ABBV-184: A Novel Survivin-specific TCR/CD3 Bispecific T-cell Engager is Active against Both Solid Tumor and Hematologic Malignancies.

CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematologic and solid tumors, treatment of acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cell lines with ABBV-184 results in T-cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2-positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.

Neoadjuvant Trastuzumab and Pertuzumab in Combination with Standard Chemotherapy for HER2-Positive Early Breast Cancer: Real-World Practice in Cuba.

PURPOSE: Dual HER2 blockade chemotherapy is the standard of care for localized HER2+ breast cancer (BC). However, despite the efficacy of neoadjuvant therapy, relapses occurring in around 10% of patients highlight the need to improve its clinical approach. Therefore, this study aimed to evaluate the effectiveness/safety of neoadjuvant therapy with subcutaneous (SC) trastuzumab- pertuzumab chemotherapy (real world) to extend the evidence, which comes mainly from clinical trials (selected population; intravenous [IV] trastuzumab). MATERIALS AND METHODS: A prospective, longitudinal, observational study in a Cuban hospital. POPULATION: women aged ≥18 years with histologically confirmed HER2+ early-stage BC (2017-2021) eligible for neoadjuvant treatment (IV pertuzumab, SC trastuzumab, taxane-based chemotherapy). The aim was to determine the pathological complete response (pCR) rate to this scheme, its safety, and the impact of patient's characteristics on the outcomes. RESULTS: Eighty-seven women were included: n=29 (DPT [docetaxel-IV pertuzumab- SC trastuzumab 600 mg; 4 cycles]); n=58 (ddAC-DPT [dose-dense anthracycline-based scheme+DPT]; 8 cycles). The median age was 57 years (range 30-83), ECOG 0: 97%. Time from diagnosis to treatment (median) was 28 days. The overall pCR rate was 62.1% (55.2%, DPT; 66.5%, ddAC-DPT; p =0.351); HR+, 47.7% vs. HR-, 76.7% (p=0.006). There were no statistically significant differences based on nodal status, stage, or Ki-67 levels. Overall, 94.2% of patients experienced ≥1 adverse event related to treatment, all of them grade 1-3 and more common with ddAC-DPT. The main cause of treatment delays (n=19; ddAC-DPT, 16; DPT, 3) was treatment-related toxicities. CONCLUSION: Neoadjuvant trastuzumab (SC) and pertuzumab plus chemotherapy for HER2+ early-stage BC showed benefits in a real-life setting, with an acceptable safety profile.

Association of bovine viral diarrhea virus, bovine herpesvirus 1, and Neospora caninum with late embryonic losses in highly supplemented grazing dairy cows.

The objectives of this study were: 1- to evaluate the association of Bovine Viral Diarrhea Virus (BVDV), Bovine Herpes Virus 1 (BoHV-1), and Neospora caninum (N. caninum) with the risk for Late Embryonic Loss (LEL) in grazing dairy cows, 2- to evaluate blood progesterone concentration at the time of LEL occurrence, and 3- to describe a novel ultrasound-guided technique for conceptus sampling. We run a prospective cohort study involving 92 cows (46 LEL and 46 NLEL). An LEL cow was that having an embryo with no heartbeat, detached membranes, or floating structures, including embryo remnants detected at pregnancy check by ultrasonography (US) 28-42 days post-AI, whereas an NLEL cow was that with embryo heartbeats detectable by US at pregnancy check 28-42 d post-IA. We took two blood samples from every cow at pregnancy check by US (the day of LEL detection) and 28 d later to perform serological diagnosis of BVDV, BoHV-1, and N. caninum; and to measure blood progesterone concentration at pregnancy check (28-42 d post-AI). We also sampled the conceptus from all the LEL cows. We performed PCR to detect BVDV, BoHV-1, and N. caninum in sampled conceptuses from LEL cows. Finally, we evaluated the associations of risk factors (serological titers, seroconversion, and progesterone) with LEL odds with logistic models. The risk for LEL was associated with serological titers to BVDV (P = 0.03) and tended to be associated with seroconversion to BVDV, given that 19.6% (9/46) in LEL and 6.5% (3/46) in NLEL cows seroconverted to BVDV (P = 0.09). In addition, BVDV was detected in conceptuses from LEL cows that seroconverted to BVDV but not in LEL cows that did not seroconvert. Conversely, the risk for LEL was not associated with the titers or seroconversion to BoHV-1 and N. caninum. BoHV-1 and N. caninum were not identified in any of the conceptuses. Finally, blood progesterone concentration was similar in LEL and NLEL cows, and it was not associated with the risk for LEL (P = 0.54). In conclusion, BVDV infection is a risk factor for LEL in dairy cows.

ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition.

BACKGROUND: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. METHODS: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. RESULTS: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. CONCLUSIONS: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.

Convolutional Neural Networks for Long Time Dissipative Quantum Dynamics.

Exact numerical simulations of dynamics of open quantum systems often require immense computational resources. We demonstrate that a deep artificial neural network composed of convolutional layers is a powerful tool for predicting long-time dynamics of open quantum systems provided the preceding short-time evolution of a system is known. The neural network model developed in this work simulates long-time dynamics efficiently and accurately across different dynamical regimes from weakly damped coherent motion to incoherent relaxation. The model was trained on a data set relevant to photosynthetic excitation energy transfer and can be deployed to study long-lasting quantum coherence phenomena observed in light-harvesting complexes. Furthermore, our model performs well for the initial conditions different than those used in the training. Our approach reduces the required computational resources for long-time simulations and holds the promise for becoming a valuable tool in the study of open quantum systems.

Dataset for gait analysis and assessment of fall risk for older adults.

This article presents a five-part dataset for human gait analysis in a healthy older adult population (37 women and seven men; age 69.98 ± 8.57 years, body mass index 27.71 ± 4.57). Part 1 compromises demographic data for the 44 participants, along with the results of the Short Physical Performance Battery (SPPB) motor function test and the Mini-Mental State Examination (MMSE). We used the MMSE to ensure the participants could understand the experimental protocol instructions. Part 2 presents the anthropometric measurements of the participants. Part 3 shows the results for each item of the Gait component of the Performance Oriented Mobility Assessment (POMA-G). Part 4 contains five files per participant, storing motion-capture data for the lower limb in the Coordinate 3D (C3D) format. These files were generated using a Vicon motion analysis system, consisting of 24 reflective markers and seven cameras (Vantage V5) sampled at 100 Hz. Part 5 contains 26 gait parameters for each C3D file obtained using Nexus 2.9.3. The dataset is available in a Mendeley repository (Reserved DOI: 10.17632/xgw6bg3g8h.1).

Use of Tyre-Derived Aggregate as Backfill Material for Wave Barriers to Mitigate Railway-Induced Ground Vibrations.

The use of piles as barriers to mitigate vibrations from rail traffic has been increasing in theoretical and practical engineering during the last years. Tyre-derived aggregate (TDA) is a recycled material with some interesting applications in civil engineering, including those related to railway engineering. As a novelty, this paper combines the concept of pile wave barriers and TDA material and investigates the mitigation effect of pile barriers made of TDA on the vibrations transmitted by rail traffic. This solution has a dual purpose: the reduction of railway vibrations and the recycling of a highly polluting material. The mitigation potential of this material when used as backfill for piles is analysed using a numerical scheme based on a 3D finite-difference numerical model formulated in the space/time domain, which is also experimentally validated in this paper in a real case without pile barriers. The numerical results show insertion loss (IL) values of up to 11 dB for a depth closed to the wavelength of Rayleigh wave. Finally, this solution is compared with more common backfills, such as concrete and steel tubular piles, showing that the TDA pile is a less effective measure although from an environmental and engineering point of view it is a very competitive solution.

Identification and sub-cellular localization of a NAD transporter in Leishmania braziliensis (LbNDT1).

Nicotinamide adenine dinucleotide (NAD) is one of the central molecules involved in energy homeostasis, cellular signaling and antioxidative defense systems. Consequently, its biosynthetic pathways and transport systems are of vital importance. The nicotinamide/nicotinate mononucleotide adenylyltransferase (NMNAT), a key enzyme in the biosynthesis of NAD, is distributed in all domains of life and exhibits various isoforms in free-living organisms in contrast with intracellular parasites, which displays a single enzyme. In Leishmania braziliensis a unique cytosolic NMNAT has been reported to date and the mechanisms through which adequate levels of NAD are maintained among the different sub-cellular compartments of this parasite are unknown. Experimental evidences have related the transport of NAD to the Nucleotide Transporters (NTTs) family, whose members are located in the cytoplasmic membrane of parasitic life organisms. Additionally, the Mitochondrial Carrier Family (MCF), a group of proteins located in the membrane of internal organelles such as the mitochondria of free life organisms, has been implicated in NAD transport. Applying bioinformatics tools, the main characteristics of the MCF were found in a transporter candidate that we have designated as Nicotinamide Adenine Dinucleotide Transporter 1 of L. braziliensis (LbNDT1). The expression of LbNDT1 was tested both in axenic amastigotes and promastigotes of L. braziliensis, through immunodetection using polyclonal avian antibodies produced in this study. N-glycosylation of LbNDT1 was observed in both stages. Additionally, a possible partial mitochondrial distribution for LbNDT1 in amastigotes and a possible glycosomal location in promastigotes are proposed. Finally, the capability of LbNDT1 to transport NAD was confirmed by complementation assays in Saccharomyces cerevisiae. Our results demonstrate the existence of LbNDT1 in L. braziliensis becoming the first NAD transporter identified in protozoan parasites to date.

Electronic system for step width estimation using programmable system-on-chip technology and time of flight cameras.

This paper proposes a low-cost portable electronic system for estimating step width during the human gait cycle. This device, intended to support the Walking Stance item of the fall risk assessment test Performance Oriented Mobility Assessment (POMA), contains three electronic boards, comprising two sensing nodes and a concentrator. Each sensing node contains a force sensitive resistor (FSR) and time-of-flight camera (TOF). Each FSR is placed inside the subject's shoe, while each TOF camera is located at the back of their foot. The FSR detects contact between heel and ground, and the TOF measures the distance to a barrier located on the right side of the walking path. Step width is calculated as the difference between the TOF measurements. After the walk is complete, the information obtained by the FSRs and TOFs is sent via a 433 MHz wireless communication to the concentrator board, which is connected to the USB port of a personal computer (PC). The proposed step width measurement system was validated with an infrared based motion capture (Vicon Corp.), giving an error equal to 11.4%  ±  5.5%.

Removal and Extraction of Carboxylic Acids and Non-ionic Compounds with Simple Hydroxides and Layered Double Hydroxides.

Carboxylic acids are an important natural component as a final product or intermediates for syntheses. They are produced in plants, animals and also as products from biotechnological processes. This review presents the use of single hydroxide particles and layered double hydroxides as alternative adsorbents to remove carboxylic acids from liquid media. The proposal to use hydroxide particles is based on its affinity to adsorb or intercalate carboxylic acids. Besides, the change in properties of the adsorbate-sorbate product evinces that this intermediate can be used as a vehicle to transport and release carboxylic acids. Additional examples will also be presented to prove that layered hydroxides are capable of removing non-ionic compounds from wine, milk and tomato. The use of layered compounds to remove active ingredients could reduce the number of separations steps, costs and reduce or eliminate solvents, thus encouraging the design of industrial processes of separation using hydroxides particles.

Late embryonic losses in supplemented grazing lactating dairy cows: Risk factors and reproductive performance.

The main objective of this study was to evaluate the risk factors for late embryonic loss (LEL) in supplemented grazing dairy cows. Additional objectives were to assess the incidence of LEL and its association with the reproductive performance of cows. A data set containing productive, reproductive, and health records of 13,551 lactations was used. A retrospective case-control study involving 631 cows with LEL (cases) and 2,524 controls (4 controls per case within each study year) was run. A case of LEL was defined when the embryo had no heartbeat or there was evidence of detached membranes or floating structures including embryo remnants by ultrasonography (US) at 28 to 42 d post-artificial insemination (AI), whereas a non-case was defined as a cow diagnosed with positive pregnancy by US 28 to 42 d post-AI and reconfirmed as pregnant 90 ± 7 d post-AI. Four controls per case were randomly selected from the non-cases with a temporal matching criterion (±3 d around the date of the fecundating AI of the case). Multivariable logistic models were offered with the following predictors: year of LEL (2011 through 2015), season of LEL (summer vs. fall vs. winter vs. spring), parity (1 vs. 2 vs. ≥3), uterine disease (UD), non-uterine disease (NUD), body condition score at parturition, body condition score at 28 to 42 d post-AI (BCS-LEL), days in milk (DIM), and daily milk yield (MY). Statistical significance was set at P < 0.05 and a tendency was set at P ≤ 0.10. We found that 4.7, 22, and 23% of cows had LEL, UD, and NUD, respectively. Cases tended to have higher daily MY than controls (32.5 vs. 31.8 kg); also, cases had much longer calving to pregnancy interval (226 vs. 118 d), lower hazard of pregnancy [hazard ratio = 0.39, 95% confidence interval (CI) = 0.35-0.43], and higher odds for non-pregnancy [odds ratio (OR) = 2.89, 95% CI = 2.37-3.54] than controls. We found that the odds for LEL increased with parity number (OR = 2.48, 95% CI = 1.99-3.08 for parity ≥3) and with BCS-LEL <2.50 (OR = 1.81, 95% CI = 1.33-2.47). Conversely, the odds for LEL decreased with BCS-LEL >3.00 (OR = 0.70, 95% CI = 0.53-0.91). The odds for LEL increased with UD (OR = 1.23, 95% CI = 1.01-1.49), NUD (OR = 1.24, 95% CI = 1.01-1.54), DIM (OR = 1.03, 95% CI = 1.00-1.05), and daily MY (OR = 1.14, 95% CI = 1.04-1.25) in univariable models only. Finally, the odds for LEL were not associated with year, season, DIM, and body condition score at parturition. In conclusion, LEL is associated with extended calving to pregnancy interval, and among its risk factors are parity number and BCS-LEL.

Innovative assembly strategy contributes to understanding the evolution and conservation genetics of the endangered Solenodon paradoxus from the island of Hispaniola.

Solenodons are insectivores that live in Hispaniola and Cuba. They form an isolated branch in the tree of placental mammals that are highly divergent from other eulipothyplan insectivores The history, unique biology, and adaptations of these enigmatic venomous species could be illuminated by the availability of genome data. However, a whole genome assembly for solenodons has not been previously performed, partially due to the difficulty in obtaining samples from the field. Island isolation and reduced numbers have likely resulted in high homozygosity within the Hispaniolan solenodon (Solenodon paradoxus). Thus, we tested the performance of several assembly strategies on the genome of this genetically impoverished species. The string graph-based assembly strategy seemed a better choice compared to the conventional de Bruijn graph approach due to the high levels of homozygosity, which is often a hallmark of endemic or endangered species. A consensus reference genome was assembled from sequences of 5 individuals from the southern subspecies (S. p. woodi). In addition, we obtained an additional sequence from 1 sample of the northern subspecies (S. p. paradoxus). The resulting genome assemblies were compared to each other and annotated for genes, with an emphasis on venom genes, repeats, variable microsatellite loci, and other genomic variants. Phylogenetic positioning and selection signatures were inferred based on 4,416 single-copy orthologs from 10 other mammals. We estimated that solenodons diverged from other extant mammals 73.6 million years ago. Patterns of single-nucleotide polymorphism variation allowed us to infer population demography, which supported a subspecies split within the Hispaniolan solenodon at least 300 thousand years ago.

Potential erosive effect of mouthrinses on enamel and dentin.

This in vitro study measured the pH values, titratable acidity (TA), and erosive potential of commercially available mouthrinses. A pH analysis of 6 mouthrinses (Listerine Total Care, Listerine Ultraclean, Listerine Original, Crest Pro-Health, Scope Classic, and ACT Total Care) was performed using a calibrated pH meter, and the neutralizable acidity was measured by titrating the mouthwashes against 0.1 M of sodium hydroxide. A gravimetric analysis was performed by submerging human enamel and dentin specimens in 5 mL of each mouthrinse for a total of 2 weeks. Specimens were weighed on a calibrated analytical balance at baseline, 24 hours, 48 hours, 96 hours, 1 week, and 2 weeks, and finally the loss of mass was calculated. The differences in erosive potential among the 6 mouthrinses were verified using nonparametric tests (Kruskal-Wallis and Mann- Whitney). The level of significance was set at 0.05. The mouthrinses were found to have the following mean pH/ TA values: Crest Pro-Health, 7.05/0.00; ACT Total Care, 6.31/5.44; Scope Classic, 5.18/0.42; Listerine Original, 3.98/9.26; Listerine Total Care, 3.43/5.88; and Listerine Ultraclean, 3.87/10.36. A significant correlation between pH and TA was observed for this dataset (P > 0.0001). No statistically significant difference in enamel loss among the groups was observed (P = 0.0631). However, a significant difference in dentin loss was observed among the 6 mouthrinses (P = 0.0011). Within the limitations of this in vitro study, it can be concluded that some mouthrinses have a pH lower than the critical pH of enamel and dentin. There is a significant association between acidic pH values and higher TA. Some of the tested mouthrinses presented an erosive potential on dentin.

Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig.

Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.

Lokomat therapy in Colombia: Current state and cognitive aspects.

Neurological disorders frequently affect walking function which is one of the most fundamental skills to improve quality of life and autonomy, and Lokomat has been a key piece for gait's rehabilitation. In this study, a diagnosis about the development of the Robot-assisted therapy rehabilitation with Lokomat in Colombia is made. The study was performed by collecting some anthropometric and demographic data of the patients that use Lokomat, followed by a survey of cognitive aspects. With the purpose to compare the current state of the robotic therapies it was found that in Colombia the benefits of this treatment have not being fully exploited. Regarding the cognitive aspects, most of the patients that use Lokomat as a rehabilitation therapy feel comfortable (47%), very safe (68%) and have a perpective of significant results with the therapy (68%). However, when compared the number of patients in therapy with Lokomat with the number of the population that has gait disabilities, it is found that few Colombians have access to this type of therapy.

Mitogenomic sequences support a north-south subspecies subdivision within Solenodon paradoxus.

Solenodons are insectivores found only in Hispaniola and Cuba, with a Mesozoic divergence date versus extant mainland mammals. Solenodons are the oldest lineage of living eutherian mammal for which a mitogenome sequence has not been reported. We determined complete mitogenome sequences for six Hispaniolan solenodons (Solenodon paradoxus) using next-generation sequencing. The solenodon mitogenomes were 16,454-16,457 bp long and carried the expected repertoire of genes. A mitogenomic phylogeny confirmed the basal position of solenodons relative to shrews and moles, with solenodon mitogenomes estimated to have diverged from those of other mammals ca. 78 Mya. Control region sequences of solenodons from the northern (n = 3) and southern (n = 5) Dominican Republic grouped separately in a network, with FST = 0.72 (p = 0.036) between north and south. This regional genetic divergence supports previous morphological and genetic reports recognizing northern (S. p. paradoxus) and southern (S. p. woodi) subspecies in need of separate conservation plans.

Investigación básica experimental para la definición de los parámetros críticos en el proceso de obtención de soluciones concentradas de propóleos (SCP) / Experimental basic research to define critical parameters in the process of obtaining concentrated solutions of propolis (CSP)

Introducción: los procesos de obtención de SCP han sido desarrollados por diferentes investigadores tanto a nivel nacional como internacional. Objetivo: definir los parámetros críticos del proceso de obtención de SCP, para incrementar el rendimiento y la calidad de este producto y sus derivados. Métodos: se utilizó el método de purificación de Pichansky, con algunas modificaciones en las siguientes variables: relación masa/volumen, concentración del etanol y el tiempo de agitación. Los materiales utilizados están avalados por el Sistema de Gestión de Calidad del Centro. Resultados: las variantes #2 y #4 del proceso de extracción, utilizadas a escala de laboratorio, son las de mejores resultados, ya que se obtuvo un rango de porcentaje sólidos totales entre un 12,4 y 14,3 %, con un rendimiento entre un 48,5 y 83,0 %; siendo seleccionada la variante #4 para elaborar los lotes experimentales a escala de reactor. Conclusiones: las variables estudiadas: tiempo de agitación, concentración de etanol y relación masa/volumen, así como el porcentaje de los sólidos totales, el porcentaje del rendimiento y las propiedades organolépticas, respondieron positivamente en las variantes #2 y #4, las cuales permitieron cumplir con los objetivos propuestos en esta investigación, y pueden emplearse en la elaboración de los lotes productivos dependiendo de la concentración de las soluciones alcohólicas de propóleos que se quieran producir.

Introduction: SCP's processes of obtaining Propolis have been developed by different investigators so much nationally like international. Objective: To define SCP's critical parameters of the process of obtaining, to increment the performance and the quality of this product and his by-products. Methods: Pichansky's method of purification, with some modifications was utilized to the variables following: Relation mass/volume, concentration of ethanol and the time of agitation. The utilized materials are guaranteed for the Quality Management System of the Center. Results: The variants #2 and #4 of the process of extraction, utilized to scale of laboratory, gave better results, obtaining percentage's range solid totals between 12.4 and 14.3 %, with a performance between 48.5 and 83.0 %. Variant #4 was selected in order to make the experimental lots at reactor scale. Conclusions: the studied variables: Time agitation, concentration of ethanol and the relation mass/volume, as well as the percentage of the solid totals, the percentage of the performance and organoleptic properties, of variants #2 and #4, allowed carrying out the objectives proposed in this investigation. These variables responded positively in the variants and can be used in the elaboration of the productive lots considering the concentration of alcoholic propolis' solutions required.

Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors.

UNLABELLED: Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported. Here the data reveal that veliparib, olaparib, niraparib, and talazoparib (BMN-673) potentiate the cytotoxicity of alkylating agents. Consistent with this, all four drugs possess PARP1 trapping activity. Using biochemical and cellular approaches, we directly probe the trapping mechanism for an allosteric component. These studies indicate that trapping is due to catalytic inhibition and not allostery. The potency of PARP inhibitors with respect to trapping and catalytic inhibition is linearly correlated in biochemical systems but is nonlinear in cells. High-content imaging of γH2Ax levels suggests that this is attributable to differential potentiation of DNA damage in cells. Trapping potency is inversely correlated with tolerability when PARP inhibitors are combined with temozolomide in mouse xenograft studies. As a result, PARP inhibitors with dramatically different trapping potencies elicit comparable in vivo efficacy at maximum tolerated doses. Finally, the impact of trapping on tolerability and efficacy is likely to be context specific. IMPLICATIONS: Understanding the context-specific relationships of trapping and catalytic inhibition with both tolerability and efficacy will aid in determining the suitability of a PARP inhibitor for inclusion in a particular clinical regimen.

Derivación submandibular para garantizar la vía respiratoria en la traumatologia facial / Submandibular bypass to secure the airway in facial trauma

Introducción: uno de los recursos más efectivos en traumatismos maxilofaciales es el empleo de la traqueostomía, esta se conoce desde hace más de doscientos años. Pocas intervenciones quirúrgicas han salvado tantas vidas como la traqueostomía pues esta, permite garantizar una vía respiratoria segura para el paciente, pero como todo proceder quirúrgico no está exenta de complicaciones. La derivación endotraqueal submandibular se presenta como una alternativa viable en los casos que se requiera una traqueostomía temporal, esta consiste en el paso del tubo endotraqueal de la boca para el exterior a través de una incisión en la región submandibular. Se denomina fractura panfacial cuando las lesiones comprometen los tercios superiores, medio e inferior da la cara y que resulta en una perturbación grave de la arquitectura facial. Objetivos: dar a conocer siete casos realizados desde el 2006 hasta la actualidad, cuatro en el Hospital General Docente "Abel Santamaría Cuadrado" de Pinar del Rio, Cuba, y tres en la Clínica Multiperfil de Luanda, Angola. Métodos: se exponen la técnica descrita por Altemir y detallada por Guevara Mantilla y cols en sus cuatro fases. Los pacientes fueron llevados al quirófano de forma urgente y electiva mediante coordinación con el Servicio de Anestesiología y Reanimación. Se realizó, primero la derivación submandibular y seguidamente el proceder programado para cada paciente. Conclusiones: el proceder permite un adecuado control de la vía respiratoria y constituye una alternativa segura y eficaz en pacientes con traumas complejos del tercio medio facial. No se han encontraron complicaciones ni durante ni en el posoperatorio.

Introduction: tracheostomy is one of the most effective resources in the treatment of facial trauma. This technique has been used for more than two hundred years. Few surgical interventions have saved as many lives as tracheostomy, since it makes it possible to secure a safe airway for the patient. However, as with all surgical procedures, tracheostomy may also have complications. Submandibular endotracheal bypass is a viable alternative when temporary tracheostomy is required. It consists in the passage of an endotracheal tube from the mouth outwards through an incision in the submandibular region. It is called panfacial fracture when the lesions compromise the upper, middle and lower thirds of the face, resulting in serious disturbance of the facial architecture. Objectives: present seven cases treated from 2006 to the present: four at Abel Santamaría Cuadrado General Teaching Hospital in Pinar del Río, Cuba, and three at the Multiprofile Clinic of Luanda, Angola. Methods: a presentation is provided of the four stages of the technique described by Altemir and detailed by Guevara Mantilla and cols. Patients were carried to the operating room for emergency and elective surgery prior coordination with the Anesthesiology and Resuscitation Service. Submandibular bypass was performed first, followed by the procedure scheduled for each patient. Conclusions: the procedure allows appropriate control of the airway and constitutes a safe, effective alternative for patients with complex trauma of the facial middle third. No complications were found during surgery or in the postoperative period.

Autotrasplante de células madre adultas en defecto óseo de rama mandibular por quiste dentígero / Autotransplantation of adult stem cells in an osseous defect of the mandibular branch per dentigerous cyst

Propósitos del estudio: indagar en la formación ósea de cavidades quísticas de los maxilares a partir de células madres adultas. Método: se realiza la presentación de un paciente que presentaba un quiste dentígero en rama mandibular izquierda y que había provocado gran destrucción ósea, lo cual se comprobó al examen físico y estudios complementarios, tomografía axial compuarizada (TAC) e imágenes gráficas (Fotos). Se decide colocar las células madres adultas, previa valoración y preparación del paciente con el servicio de hematología y medicina transfusional. Se describe la conducta médico-quirúrgica realizada y su diagnóstico anatomopatológico. Se presenta de forma gráfica la evolución clínico radiológico del paciente, inmediato, a los tres meses y a los dos años de evolución. Resultados: quedó identificado que las células madres adultas inducen la regeneración ósea en las cavidades quísticas de los maxilares. Se discutió la evolución del paciente según la literatura consultada. Conclusiones: Se puede expresar que lo identificado en este caso confirma el uso de células madres adultas en la regeneración ósea de cavidades quísticas de los maxilares, además de abrir nuevas perspectivas en el tratamiento de otras afecciones del territorio maxilofacial como fracturas, artrosis de la ATM, defectos por lesiones oncológicas, por lo que se justifica la realización de proyectos investigativos que apoyen la utilización de esta nueva terapéutica.

Purpose of the study: to investigate about the osseous formation of cystic cavities of the maxillaries from adult stem cells. Method: a patient presenting a dentigerous cyst in the left mandibular branch that provoked a large osseous destruction, which was confirmed by means physical examination, complementary studies, Computerized Axial Tomography (CAT) and graphic images (photographs). Adult stem cells were placed, in view of a prior assessment and preparation of the patient in hematology service and transfusion medicine. Medical-surgical approach and pathological diagnosis were described, presenting in graphics the clinical and radiological improvement almost immediately, at three months and at two years. Results: it was identified that adult stem cells induce osseous regeneration in the cystic cavities of maxillaries. The evolution of the patient was discussed according to the medical literature reviewed. Conclusion: the use of adult stem cells to treat the osseous regeneration of cystic cavities of the maxillaries was confirmed in this case, and new perspectives of treatment for other maxillofacial illnesses can be opened, as for fractures, osteoarthritis of the Temporal Mandibular Articulation and defects provoked by cancer lesions, etc. Research projects sustaining the use of this new therapy are necessary.