A comprehensive preclinical study supporting clinical trial of oncolytic chimeric poxvirus CF33-hNIS-anti-PD-L1 to treat breast cancer.

CF33-hNIS-anti-PD-L1 is an oncolytic chimeric poxvirus encoding two transgenes: human sodium iodide symporter and a single-chain variable fragment against PD-L1. Comprehensive preclinical pharmacology studies encompassing primary and secondary pharmacodynamics and biodistribution and safety studies were performed to support the clinical development of CF33-hNIS-anti-PD-L1. Most of the studies were performed in triple-negative breast cancer (TNBC) models, as the phase I trial is planned for patients with TNBC. Biological functions of virus-encoded transgenes were confirmed, and the virus demonstrated anti-tumor efficacy against TNBC models in mice. In a good laboratory practice (GLP) toxicology study, the virus did not produce any observable adverse effects in mice, suggesting that the doses proposed for the clinical trial should be well tolerated in patients. Furthermore, no neurotoxic effects in mice were seen following intracranial injection of the virus. Also, the risk for horizontal transmission of CF33-hNIS-anti-PD-L1 was assessed in mice, and our results suggest that the virus is unlikely to transmit from infected patients to healthy individuals. Finally, the in-use stability and compatibility of CF33-hNIS-anti-PD-L1 tested under different conditions mimicking the clinical scenarios confirmed the suitability of the virus in clinical settings. The results of these preclinical studies support the use of CF33-hNIS-anti-PD-L1 in a first-in-human trial in patients with TNBC.

Complications of Renal Transplantation That Influence the Presence of Hyperuricemia in Its First Year of Evolution.

INTRODUCTION: Renal transplantation (RT) has evolved to improve its functionality. Some factors have been little studied, one of which is hyperuricemia and its impact on renal graft function. The objective of this study is to determine the prevalence of complications of renal transplantation and its influence on hyperuricemia values in the first year of evolution. MATERIAL AND METHODS: The authors completed a retrospective, observational study of 2 RT units in Mexico from January 2013 to December 2017. In total, 1009 files met the inclusion criteria; the levels of uric acid (UA) and creatinine (Cr) were determined before transplantation and in months 1, 3, 6, 9, and 12 after transplantation. Descriptive analysis was performed with measures of central tendency, measures of dispersion, difference of means with Student t test, and SPSS version 25 (IBM, Armonk, NY, United States). RESULTS: The mean pretransplant UA was 6.24 mg/dL (standard deviation [SD] 1.97); per month was 4.73 mg/dL (SD 1.49). There is a difference in means between categorized groups of UA in the 5 post-RT moments (1, 3, 6, 9, and 12 months). A positive correlation of 0.41 to 0.47 was found with Spearman's test. The delayed function of the graft influenced in the first month after transplant in presenting hyperuricemia and acute dysfunction in month 6 showed that the rejection had no significance at any time. CONCLUSIONS: The relationship between the values of UA and Cr in the RT represents a moderate positive correlation; delayed graft function in the first month impacts the presence of hyperuricemia, as well as acute dysfunction at month 6 after transplantation.

Radiomics Driven Diffusion Weighted Imaging Sensing Strategies for Zone-Level Prostate Cancer Sensing.

Prostate cancer is the most commonly diagnosed cancer in North American men; however, prognosis is relatively good given early diagnosis. This motivates the need for fast and reliable prostate cancer sensing. Diffusion weighted imaging (DWI) has gained traction in recent years as a fast non-invasive approach to cancer sensing. The most commonly used DWI sensing modality currently is apparent diffusion coefficient (ADC) imaging, with the recently introduced computed high-b value diffusion weighted imaging (CHB-DWI) showing considerable promise for cancer sensing. In this study, we investigate the efficacy of ADC and CHB-DWI sensing modalities when applied to zone-level prostate cancer sensing by introducing several radiomics driven zone-level prostate cancer sensing strategies geared around hand-engineered radiomic sequences from DWI sensing (which we term as Zone-X sensing strategies). Furthermore, we also propose Zone-DR, a discovery radiomics approach based on zone-level deep radiomic sequencer discovery that discover radiomic sequences directly for radiomics driven sensing. Experimental results using 12,466 pathology-verified zones obtained through the different DWI sensing modalities of 101 patients showed that: (i) the introduced Zone-X and Zone-DR radiomics driven sensing strategies significantly outperformed the traditional clinical heuristics driven strategy in terms of AUC, (ii) the introduced Zone-DR and Zone-SVM strategies achieved the highest sensitivity and specificity, respectively for ADC amongst the tested radiomics driven strategies, (iii) the introduced Zone-DR and Zone-LR strategies achieved the highest sensitivities for CHB-DWI amongst the tested radiomics driven strategies, and (iv) the introduced Zone-DR, Zone-LR, and Zone-SVM strategies achieved the highest specificities for CHB-DWI amongst the tested radiomics driven strategies. Furthermore, the results showed that the trade-off between sensitivity and specificity can be optimized based on the particular clinical scenario we wish to employ radiomic driven DWI prostate cancer sensing strategies for, such as clinical screening versus surgical planning. Finally, we investigate the critical regions within sensing data that led to a given radiomic sequence generated by a Zone-DR sequencer using an explainability method to get a deeper understanding on the biomarkers important for zone-level cancer sensing.

Anemia and Erythrocytes: Behavior and Prevalence 1 Year After Kidney Transplant.

INTRODUCTION: Renal transplantation presents multiple complications after its completion, some of them related to the behavior of hemoglobin levels. The objective of this study is to determine the behavior and prevalence of anemia and erythrocytosis in the first year after renal transplantation. MATERIAL AND METHODS: A retrospective, observational study was conducted of a cohort of patients of the 21st Century National Medical Center in Mexico of transplants performed from January 1, 2013 to December 31, 2017. A total of 649 met the inclusion criteria. Pre-transplant hemoglobin (Hb) levels were determined, as well as levels 1 month, 3, 6, 9, and 12 months after transplantation, and the prevalence of anemia and erythrocytosis was determined in each month. Descriptive analysis was performed with measures of central tendency and measures of dispersion. The statistical program SPSS version 25 was used. RESULTS: The mean pre-transplant Hb was 10.69 g/dL (standard deviation [SD] 2.04). One year after the renal transplant, Hb averaged 14.45 g/dL (SD 2.30), which meant an increase over the first year after renal transplantation of 3.76 g/dL. Pre-transplant anemia occurred in 73.1% of patients, and erythrocytosis in 0.1%; 12.9% of patients and 5.9% in erythrocytosis continued with anemia for a year. CONCLUSIONS: Renal transplantation allows Hb levels to recover in a multifactorial way; however, the persistence of anemia and erythrocytes creates a study challenge in any transplant unit, due to their prevalence of 12.9 and 5.9% respectively.

Polymeric hollow microcapsules (PHM) via cellulose nanocrystal stabilized Pickering emulsion polymerization.

A practical and sustainable method to prepare polymeric hollow microcapsules (PHMs) using cellulose nanocrystal (CNC) stabilized Pickering emulsion polymerization was developed. Pristine CNCs hydrolyzed from wood pulp are hydrophilic and could be employed as emulsifiers to prepare oil-in-water (O/W) Pickering emulsions. The O/W Pickering emulsions were used as templates for the Pickering emulsion polymerization of hydrophobic monomers inside the emulsion droplets. The crosslinked hydrophobic polymers phase separated and partitioned to the interface of the Pickering emulsion, leading to the formation of hydrophobic PHMs. Correspondingly, cinnamate modified CNCs with less surface hydrophilicity were employed as emulsifiers to obtain water-in-oil (W/O) inverse Pickering emulsions, which were then used as templates for inverse Pickering emulsion polymerization of hydrophilic monomers to prepare hydrophilic PHMs. Therefore, both hydrophobic and hydrophilic PHMs could be obtained via this approach. Herein, polystyrene, poly(4-vinylpyridine), and poly(N-isopropyl acrylamide) hollow microcapsules were prepared as models, where the size, crosslinking density, shell structure and stimuli-responsive properties of PHMs could be tuned by varying the synthesis parameters.

Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials.

PURPOSE: SER120 desmopressin intranasal spray is the first U.S. Food and Drug Administration approved pharmacotherapy for nocturia. We evaluated its efficacy and safety in 2 randomized, double-blind, placebo controlled studies, DB3 and DB4. MATERIALS AND METHODS: A total of 1,333 intent to treat patients 50 years old or older with 2.16 or more nocturic voids per night during a 2-week screening period were randomized equally to SER120 intranasal spray 1.66 or 0.83 mcg, or placebo for a 12-week treatment. Co-primary end points were the mean change from baseline in nocturic episodes per night and the percent of patients with a 50% or greater reduction in mean nocturic episodes per night. Secondary end points were the validated INTU (Impact of Nighttime Urination) quality of life questionnaire in DB4, time to the first nocturic void and the percent of nights with 1 or fewer nocturic voids. RESULTS: Each SER120 dose showed statistical significance vs placebo for the 2 co-primary end points, including the mean nocturic episodes per night (-1.4 with 0.83 mcg and -1.5 with 1.66 mcg vs -1.2 with placebo, each p <0.0001), the percent of patients with a 50% or greater reduction in mean nocturic episodes per night (37.9% with 0.83 mcg and 48.7% with 1.66 mcg vs 30.3% with placebo, p = 0.0227 and <0.0001, respectively) as well as for all secondary end points in the pooled analyses. The 1.66 mcg dose demonstrated significant improvements in the INTU score (p = 0.0255). The incidence of hyponatremia, defined as serum sodium 125 mmol/l or less regardless of symptoms or less than 130 mmol/l with symptoms, was 1.1%, 0% and 0.2% in the 1.66 and 0.83 mcg, and placebo groups, respectively. Other adverse events were similar across treatment groups. CONCLUSIONS: SER120 demonstrated significant improvements over placebo for co-primary and secondary efficacy end points that corresponded with quality of life improvements. SER120 at each dose had an acceptable safety profile.

In vitro metabolic engineering for the salvage synthesis of NAD(.).

Excellent thermal and operational stabilities of thermophilic enzymes can greatly increase the applicability of biocatalysis in various industrial fields. However, thermophilic enzymes are generally incompatible with thermo-labile substrates, products, and cofactors, since they show the maximal activities at high temperatures. Despite their pivotal roles in a wide range of enzymatic redox reactions, NAD(P)(+) and NAD(P)H exhibit relatively low stabilities at high temperatures, tending to be a major obstacle in the long-term operation of biocatalytic chemical manufacturing with thermophilic enzymes. In this study, we constructed an in vitro artificial metabolic pathway for the salvage synthesis of NAD(+) from its degradation products by the combination of eight thermophilic enzymes. The enzymes were heterologously produced in recombinant Escherichia coli and the heat-treated crude extracts of the recombinant cells were directly used as enzyme solutions. When incubated with experimentally optimized concentrations of the enzymes at 60°C, the NAD(+) concentration could be kept almost constant for 15h.

Redirection of the Reaction Specificity of a Thermophilic Acetolactate Synthase toward Acetaldehyde Formation.

Acetolactate synthase and pyruvate decarboxylase are thiamine pyrophosphate-dependent enzymes that convert pyruvate into acetolactate and acetaldehyde, respectively. Although the former are encoded in the genomes of many thermophiles and hyperthermophiles, the latter has been found only in mesophilic organisms. In this study, the reaction specificity of acetolactate synthase from Thermus thermophilus was redirected to catalyze acetaldehyde formation to develop a thermophilic pyruvate decarboxylase. Error-prone PCR and mutant library screening led to the identification of a quadruple mutant with 3.1-fold higher acetaldehyde-forming activity than the wild-type. Site-directed mutagenesis experiments revealed that the increased activity of the mutant was due to H474R amino acid substitution, which likely generated two new hydrogen bonds near the thiamine pyrophosphate-binding site. These hydrogen bonds might result in the better accessibility of H+ to the substrate-cofactor-enzyme intermediate and a shift in the reaction specificity of the enzyme.

Beating the odds: A case report on the successful management of a non-immune hydrops fetalis due to hemoglobin Bart's disease / Philippine Journal of Obstetrics and Gynecology

Hemoglobin Bart's hydrops fetalis, characterized by a deletion of all four a-globin genes is the most severe and lethal form of Thalassemia disease. Mortality rate usually ranges from 60-100% of cases. Given the poor overall prognosis, most countries resort to pregnancy termination or expectant management as the only options to offer affected pregnancies.This paper presents a case of the successful management of a primigravid, diagnosed with hydrops fetalis at 29 4/7 weeks age of gestation. She delivered successfully to a live, preterm, baby boy who was later found out to have hydrops fetalis due to Hemoglobin Bart's disease, and currently, continues to thrive past eight months of age.This report aims to improve the clinicians' knowledge regarding the work up and management of pregnant patients diagnosed with hydrops fetalis, and increase the clinician's awareness on the epidemiology, importance of targeted screening, and diagnosis of Alpha-Thalassemia in Filipino patients.

Requirement of lid2 for interfacial activation of a family I.3 lipase with unique two lid structures.

A family I.3 lipase from Pseudomonas sp. MIS38 (PML) is characterized by the presence of two lids (lid1 and lid2) that greatly change conformation upon substrate binding. While lid1 represents the commonly known lid in lipases, lid2 is unique to PML and other family I.3 lipases. To clarify the role of lid2 in PML, a lid2 deletion mutant (ΔL2-PML) was constructed by deleting residues 35-64 of PML. ΔL2-PML requires calcium ions for both lipase and esterase activities as does PML, suggesting that it exhibits activity only when lid1 is fully open and anchored by the catalytically essential calcium ion, as does PML. However, when the enzymatic activity was determined using triacetin, the activity of PML exponentially increased as the substrate concentration reached and increased beyond the critical micellar concentration, while that of ΔL2-PML did not. These results indicate that PML undergoes interfacial activation, while ΔL2-PML does not. The activities of ΔL2-PML for long-chain triglycerides significantly decreased while its activity for fatty acid ethyl esters increased, compared with those of PML. Comparison of the tertiary models of ΔL2-PML in a closed and open conformation, which are optimized by molecular dynamics simulation, with the crystal structures of PML suggests that the hydrophobic surface area provided by lid1 and lid2 in an open conformation is considerably decreased by the deletion of lid2. We propose that the hydrophobic surface area provided by these lids is necessary to hold the micellar substrates firmly to the active site and therefore lid2 is required for interfacial activation of PML.

Press report: WHO criticized for neglecting evidence.

A study published in The Lancet reveals that when developing "evidence-based" guidelines, the World Health Organization routinely forgets one key ingredient: evidence. The study is based on interviews with senior WHO officials and analyses of various guidelines to determine how they were produced. The authors found a distinctly non-transparent process.