 proteins) of the conformational diversity of proteins crystallized in aqueous and co-crystallized or soaked in non-aqueous media. RESULTS: Using proteins' experimentally determined conformational diversity taken from CoDNaS database, we found that proteins in non-aqueous media display much lower conformational diversity when compared to the corresponding conformers obtained in water. When conformational diversity is compared between conformers obtained in different non-aqueous media, their structural differences are larger and mostly independent of the presence of cognate ligands. We also found that conformers corresponding to non-aqueous media have larger but less flexible cavities, lower number of disordered regions and lower active-site residue mobility. CONCLUSIONS: Our results show that non-aqueous media conformers have specific structural features and that they do not adopt extreme conformations found in aqueous media. This makes them clearly different from their corresponding aqueous conformers.

Biocatalytic approaches applied to the synthesis of nucleoside prodrugs.

Nucleosides are valuable bioactive molecules, which display antiviral and antitumour activities. Diverse types of prodrugs are designed to enhance their therapeutic efficacy, however this strategy faces the troublesome selectivity issues of nucleoside chemistry. In this context, the aim of this review is to give an overview of the opportunities provided by biocatalytic procedures in the preparation of nucleoside prodrugs. The potential of biocatalysis in this research area will be presented through examples covering the different types of nucleoside prodrugs: nucleoside analogues as prodrugs, nucleoside lipophilic prodrugs and nucleoside hydrophilic prodrugs.

A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma.

To determine the maximum tolerated dose of irinotecan administered every 2 weeks, in combination with a fixed and continuous administration of temozolomide, in patients with glioblastoma at first relapse. Patients received oral temozolomide at a fixed and continuous dose of 50 mg/m divided into three daily doses, except for a single 100 mg/m dose, administered before every irinotecan infusion. Irinotecan was given intravenously on days 8 and 22 of 28-day cycles. The starting dose of irinotecan was 100 mg/m, and this was escalated by increments of 15 mg/m in cohorts of 3-6 evaluable patients. Determination of the dose-limiting toxicity was based on toxicities recorded from day 1 of the first cycleto day 8 of the third cycle. Enzyme-inducing antiepileptic drugs were not allowed. Tumor response was assessed by MRI every 8 weeks. Twelve patients were enrolled in this phase I study. The three patients enrolled at dose level 1 and six of nine patients enrolled at dose level 2 were evaluable for toxicity. The maximum tolerated dose of irinotecan was 100 mg/m. The dose-limiting toxicities were hematologic and gastrointestinal. Nine patients were evaluable for response: one patient achieved a partial response, four patients remained stable, and four patients had disease progression. The combination of metronomic temozolomide and irinotecan every 2 weeks can be safely administered at the recommended doses; a phase II study with this combination was started and has completed accrual.

An efficient and mild access to N-acetyl protected purine nucleosides based on a chemoselective enzymatic hydrolysis.

N-Monoacetylated derivatives of ribo- (adenosine, guanosine) and 2'-deoxyribonucleosides (2'-deoxyadenosine and 2'-deoxyguanosine), useful as oligonucleotide building blocks, were obtained in 88-100% by enzymatic chemoselective hydrolysis of the corresponding peracetylated nucleosides. Among the tested hydrolases, most satisfactory results were found with acylase I from Aspergillus melleus and Candida antarctica lipase B. For acylase I, the observed chemoselectivity towards ester hydrolysis, without amide reaction, broadens the information about the selectivity of the enzyme and its synthetic applications in the field of nucleosides.

Lipases in green chemistry: acylation and alcoholysis on steroids and nucleosides.

In this article, we describe the application of lipases in acylation and alcoholysis reactions on steroids and nucleosides. In the field of steroids, a variety of acetyl and fatty acid derivatives of androstanes, pregnanes, and cholestanes have been prepared through lipase-catalyzed acylation and alcoholysis reactions taking advantage of the high regio- and stereoselectivity of these enzymes. The substrates as well as the products show a high degree of biological activity as neurosteroids, hormones, and glucocorticoids. The regioselective preparation of diacylated nucleosides by means of an enzymatic alcoholysis allowed the synthesis of nucleosides prodrugs or modified nucleosides. The quantitative full deacylation and dealkoxycarbonylation of nucleosides and steroids is a mild synthetic method for the deprotection of these labile compounds. Some of the reported steroid and nucleoside products are novel, and it is not possible to obtain them satisfactorily by following traditional synthetic procedures. The advantages presented by this methodology, such as selectivity, mild reaction conditions, and low environmental impact, make the lipases an important tool in the application of the principles of Green Chemistry, offering a convenient way to prepare derivatives of natural compounds with a great potential in the pharmaceutical industry.

Advanced-stage primary cutaneous T-cell lymphoma treated with bexarotene and denileukin diftitox.

Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes considerable side effects. The combination of bexarotene and denileukin diftitox is associated with an acceptable safety profile and a likely synergistic effect because bexarotene is capable of modulating expression of IL-2 receptor and enhance the susceptibility of T-cell leukemia cells to denileukin diftitox. In the case reported here, the response to this combined treatment was satisfactory and well tolerated. The patient showed a complete regression of pruritus, restlessness, and insomnia. Skin lesions improved partially, and lymphadenopathy was reduced and finally disappeared completely.

Effectiveness of bosentan in the treatment of ischemic lesions in a case of thromboangiitis obliterans (Buerger disease): a case report.

Buerger disease or thromboangiitis obliterans (TAO) is a thrombotic occlusive, non-atherosclerotic segmental inflammatory disease that affects the small and medium-sized arteries and veins in the extremities of the limbs, frequently requiring amputation. Cessation of tobacco use is the only known effective treatment, though preliminary results from the use of pharmacological therapy implicated in pathogenesis of TAO have demonstrated noticeable clinical improvement of patients. We report the case of a 35-year-old woman with active TAO, refractory to smoking cessation and conventional therapy, who exhibited a favorable clinical response to treatment with bosentan, an oral dual endothelin receptor antagonist, administered on a compassionate-use basis. Six months after starting bosentan therapy, the pain and trophic lesions in the patient's toes had completely disappeared. Bosentan was well tolerated, without any observed adverse reaction. The findings of this case report suggest that bosentan may be considered a therapeutic option for patients with active disease, despite quitting smoking, or for those who fail in absolute abstention from smoking.

Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study.

BACKGROUND AND PURPOSE: Continuous positive airway pressure (CPAP) is an effective treatment for sleep apnea (SA), although the evidence for improving chronic heart failure (CHF) is inconclusive. Our aim was to evaluate the effect of CPAP treatment on the left ventricle ejection fraction (LVEF) among other cardiological variables in a randomized, multicenter, placebo (sham-CPAP)-controlled study. METHODS: After the selection procedure, 60 patients with CHF with LVEF<45% and SA with an apnea-hypopnea index (AHI)>10/h were evaluated at baseline, and after 3 months of treatment with optimal CPAP or sham-CPAP. The assessment was based on the LVEF, hypertension, daytime sleepiness (Epworth sleepiness scale [ESS]), quality of life (SF-36), New York Heart Scale (NYHA score), dyspnea (by using the Borg scale) and exercise tolerance (6-min walk test). RESULTS: The mean AHI was normalized in the optimal CPAP group but not in the sham-CPAP group. The LVEF showed a significant improvement in the group of patients treated with CPAP (2.5; 95% CI: 0.6 to 4.3), which was not observed in the sham-CPAP group (0.0; 95% CI: -2.1 to 2.1). However, the change in the LVEF from baseline to 3 months was not significantly greater in the whole group (obstructive and Cheyne-Stokes events) treated with CPAP than in the control group (p: 0.07). In patients with only obstructive sleep apnea (OSA), who account for 83% of the total population, there was a significant improvement in the LVEF in the group of patients treated with CPAP but no such improvement in the sham-CPAP group. In this OSA group, the change in the LVEF from baseline to 3 months was significantly greater in the group treated with CPAP than in the sham-CPAP group (p: 0.03). The other variables studied were not modified. When the patients were divided according to the severity of the LVEF (a LVEF cut-off of 30%), improvement was observed in those with a LVEF>30. No changes were found in the other cardiological variables. CONCLUSIONS: CPAP therapy proved to be useful in patients with associated sleep-disordered breathing and CHF. The improvement was more marked in patients with a LVEF>30%. However, the increased LVEF in the CPAP group was not accompanied by changes in the other cardiological variables.

Two new dialkoxycarbonylated nucleosides obtained through a regioselective enzymatic alcoholysis.

Two new compounds, 2',3'-di-O-ethoxycarbonyluridine and 2',3'-di-O-ethoxycarbonylinosine, were obtained through a Candida antarctica lipase B catalysed regioselective ethanolysis of the corresponding trialcoxycarbonylated nucleosides with benzyl alcohol in 1,4-dioxane at 30 degrees C.

Microbial hydrolysis of acetylated nucleosides.

Enzymatic hydrolysis of acetylated nucleosides using microbial whole cells has been carried out for the first time. Unlike Candida antarctica B lipase-catalysed alcoholysis, none of the tested microorganisms displayed a common deacetylation profile. Depending on the substrate and the biocatalyst used, 5'-selective deprotection or mixtures of mono O-acetylated products were obtained.

CO(2)-fixing enzymes during moulting from third larval to fourth larval stage of Anisakis simplex and Hysterothylacium aduncum (Nematoda: Anisakidae).

The fixing of CO(2) is an important metabolic process for many organisms. In the anisakid nematodes, CO(2) has been shown to be necessary for their development, at least in vitro. The presence of CO(2) stimulates the moulting (M3) of the larvae from the third (L3) to the fourth (L4) stage and prolongs the survival, at least, in vitro. We determined the activity of CO(2)-fixing enzymes, common to many organisms, in two anisakids: Anisakis simplex, a parasite of cetaceans, and Hysterothylacium aduncum, a parasite of fish. Although no activity was detected for pyruvate carboxylase or carboxylating-malic enzyme, we detected phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxylase (PEPC) activity. In A. simplex, PEPCK was clearly higher than that of PEPC throughout the moulting process studied. In H. aduncum, although the activity of both enzymes was of similar magnitude, they showed different behaviour; PEPCK activity decreased after the moulting to L4, PEPC activity increased so that the ratio PEPCK/PEPC activity decreased from 1.90 before moulting to 0.59 after.

Fusidic acid suspension twice daily: a new treatment schedule for skin and soft tissue infection in children, with improved tolerability.

OBJECTIVE: This multicentre, randomized, double-blind, parallel group study aimed to compare a new regimen of fusidic acid suspension against a standard regimen in children with skin and soft tissue infections. METHODS: Treatment groups were given either a new regimen of fusidic acid suspension (20 mg/kg divided b.i.d.) or a standard regimen (50 mg/kg divided t.i.d.), which were administered for 5 days in both groups and for a further 5 days if evidence of infection persisted. Assessment of those cured was carried out 14 days. RESULTS: Both regimens were effective. Cure was achieved in 194 (91.1%) of the 213 children given the new b.i.d. dosage and for 194 (89.4%) of the 217 children given the standard t.i.d. dosage (intention-to-treat population; p=0.72). Cure was maintained at the follow-up assessment for 94.8% (181 of 191) and 95.7% (180 of 188), respectively, of the children. Bacteriological cure of infections due to fusidic acid susceptible Staphylococcus aureus and/or group A beta-haemolytic streptococci, with elimination of pathogens, was achieved in all 121 (100%) children treated with the new b.i.d. regimen and in 123 (99.2%) of the 124 children treated with the standard TID regimen. CONCLUSION: The new twice-daily regimen had significantly better tolerance (p=0.025).

Dermatitis granulomatosa sobre lesiones cicatrizales de herpes zóster / Granulomatous dermatitis within herpes zoster scars

El desarrollo de lesiones granulomatosas sobre lesiones cicatrizales de herpes zóster es un fenómeno poco frecuente que se caracteriza clínicamente por la aparición de pápulas o nódulos de consistencia dura, infiltrados y de coloración rosada o violácea, de semanas a meses después de la infección viral. En este artículo se presenta el caso de un varón de 73 años de edad, con antecedente de leucemia linfática crónica, que desarrolló una dermatitis granulomatosa localizada en el territorio metamérico previamente afectado por una infección por el virus del herpes zóster. Las lesiones muestran una expresión clínica excepcional en forma de placas eritematoparduscas y áreas edematosas, en ausencia de lesiones papulosas o nodulares infiltradas. Así mismo, presenta la particularidad histológica de la presencia de granulomas de tipo tuberculoide con zonas de foliculitis granulomatosa (AU)

Pénfigo: estudio retrospectivo de 52 casos / Pemphigus: a retrospective study of 52 cases

Introducción: El término pénfigo incluye un conjunto de enfermedades ampollosas de origen autoinmune que pueden afectar a piel y mucosas y con una elevada mortalidad si no se tratan. Material y métodos: Presentamos una serie de 52 pacientes diagnosticados de alguna variedad de pénfigo vistos en el Servicio de Dermatología del Hospital Universitario 12 de Octubre de Madrid entre 1972 y 2003. Se revisan las características de cada paciente. Los datos se analizaron con el programa estadístico SPSS 11.0.Resultados: Encontramos una afectación similar de mujeres y varones, con una media de edad de 52 años. El diagnóstico más frecuente fue el de pénfigo vulgar en 65,4% seguido de pénfigo foliáceo en el 25%. Todos nuestros enfermos fueron tratados con corticoides orales y la mayoría además con algún fármaco adyuvante, el más usado la azatioprina en el 66%. La mayoría de los pacientes (68%) presentaron alguna complicación, aunque en general fueron leves; las más frecuentes fueron las infecciones cutáneas en el 40% de los enfermos seguidas de cuadros de acné-foliculitis en el 25%. Se produjeron 2 muertes, una por una trombosis ileofemoral y otra por sepsis, lo que supone una mortalidad del 4,5% (AU)