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Technologies for automating animal management and monitoring tasks can improve efficiency and productivity of livestock production. We developed the e-Synch system for automated control and monitoring the estrous cycle of cattle through intravaginal hormone delivery and sensing. Thus, our objective was to evaluate luteinizing hormone (LH) concentrations after intravaginal instillation of the Gonadotropin-releasing hormone (GnRH) analogue Gonadorelin with the e-Synch system. This system consists of an intravaginal electronically controlled automated hormone delivery and sensing device integrated with an IoT platform. Lactating Holstein cows with their estrous cycle synchronized were used in two experiments (Exp). In Exp 1, at 48 h after induction of luteolysis, cows (n=5-6 per group) were randomized to receive 100 µg of Gonadorelin through intramuscular (i.m.) injection, 100 µg of Gonadorelin in a 2 mL solution delivered with e-Synch, and an empty e-Synch device. In Exp 2, at 48 h after induction of luteolysis cows (n=6-7 per group) were randomized to receive 100 µg of Gonadorelin i.m., or an intravaginal treatment with e-Synch consisting of 100 or 1,000 µg of Gonadorelin in 2 or 10 mL of solution containing 10% citric acid as absorption enhancer. Circulating concentrations of LH were analyzed with linear mixed models with or without repeated measurements. In Exp 1, cows in the i.m. Gonadorelin treatment had a surge of LH whereas cows in the other two treatments did not have a surge of LH for up to 8 h after treatment. In Exp 2, the 1,000 µg dose of Gonadorelin elicited more LH release than the 100 µg dose, regardless of solution quantity. The overall LH response as determined by area under the curve, mean, and maximum LH concentrations was similar between cows receiving 1,000 µg of Gonadorelin delivered with e-Synch and 100 μg of Gonadorelin i.m. Increasing volume of solution for delivering the same dose of Gonadorelin partially increased LH release only for the 100 µg dose. We conclude that the e-Synch system could be used to automatically release Gonadorelin in a dose and volume that induces a surge of LH of similar magnitude than after i.m. injection of 100 μg of Gonadorelin. Also, the dose of Gonadorelin delivered by e-Synch is more critical than the volume of solution used.

La enseñanza de ciencias y matemática en niveles secundario y universitario ha permanecido estancada, compartimentizada y orientada a la exposición del docente. Últimamente han aparecido voces sobre necesidad de un cambio sustancial de paradigma, centrado en diversos elementos que se detallan en el trabajo. Al adoptar ese corrimiento de paradigma se introducen nuevas tecnologías y métodos para el aprendizaje experimental de ciencias asistido por TICs. Se realizan experiencias cuyos datos permiten inducir un modelo del fenómeno en estudio, el cual es validado por medio de un ajuste de los valores experimentales con la predicción del modelo. Mediante la aplicación de estas Unidades Didácticas se pretende que los alumnos adquieran las competencias científicas básicas enunciadas en variadas publicaciones. Para cada Sesión de Aprendizaje Activo se presenta una secuencia de experiencias, de tal manera que cada una de ellas dé razón a la siguiente. Se demuestra un ejemplo de modelado de campo magnético producido por una corriente eléctrica en una bobina. Se realizan mediciones con un magnetómetro ligado a interfaz, computadora y programa computacional. Con Unidades Didácticas como la mencionada, los alumnos aprenderán a experimentar y modelar fenómenos de la vida real, que es un objetivo de la capacitación del capital humano.

Alzheimer's Disease (AD), reported for the first time in 1906, is a common disease that remains incurable to this day. In the past, a family of treatments using Cu(II) chelators failed during clinical trials, evidencing the importance of pre-clinical studies. In this work, we performed electrochemical characterisation of TDMQ20, a new potential drug against AD, using electrochemistry and spectroelectrochemistry. On the basis of voltammetry, we determined that TDMQ20 undergoes a two-step irreversible oxidation process and a one-step irreversible reduction process. Both oxidation and reduction reactions are pH-sensitive. Bidimensional UV-Vis spectroelectrochemistry (UV-Vis-SEC) allowed us to confirm that oxidation of TDMQ20 can occur both on the aliphatic chain and on the aromatic ring. The results expand the knowledge of the TDMQ20 redox activity in the human body which is important from the point of view of the toxicity of the proposed therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: CD38 and BCMA are proteins expressed at high levels in multiple myeloma cells, so they are targets for the development of mono- or multispecific antibodies., Areas Covered: Patent US20240132615 describes anti-CD3/BCMA/CD38 trispecific antibodies and a method of treating relapsed/refractory multiple myeloma pharmaceutically. In vitro and preclinical results show that anti-CD3/BCMA/CD38 trispecific antibodies have stronger binding affinity and killing potency compared to daratumumab, isatuximab, and teclistamab antibodies., Expert Opinion: The trispecific structure and a silenced Fc are pharmaceutical advantages of the anti-CD3/BCMA/CD38 antibody for the treatment of relapsed or refractory multiple myeloma.

Tuberculosis (TB) killed approximately 1.3 million people in 2022 and remains a leading cause of death from the bacteria Mycobacterium tuberculosis (M.tb); this number of deaths was surpassed only by COVID-19, caused by the SARS-CoV-2 virus. The alarming emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M.tb strains presents an urgent need for effective new treatments. Our study aimed to determine the synergistic effects of antibiotic combinations against M.tb. Using a high-throughput in vitro checkerboard assay, we evaluated the interactions of Bedaquiline (BDQ) and other antibiotics including Capreomycin (CAP), Linezolid (LIN), and Sutezolid (SUT) against M.tb H37Rv. BDQ and CAP demonstrated in vitro enhanced effect, which prompted further investigation in vivo using the murine low dose aerosol (LDA) model. After aerosol challenge with M.tb, C57BL/6 mice were treated with BDQ, CAP, or their combination, starting 28 days post-infection. The antimicrobial treatment lasted four weeks, and the bacterial burden in lung and spleen tissues was assessed at the end of treatment. At 4 weeks post-treatment, a significant reduction in bacterial load was observed within the lungs and spleens of mice given BDQ alone or given as a BDQ/CAP combination compared to the untreated group. In contrast, CAP monotherapy led to an increase in bacterial load within the lung and no significant difference in bacterial burden in the spleen in comparison to the untreated mice. These results were confirmed in the guinea pig model of TB, where both BDQ and the BDQ/CAP combination treatment led to a decrease in bacterial burden in the lung and spleen, whereas CAP had no significant effect on bacterial burden at the 4-week post treatment timepoint. We next determined whether there may be differences in vitro with the BDQ/CAP combination against M.tb lineages 1, 2 and 4. We determined that in vitro enhanced effect was not observed in some representative strains of M.tb lineage 4, indicating variability in drug effectiveness across M.tb lineages. This research underscores the complexity of TB treatment and the critical need for innovative approaches to combat this global health threat., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Pyridine, a compound with a heterocyclic structure, is a key player in medicinal chemistry and drug design. It is widely used as a framework for the design of biologically active molecules and is the second most common heterocycle in FDA-approved drugs. Pyridine is known for its diverse biological activity, including antituberculosis, antitumor, anticoagulant, antiviral, antimalarial, antileishmania, anti-inflammatory, anti-Alzheimer's, antitrypanosomal, antimalarial, vasodilatory, antioxidant, antimicrobial, and antiproliferative effects. This review, spanning from 2022 to 2012, involved the meticulous identification of pyridine derivatives with antiproliferative activity, as indicated by their minimum inhibitory concentration values (IC50) against various cancerous cell lines. The aim was to determine the most favorable structural characteristics for their antiproliferative activity. Using computer programs, we constructed and calculated the molecular descriptors and analyzed the electrostatic potential maps of the selected pyridine derivatives. The study found that the presence and positions of the -OMe, -OH, -C=O, and NH2 groups in the pyridine derivatives enhanced their antiproliferative activity over the cancerous cellular lines studied. Conversely, pyridine derivatives with halogen atoms or bulky groups in their structures exhibited lower antiproliferative activity.

Bidimensional spectroelectrochemistry (Bidim-SEC) is an instrumental technique that provides operando UV/vis absorption information on electrochemical processes from two different points of view, using concomitantly a parallel and a normal optical configuration. The parallel configuration provides information about chemical species present in the diffusion layer, meanwhile the normal arrangement supplies information about changes occurring both in the diffusion layer and, mainly, on the electrode surface. The choice of a suitable cell to perform Bidim-SEC experiments is critical, especially while working under a thin-layer regime. So far, most of the proposed Bidim-SEC cells rely on the use of spacers to define the thin-layer thickness, which leads to working with constant thickness values. Herein, we propose a novel Bidim-SEC cell that enables easy-to-use micrometric control of the thin-layer thickness using a piezoelectric positioner. This device can be used for the study of complex interfacial systems and also to easily measure the key parameters of an electrochemical process. As a proof of concept, the study of the roughening of a gold electrode in KCl medium is performed, identifying key steps in the passivation and nanoparticle generation on the gold surface.

Raman signal enhancement is fundamental to develop different analytical tools for chemical analysis, interface reaction studies, or new materials characterization, among others. Thus, phenomena such as surface-enhanced Raman scattering (SERS) have been used for decades to increase the sensitivity of Raman spectroscopy, leading to a huge development of this field. Recently, an alternative method to SERS for the amplification of Raman signals has been reported. This method, known as electrochemical surface oxidation-enhanced Raman scattering (EC-SOERS), has been experimentally described. However, to date, it has not yet been fully understood. In this work, new experimental data that clarify the origin of the Raman enhancement in SOERS are provided. The use of a complete and unique set of combined spectroelectrochemistry techniques, including time-resolved operando UV-vis absorption, fluorescence, and Raman spectroelectrochemistry, reveals that such enhancement is related to the generation of dielectric or semiconductor nanocrystals on the surface of the electrode and that the interaction between the target molecule and the dielectric substrate is mediated by metal cations. According to these results, the interaction metal electrode-nanocrystal-metal cation-molecule is proposed as being responsible for the Raman enhancement in Ag and Cu substrates. Elucidation of the origin of the Raman enhancement will help to promote the rational design of SOERS substrates as an attractive alternative to the well-known SERS phenomenon.

Aim: the activity of patent claims by Mexican pharmaceutical companies is unknown. Objective: analyse the trend in patents of Mexican pharmaceutical companies. Method: a search for patents was carried out in the patent database of the Mexican Institute of Industrial Property, using the list of Mexican pharmaceutical companies belonging to the Mexican Association of Pharmaceutical Research Industries, and the codes A61K, A61P and C07 of the International Patent Classification. Results: the leading companies in patent applications were Liomont, Senosiain and RIMSA; however, Mexican pharmaceutical companies claim very few patents, only 266 patent applications in the period 2000-2020, with a technological factor with a value of zero, and a commercial factor of little value. Conclusion: Mexican pharmaceutical companies lack a robust patent system, without growth, and with a low percentage of patents with high commercial value.

Background: Multiparameter flow cytometry (FC) immunophenotyping is a key tool for detailed identification and characterization of human blood leucocytes, including B-lymphocytes and plasma cells (PC). However, currently used conventional data analysis strategies require extensive expertise, are time consuming, and show limited reproducibility., Objective: Here, we designed, constructed and validated an automated database-guided gating and identification (AGI) approach for fast and standardized in-depth dissection of B-lymphocyte and PC populations in human blood., Methods: For this purpose, 213 FC standard (FCS) datafiles corresponding to umbilical cord and peripheral blood samples from healthy and patient volunteers, stained with the 14-color 18-antibody EuroFlow BIgH-IMM panel, were used., Results: The BIgH-IMM antibody panel allowed identification of 117 different B-lymphocyte and PC subsets. Samples from 36 healthy donors were stained and 14 of the datafiles that fulfilled strict inclusion criteria were analysed by an expert flow cytometrist to build the EuroFlow BIgH-IMM database. Data contained in the datafiles was then merged into a reference database that was uploaded in the Infinicyt software (Cytognos, Salamanca, Spain). Subsequently, we compared the results of manual gating (MG) with the performance of two classification algorithms -hierarchical algorithm vs two-step algorithm- for AGI of the cell populations present in 5 randomly selected FCS datafiles. The hierarchical AGI algorithm showed higher correlation values vs conventional MG (r 2 of 0.94 vs. 0.88 for the two-step AGI algorithm) and was further validated in a set of 177 FCS datafiles against conventional expert-based MG. For virtually all identifiable cell populations a highly significant correlation was observed between the two approaches (r 2 >0.81 for 79% of all B-cell populations identified), with a significantly lower median time of analysis per sample (6 vs. 40 min, p=0.001) for the AGI tool vs. MG, respectively and both intra-sample (median CV of 1.7% vs . 10.4% by MG, p<0.001) and inter-expert (median CV of 3.9% vs . 17.3% by MG by 2 experts, p<0.001) variability., Conclusion: Our results show that compared to conventional FC data analysis strategies, the here proposed AGI tool is a faster, more robust, reproducible, and standardized approach for in-depth analysis of B-lymphocyte and PC subsets circulating in human blood., Competing Interests: JvD, AO, AMB, MB, EB, MP and AH-D, are listed as co inventors on the EuroFlow patent “Means and methods for multiparameter cytometry-based leukocyte subsetting” NL2844751, filing date 5 November 2019, owned by the EuroFlow scientific consortium, which describes the flow cytometry panel used in this study, and RF and AO are listed as co inventors on the patent “Method of digital information classification” US 10,133,962 B2, filing date 9 June 2017 owned by Cytognos S.L. JvD and AO report to be chairmen of the EuroFlow Scientific Foundation, which receives royalties from licensed patents, which are collectively owned by the participants of the EuroFlow Consortium. These royalties are exclusively used for continuation of the EuroFlow collaboration and sustainability of the EuroFlow consortium. JvD and AO report an Educational Services Agreement and a Scientific Advisor Agreement from BD Biosciences San Joseé, CA; all related fees and honoraria are for the involved University Departments at University of Salamanca. AH-D, GG and RF are employees of Cytognos S.L. Salamanca Spain. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Delgado, Fluxa, Perez-Andres, Diks, van Gaans-van den Brink, Barkoff, Blanco, Torres-Valle, Berkowska, Grigore, van Dongen and Orfao.)

Repurposing of approved drugs allows strong savings in time and investment. Rimantadine is an FDA-approved drug for prevention and treatment of influenza A infection. Patent US2021330605 describes the use of rimantadine, an adamantane derivative, for the treatment of melanoma, breast cancer and head and neck squamous cell carcinoma. Rimantadine inhibited proliferation of cell lines of melanoma, breast cancer, and head and neck squamous cell carcinoma, increased the survival of mice injected with cancer cell lines and restores the expression of MHC class I. Rimantadine has the potential to be used successfully in the treatment of head and neck squamous cell carcinoma.

Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of Pneumocystis carinii pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-atovaquone has the potential to be used successfully in the treatment of various types of tumors.

Objective: To determine if statewide marijuana laws impact upon the detection of drugs and alcohol in victims of motor vehicle collisions (MVC)., Methods: A retrospective analysis of data collected at trauma centers in Arizona, California, Ohio, Oregon, New Jersey, and Texas between 2006 and 2018 was performed. The percentage of patients testing positive for marijuana tetrahydrocannabinol (THC) was compared to the percentage of patients driving under the influence of alcohol (blood alcohol level >0.08 g/dL) that were involved in an MVC., Results: The data were analyzed to evaluate the trends in THC and alcohol use in victims of MVC, related to marijuana legalization. The change in incidence of THC detection (percentage) over the time period where data were available are as follows: Arizona 9.5% (0.4 to 9.9), California 5.4% (20.8 to 26.2), Ohio 5.9% (6.7 to 12.6), Oregon 3% (3.0 to 6.0), New Jersey 2.3% (2.7 to 5.0), and Texas 15.3% (3.0 to 18.3). Alcohol use did not change over time in most states. There did not appear to be a relationship between the legalization of marijuana and the likelihood of finding THC in patients admitted after MVC. In fact, in Texas, where marijuana remains illegal, there was the largest change in detection of THC., Conclusions: There was no apparent increase in the incidence of driving under the influence of marijuana after legalization. In addition, the changes in marijuana legislation did not appear to impact alcohol use.

Aim : pharmaceutical patenting activity in developing countries, including Mexico, is unknown. Objective : determine the activity of pharmaceutical patents by Mexican universities. Method : using 'university' as keyword and A61K, A61P and C07 as International Patent Classification codes, was searched to generate a perspective of pharmaceutical patent applications by Mexican universities. Results : 227 patents (186 granted patents + 41 not-granted patents) were claimed in the period 2000-2018. The leading university was the National Autonomous University of Mexico, followed by the Instituto Politecnico Nacional, Universidad Autonoma de Nuevo León and Universidad Autonoma de Puebla. The pharmaceutical concerns addressed were led by the fields of infectious, cancer and diabetes. Conclusion : in Mexican universities, the licensing of pharmaceutical patents is still in its early stages.

Introduction: LAG-3 is considered to be the third point of immunological control in relation to clinical trials that address cancer treatment, only behind PD-1 and CTLA-4, due to its role as a suppressor of the immune response and enhancer of differentiation of Treg cells., Areas Covered: The authors focus on emphasizing the strategy of development of LAG-3 inhibitors to develop anticancer therapeutics, especially from the perspective of designing new monoclonal and bispecific antibodies against LAG-3. This article also covers details of patents and clinical trials of LAG-3 inhibitors reported in the literature. In addition, we highlight as future research challenges the design and development of peptides and small molecules as inhibitors of LAG-3 function., Expert Opinion: Three approaches have been used for the development of LAG-3 inhibitors, and they include inhibitory LAG-3 binding peptides and antagonist monoclonal and multispecific antibodies. These approaches include more than 100 clinical trials of 21 molecules that bind to LAG-3 and block its binding to MHC II. However, these approaches do not cover the design and development of peptides and small molecules that could inhibit the function of LAG-3, for which it is necessary to develop new alternatives that cover this gap.

American trypanosomiasis is a neglected tropical disease and an endemic problem in 21 Latin American countries, whose treatment relies on only two US FDA-approved drugs: benznidazole and nifurtimox. Patent literature reveals vital information on new trends in therapies for various diseases, including Chagas disease. The authors used the patent databases of the world's major patent offices to generate an overview of patent trends related to the treatment of Chagas disease. A total of 50 patent families were collected and grouped as 'small molecules', 'pharmaceutical compositions of known compounds' and vaccines. From the results and interpretation, it can be concluded that the treatment of Chagas disease receives little attention in the field of patents and that the upward trend is minimal.

Cancer drug repurposing is an attractive approach that leads to savings in time and investment. Adapalene, the first medical application of which was for the treatment of acne, has been described as a repurposing drug for the treatment of various types of cancer. Patent application CN111329851 describes the use of adapalene for the treatment of melanoma, by assays carried out on melanoma cell lines. Adapalene demonstrated antiproliferative activity in melanoma cell lines via S-phase arrest-dependent apoptosis mediated by DNA damage through an increase in the expression of p-ATM and p-chk2 and a decrease in the expression of p-BRCA1 and Rad51. Even though no evidence on efficacy and efficiency is shown in preclinical and clinical studies, CN111329851 patent shows that adapalene may be a repurposing drug for the treatment of melanoma.

Inhibition of the PD-1/PD-L1 pathway is a target for the development of new therapies. US10710986 patent describes a small molecule that targets PDL-1/PD-1 interactions and triggers antitumor activity against colorectal cancer. However, it does not describe biological assays that allow us to suppose that this small molecule may be active in other types of cancer. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this compound surpasses the action of therapy in cancer.

Antigen-specific serum immunoglobulin (Ag-specific Ig) levels are broadly used as correlates of protection. However, in several disease and vaccination models these fail to predict immunity. In these models, in-depth knowledge of cellular processes associated with protective versus poor responses may bring added value. We applied high-throughput multicolor flow cytometry to track over-time changes in circulating immune cells in 10 individuals following pertussis booster vaccination (Tdap, Boostrix ® , GlaxoSmithKline). Next, we applied correlation network analysis to extensively investigate how changes in individual cell populations correlate with each other and with Ag-specific Ig levels. We further determined the most informative cell subsets and analysis time points for future studies. Expansion and maturation of total IgG1 plasma cells, which peaked at day 7 post-vaccination, was the most prominent cellular change. Although these cells preceded the increase in Ag-specific serum Ig levels, they did not correlate with the increase of Ig levels. In contrast, strong correlation was observed between Ag-specific IgGs and maximum expansion of total IgG1 and IgA1 memory B cells at days 7 to 28. Changes in circulating T cells were limited, implying the need for a more sensitive approach. Early changes in innate immune cells, i.e. expansion of neutrophils, and expansion and maturation of monocytes up to day 5, most likely reflected their responses to local damage and adjuvant. Here we show that simultaneous monitoring of multiple circulating immune subsets in blood by flow cytometry is feasible. B cells seem to be the best candidates for vaccine monitoring., Competing Interests: AD, CT, JD, AO, MP-A and MB report inventorship of the patent “Means and methods for multiparameter cytometry-based leukocyte subsetting” (NL2844751, filing date 5 November 2019) (21), owned by the EuroFlow Consortium. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Diks, Khatri, Oosten, de Mooij, Groenland, Teodosio, Perez-Andres, Orfao, Berbers, Zwaginga, van Dongen and Berkowska.)

PD-L1 and ICOS are immune control points in cancer and their presence in cancer tends to have a poor prognosis. WO2019122882 patent describes a bispecific antibody that targets PDL-1/ICOS with the potential application of cancer treatment. WO2019122882 patent describes a bispecific antibody with antitumor efficacy in CT26 model through of the depletion of T Reg cells and improved ratio of CD8 + T cells: T Reg in tumor microenvironment. The anti-PDL-1/ICOS antibody is new; however, only preclinical assays are shown using colon carcinoma model. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this antibody surpasses the action of the combinatorial therapy in cancer.

OX40 and 5T4 are molecules that play a role in T-cell expansion and cytoskeleton's disruption in cancer, respectively. US2019161555 patent describes a bispecific antibody that targets OX40/5T4 with the potential application of cancer treatment. The method of analysis of the US201916155 patent consisted of claim's analysis, as well as the chemical/biological information's analysis of the bispecific antibody. The patent includes independent claims related to bispecific antibodies that bind to OX40/5T4, DNA encoding the antibodies, a vector that harbors the DNA, a host cell that contains the vector, a pharmaceutical composition containing a pharmaceutically effective amount of the antibodies, medical use of the antibodies, use of the antibodies in the treatment or prevention of neoplastic disorders and a method of treating neoplastic disorders. Bispecific antibodies that target OX40/5T4 can activate IL-2 secretion in CD4 + T cells.

Introduction: OX40 is an immune checkpoint in cancer and its presence in cancer is a good prognosis, making it a highly relevant target for the development of new immunotherapies., Areas Covered: The patent literature reveals vital information on new trends in cancer therapies. The authors used the patent databases of the six major patent offices in the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Office of Intellectual Property of China and Korean Intellectual Property Office, to generate a panorama of patents related to OX40 agonists. Specific patents have been grouped into innovative patents and adoption patents., Expert Opinion: An increasing trend in the development of OX40 agonists in cancer, particularly in the years 2018 and 2019. United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986,178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists.

Introduction: PD-L1 and PD-1 are two immune checkpoints and their presence in various types of tumors is related to a poor prognosis; this makes them highly relevant targets in the development of new therapies. Patent US2019010232 describes bispecific anti-PD-L1/PD-1 antibodies made with Azymetric technology., Areas Covered: Three bispecific antibodies that target PD-L1/PD-1 are described in US2019010232 patent and are proposed to play a relevant role in the treatment of cancer., Expert Opinion: Three bispecific antibodies that target PD-L1/PD-1 in US2019010232 demonstrated anti-tumor activity in lung cancer. However, no evidence is shown of the action of the antibodies against other cancers. An advantage of the bispecific antibodies of US2019010232 over combinatorial therapy is a greater decrease in tumor volume.

PD-1 and CTLA-4 are checkpoint inhibitors of the immune response in cancer, making them the target molecules for the development of therapeutic antibodies. US2019161548 patent describes a bispecific antibody capable of specifically binding to PD-1 and CTLA-4 that induced the proliferation and activation of CD8 + cells, as well as the expression of induclble co-stimulator in CD4 + T cells. Clinical trials to evaluate safety, dose-limiting toxicities and maximum tolerated/administered dose are still in the patient recruitment phase, but it will be of great interest to the scientific and medical community to know if the first bispecific anti-PD-1/CLTA-4 antibody, exceeds expectations and exceeds action of the combination of nivolumab and epilimumab in the treatment of cancer.

Introduction: Due to the primary role of PD-1 and LAG-3 in regulating the immune response in tumors, there is a need to develop therapies focused on the inhibition of PD-1 and LAG-3 in order to improve the immune response in patients with cancer. The authors of US2018326054 patent propose a method to eradicate cancer by using bispecific anti-PD-1/LAG-3 antibodies., Areas Covered: The US2018326054 patent describes anti-PD-1/LAG3 antibodies, pharmaceutical composition that contains it, and their application for cancer treatment, particularly pancreatic carcinoma. Proof concept and preclinical results show anti-PD-1/LAG-3 bispecific antibodies bind and are internalized by CD4 + T cells thereby increasing their effector functions (release of Granzyme B and INF-γ) in the presence of tumor cells, and completely suppress tumors in a murine model., Expert Opinion: Anti-PD-1/LAG-3 bispecific antibodies of the US2018326054 patent are new in a general concept, but treatment data is only shown for pancreatic carcinoma. The results to be obtained in future clinical trials of safety and efficacy could conclude whether these bispecific anti-PD-1/LAG-3 antibodies will be useful in a cancer treatment scheme.

The EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance of the SCID-RTE tube that explores the presence of recent thymic emigrants (RTE) together with T-cell activation status and maturation stages and discuss its applicability in the context of the broader EuroFlow PID flow cytometry testing algorithm for diagnostic orientation of PID of the lymphoid system. We have analyzed peripheral blood cells of 26 patients diagnosed between birth and 2 years of age with a genetically defined primary immunodeficiency disorder: 15 severe combined immunodeficiency (SCID) patients had disease-causing mutations in RAG1 or RAG2 ( n = 4, two of them presented with Omenn syndrome), IL2RG ( n = 4, one of them with confirmed maternal engraftment), NHEJ1 ( n = 1), CD3E ( n = 1), ADA ( n = 1), JAK3 ( n = 3, two of them with maternal engraftment) and DCLRE1C ( n = 1) and 11 other PID patients had diverse molecular defects [ ZAP70 ( n = 1), WAS ( n = 2), PNP ( n = 1), FOXP3 ( n = 1), del22q11.2 (DiGeorge n = 4), CDC42 ( n = 1) and FAS ( n = 1)]. In addition, 44 healthy controls in the same age group were analyzed using the SCID-RTE tube in four EuroFlow laboratories using a standardized 8-color approach. RTE were defined as CD62L+CD45RO-HLA-DR-CD31+ and the activation status was assessed by the expression of HLA-DR+. Naïve CD8+ T-lymphocytes and naïve CD4+ T-lymphocytes were defined as CD62L+CD45RO-HLA-DR-. With the SCID-RTE tube, we identified patients with PID by low levels or absence of RTE in comparison to controls as well as low levels of naïve CD4+ and naïve CD8+ lymphocytes. These parameters yielded 100% sensitivity for SCID. All SCID patients had absence of RTE, including the patients with confirmed maternal engraftment or oligoclonally expanded T-cells characteristic for Omenn syndrome. Another dominant finding was the increased numbers of activated CD4+HLA-DR+ and CD8+HLA-DR+ lymphocytes. Therefore, the EuroFlow SCID-RTE tube together with the previously published PIDOT tube form a sensitive and complete cytometric diagnostic test suitable for patients suspected of severe PID (SCID or CID) as well as for children identified via newborn screening programs for SCID with low or absent T-cell receptor excision circles (TRECs)., (Copyright © 2020 Kalina, Bakardjieva, Blom, Perez-Andres, Barendregt, Kanderová, Bonroy, Philippé, Blanco, Pico-Knijnenburg, Paping, Wolska-Kuśnierz, Pac, Tkazcyk, Haerynck, Akar, Formánková, Freiberger, Svatoň, Šedivá, Arriba-Méndez, Orfao, van Dongen and van der Burg.)

Introduction : KIR is an inhibitory receptor expressed by natural killer cells that suppress the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of KIR and consequently improving the immune response in the various types of cancer. Authors of US9879082 and US2018208652 patents propose a method to eradicate cancer that utilizes anti-KIR antibody. Areas covered : US9879082 and US2018208652 patents describe an anti-KIR antibody, a pharmaceutical composition that contains it, and their application for cancer treatment, particularly, multiple myeloma and acute myeloid leukemia. Anti-KIR antibody is used to a dosage of 0.0003-3 mg antibody/kg patient weight, and is suspended in an isotonic solution consisting of sodium phosphate, sucrose, NaCl, and polysorbate 80. Expert opinion : The results of the clinical trials only support trials regarding the pharmacokinetic, pharmacodynamic, safety, and tolerability. In addition, these results demonstrate that treatment with the anti-KIR antibody can induce an antitumor response in cancer patients.

Introduction : TIGIT is an inhibitory receptor expressed by lymphocytes that suppresses the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of TIGIT and consequently improving the immune response in the various types of cancer. Authors of WO2018102536 patent propose a method to eradicate cancer utilizes anti-TIGIT antibody, etigilimab, in combination with anti-PD-1/PD-L1 antibody, nivolumab. Areas covered : WO2018102536 patent describes a method of cancer combinatorial treatment consisting of the utilization of either a pharmaceutical cocktail containing anti-TIGIT and an anti-PD-L1 antibody. Expert opinion : The results of the clinical trials only support trials regarding the tolerability of therapy with etigilimab, but does not show data related to the combined use of etigilimab and nivolumab.

Introduction : OX40 is a potent costimulatory receptor of the immune response in various types of cancer and has been used as a target for the generation of agonists of its function. Authors of WO2018202649 patent propose a method to eradicate cancer using a bispecific antibodies against OX40/CTLA-4. Areas covered : WO2018202649 patent describes several bispecific antibodies capable of specifically binding to OX40 and CTLA-4 that target regulatory T cells in the tumor microenvironment. Expert opinion : WO2018202649 patent demonstrates that bispecific antibodies against OX40/CTLA-4 have anti-tumor activity against colon, pancreatic and bladder cancer, and that there is a synergistic action with anti-PD-1 antibodies for the treatment of colon cancer. However, there is no evidence to conclude that bispecific antibodies can be used in cancers other than colon, pancreas and bladder. Likewise, the patent only describes the application in combinatorial therapy with anti-PD-1 antibodies, without presenting data relative to the combination with other immunotherapeutic agents against other checkpoint targets.

The clinical value of assessing immunoglobulin (Ig)G and IgA subclasses in addition to the isotypes of soluble Igs in serum has been well established. >20years ago, the International Union of Immunological Societies and the World Health Organization performed collaborative studies in order to validate antibody (Ab) clones for the detection of IgG and IgA subclasses for a broad range of laboratory assays, except for flow cytometry. Here we analyzed the performance of commercially available Ab clones to detect IgG and IgA subclasses in memory B-cells and plasma cells (PCs) by flow cytometry. In a first step, 28 Ab clones were evaluated in peripheral blood from healthy donors. Only 17/28 clones showed reactivity against IgG and IgA subclasses expressed on the B-cell and PC surface membrane, including Ab clones for IgG 1 (SAG1, HP6188, HP6001 and HP6186), IgG 2 (SAG2, HP6014 and HP6002), IgG 3 (SAG3, HP6095 and HP6050), IgG 4 (SAG4), IgA 1 (SAA1, H69-11.4 and B3506B4) and IgA 2 (SAA2, 2E2, and A9604D2). In a second step, for each Ig subclass a single clone was selected according to its specificity and fluorescence intensity (resolution power), for further more detailed validation (SAG1, SAG2, SAG3, SAG4, SAA1 and SAA2). This validation process was carried out in 4 different laboratories by testing the selected Ab clones in human peripheral blood, bone marrow and tonsil samples, using different staining protocols (e.g. surface membrane and/or cytoplasmic staining). All selected Ab clones displayed strong positivity, high specificity and optimal resolution between negative and positive cells. Alternative Ab clones were also validated. Thus, our results show the feasibility of using the validated Ig subclass Ab clones in combination with other B cell-associated markers for detailed dissection of the memory B-cell and PC compartments that express distinct Ig subclasses in different human tissues., (Copyright © 2017. Published by Elsevier B.V.)

Within EuroFlow, we recently developed screening tubes for hematological malignancies and immune deficiencies. Pipetting of antibodies for such 8-color 12-marker tubes however is time-consuming and prone to operational mistakes. We therefore evaluated dried formats of the lymphocytosis screening tube (LST) and of the primary immune deficiency orientation tube (PIDOT). Both tubes were evaluated on normal and/or on patient samples, comparing the mean fluorescence intensity of specific lymphocyte populations. Our data show that the dried tubes and liquid counterparts give highly comparable staining results, particularly when analyzed in multidimensional plots. In addition, the use of dried tubes may result in a reduced staining variability between different samples and thereby contributes to the generation of more robust data. Therefore, by using ready-to-use reagents in a dried single test tube format, the laboratory efficiency and quality will be improved., (Copyright © 2017 Erasmus MC, University Medical Center Rotterdam. Published by Elsevier B.V. All rights reserved.)

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints., (Copyright © 2019 Wentink, Kalina, Perez-Andres, del Pino Molina, IJspeert, Kavelaars, Lankester, Lecrevisse, van Dongen, Orfao and van der Burg.)

Idiopathic T-CD4 lymphocytopenia (ICL) is a rare and heterogeneous syndrome characterized by opportunistic infections due to reduced CD4 T-lymphocytes (<300 cells/μl or <20% T-cells) in the absence of HIV infection and other primary causes of lymphopenia. Molecular testing of ICL has revealed defects in genes not specific to CD4 T-cells, with pleiotropic effects on other cell types. Here we report for the first time an absolute CD4 lymphocytopenia (<0.01 CD4 + T-cells/μl) due to an autosomal recessive CD4 gene mutation that completely abrogates CD4 protein expression on the surface membrane of T-cells, monocytes, and dendritic cells. A 45-year-old female born to consanguineous parents consulted because of exuberant, relapsing, and treatment-refractory warts on her hands and feet since the age of 10 years, in the absence of other recurrent infections or symptoms. Serological studies were negative for severe infections, including HIV 1/2, HTLV-1, and syphilis, but positive for CMV and EBV. Blood analysis showed the absence of CD4 + T-cells (<0.01%) with repeatedly increased counts of B-cells, naïve CD8 + T-lymphocytes, and particularly, CD4/CD8 double-negative (DN) TCRαβ + TCRγδ - T-cells (30% of T-cells; 400 cells/μl). Flow cytometric staining of CD4 using monoclonal antibodies directed against five different epitopes, located in two different domains of the protein, confirmed no cell surface membrane or intracytoplasmic expression of CD4 on T-cells, monocytes, and dendritic cells but normal soluble CD4 plasma levels. DN T-cells showed a phenotypic and functional profile similar to normal CD4 + T-cells as regards expression of maturation markers, T-helper and T-regulatory chemokine receptors, TCRvβ repertoire, and in vitro cytokine production against polyclonal and antigen-specific stimuli. Sequencing of the CD4 gene revealed a homozygous (splicing) mutation affecting the last bp on intron 7-8, leading to deletion of the juxtamembrane and intracellular domains of the protein and complete abrogation of CD4 expression on the cell membrane. These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling and point out the need for better understanding the role of CD4 on thymic selection and the immune response., (Copyright © 2019 Fernandes, Perez-Andres, Blanco, Jara-Acevedo, Criado, Almeida, Botafogo, Coutinho, Paiva, van Dongen, Orfao and Faria.)

Introduction : TIM3 and PD-1 are checkpoint inhibitors in cancer that coordinate the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of TIM3 and PD-1 and consequently improving the immune response in the various types of cancer. The authors of patent EP3356411A1 propose several anti-TIM3/anti-PD-1 bispecific antibodies, as well as the method for producing them and their pharmacological application in the treatment of cancer. Areas covered : Patent EP3356411A1 describes a method by producing anti-TIM3/anti-PD-1 bispecific antibodies and their potential in cancer treatment. Expert opinion : Data supporting the patent demonstrate the ability by producing anti-TIM3/anti-PD-1 bispecific antibodies. Although the proposed methodology is very interesting and promising, further studies are necessary to assess the clinical applicability of the inventions on cancer.

Introduction : LAG-3 is checkpoint inhibitor in cancer that coordinates the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of LAG-3 and consequently improving the immune response in the various types of cancer. Areas covered : The patent literature reveals novel therapies, which provide information on cancer therapies. The authors used the patent databases of the six main patent offices of the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Intellectual Property Office of China and Korean Intellectual Property Office, to generate a detailed landscape of patents and patent applications of active companies related to LAG-3 inhibitors. Specific patents have been grouped into innovative patents and adopting patents. Expert opinion : There is a continuing development of LAG-3 inhibitors, and these inhibitors are being used in combination with other cancer treatment schemes, for example, antibodies against PD-1, PD-L1, and CTLA-4. Immutep and IO Therapeutics were the leaders in generating innovator patents, followed by Gustave Roussy Institute, and Applied Research Systems ARS. Dana-Farber Cancer Institute was the leader in the generation of adopter patents, followed by Novartis .

Introduction : OX40 is checkpoint inhibitor in cancer that coordinates the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of OX40 and consequently improving the immune response in the various types of cancer. Authors of patent US2018256711A1 propose a method to eradicate cancer that utilizes anti-OX40 agonist antibody in combination with anti-PD-L1 antagonist antibody. Areas covered : Patent US2018256711A1 describes a method of cancer combinatorial treatment consisting of the utilization of a pharmaceutical cocktail containing anti-OX40 and an anti-PD-L1 antibody. Expert opinion : The results of the clinical trials only support trials regarding the tolerability of combinatorial therapy, even when the objectives of determining the safety and pharmacokinetics of the treatment are proposed.

Guidelines for screening for primary immunodeficiencies (PID) are well-defined and several consensus diagnostic strategies have been proposed. These consensus proposals have only partially been implemented due to lack of standardization in laboratory procedures, particularly in flow cytometry. The main objectives of the EuroFlow Consortium were to innovate and thoroughly standardize the flowcytometric techniques and strategies for reliable and reproducible diagnosis and classification of PID of the lymphoid system. The proposed EuroFlow antibody panels comprise one orientation tube and seven classification tubes and corresponding databases of normal and PID samples. The 8-color 12-antibody PID Orientation tube (PIDOT) aims at identification and enumeration of the main lymphocyte and leukocyte subsets; this includes naïve pre-germinal center (GC) and antigen-experienced post-GC memory B-cells and plasmablasts. The seven additional 8(-12)-color tubes can be used according to the EuroFlow PID algorithm in parallel or subsequently to the PIDOT for more detailed analysis of B-cell and T-cell subsets to further classify PID of the lymphoid system. The Pre-GC, Post-GC, and immunoglobulin heavy chain (IgH)-isotype B-cell tubes aim at identification and enumeration of B-cell subsets for evaluation of B-cell maturation blocks and specific defects in IgH-subclass production. The severe combined immunodeficiency (SCID) tube and T-cell memory/effector subset tube aim at identification and enumeration of T-cell subsets for assessment of T-cell defects, such as SCID. In case of suspicion of antibody deficiency, PIDOT is preferably directly combined with the IgH isotype tube(s) and in case of SCID suspicion (e.g., in newborn screening programs) the PIDOT is preferably directly combined with the SCID T-cell tube. The proposed ≥8-color antibody panels and corresponding reference databases combined with the EuroFlow PID algorithm are designed to provide fast, sensitive and cost-effective flowcytometric diagnosis of PID of the lymphoid system, easily applicable in multicenter diagnostic settings world-wide.

Introduction: LAG-3 is checkpoint inhibitor in cancer that coordinates the down regulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of LAG-3 and consequently improving the immune response in the various types of cancer. Authors of patent US2018271940 propose a method to eradicate cancer that utilizes the combination of LAG-3Ig and anti-PD-1 or anti-PD-L1 antibodies. Areas covered: Patent US2018271940 describes a method consisting of the utilization of either a pharmaceutical cocktail containing LAG-3Ig and an anti-PD-1 or anti-PD-L1 antibody for activation of T cells as a potential for the treatment of cancer. Expert opinion: Data supporting the patent demonstrate the ability of LAG-3Ig and PD-1/PD-L1 to be useful in T cells activation, in addition to the reports showing that LAG-3 and anti-PD-1 and PD-L1 antibodies are therapeutic agents against cancer. Although the proposed methodology is very interesting and promising, further studies are necessary to assess the clinical applicability of the inventions on cancer.

In the rapidly evolving field of primary immunodeficiencies (PID), the EuroFlow consortium decided to develop a PID orientation and screening tube that facilitates fast, standardized, and validated immunophenotypic diagnosis of lymphoid PID, and allows full exchange of data between centers. Our aim was to develop a tool that would be universal for all lymphoid PIDs and offer high sensitivity to identify a lymphoid PID (without a need for specificity to diagnose particular PID) and to guide and prioritize further diagnostic modalities and clinical management. The tube composition has been defined in a stepwise manner through several cycles of design-testing-evaluation-redesign in a multicenter setting. Equally important appeared to be the standardized pre-analytical procedures (sample preparation and instrument setup), analytical procedures (immunostaining and data acquisition), the software analysis (a multidimensional view based on a reference database in Infinicyt software), and data interpretation. This standardized EuroFlow concept has been tested on 250 healthy controls and 99 PID patients with defined genetic defects. In addition, an application of new EuroFlow software tools with multidimensional pattern recognition was designed with inclusion of maturation pathways in multidimensional patterns (APS plots). The major advantage of the EuroFlow approach is that data can be fully exchanged between different laboratories in any country of the world, which is especially of interest for the PID field, with generally low numbers of cases per center.

Sciaenops ocellatus has a long history in aquaculture and many difficulties associated with its commercial culture have been addressed and successfully resolved; nevertheless, further research in lipid nutrition could address more comprehensive questions on the way these nutrients are utilized. The purpose of this study was to evaluate S. ocellatus growth and lipase gene expression in response to increasing dietary lipid supplementation. Four experimental diets were formulated to provide 3, 10, 16, or 23% lipid using menhaden fish oil. Twenty juveniles (mean initial weight 2.3 ± 0.1 g) were stocked per aquaria in a recirculating system; each diet was assigned to three aquaria and fed to fish for 6 weeks. At the end of the study, fish fed 3% of dietary lipid were significantly (P < 0.0001) smaller and showed significantly lower feed efficiency, condition factor, hepatosomatic index, and intraperitoneal fat than fish fed the other diets, but no differences were observed among fish fed 10, 16, or 23% lipid. A straight broken-line regression model for thermal growth coefficient provided an estimated value of 9.4% of dietary lipid as the optimal inclusion level. The bile salt-dependent lipase (BSDL) of red drum was 80.3 kDa. Relative gene expression of BSDL was significantly higher (P = 0.0007) in fish fed 10% lipid, with no differences among the other dietary treatments. Results provided could help monitor the metabolic status of farmed fish and contribute to optimize diet formulations based on maximum gene expression of BSDL for supplementation of dietary lipid.

Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated g ene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM., (© 2018 by The American Society of Hematology.)

Subjects studied Deese-Roediger-McDermott semantic-associate lists and took a recognition test. The makeup and number of test probes were manipulated. In Experiments 1 and 2A, one of three or all three distractors were semantically related to the list theme. In Experiment 2B, 6 or 30 related probes were used at test. Results showed that semantically related distractors and a longer list of test words both had a beneficial effect on the accurate discrimination of the prototype lures from the studied semantic associates and on the discrimination of studied from unstudied prototype words. These findings are inconsistent with predictions of memory interference and activation theories. We propose that the counterintuitive findings can be explained by the notion of old/new recognition as categorization learning and that relatedness and a larger number of test probes provide more accurate information about the prototype lure as a distractor, thereby improving its classification as a distractor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

How much of the Deese-Roediger-McDermott (DRM) false memory is attributable to decision criterion is so far a controversial issue. Previous studies typically used explicit warnings against accepting the critical lure to investigate this issue. The assumption is that if the false memory results from using a liberally biased criterion, it should be greatly reduced or eliminated by an explicit warning against accepting the critical lure. Results showed that warning was generally ineffective. We asked the question of whether subjects can substantially reduce false recognition without being warned when the test forces them to make a distinction between true and false memories. Using a two-alternative forced choice in which criterion plays a relatively smaller role, we showed that subjects could indeed greatly reduce the rate of false recognition. However, when the forced-choice restriction was removed from the two-item choice test, the rate of false recognition rebounded to that of the hit for studied list words, indicating the role of criterion in false recognition.

Background: Despite dramatic advances in cancer treatment that lead to long-term survival, there is an increasing number of patients presenting with clinical manifestations of cerebral metastasis in breast cancer, for whom only palliative treatment options exist., Objective: The present review based on researches aims to provide identification of recent patens of breast cancer brain metastasis that may have application in improving cancer treatment., Methods: Recent patents regarding the breast cancer brain metastasis were obtained from USPTO patent databases, Esp@cenet, Patentscope and Patent Inspiration®., Results: A total of 55 patent documents and 35 drug targets were recovered. Of these, a total of 45 patents and 10 patents were biotech drugs and chemical drugs, respectively. Among the target drugs analyzed were neurotrophin-3, protocadherin 7, CXCR4, PTEN, GABA receptor 3, L1CAM, PI3K-Akt / mTOR, VEGFR2, Claudin-5, Occludin, and NKG2A, among others., Conclusion: In this study, we found 35 drug targets for metastasis to the brain in breast cancer, with 60% of them including only one patent, which establishes that this area of research is very recent, and that these targets have recently been linked to metastasis to the brain. On the other hand, 19 drug targets, among them VEGF, VEGFR2, CXCL12, and CXCR4, have been addressed for the first time until 6 years ago, confirming that the development of drugs for brain metastasis in breast cancer is an incipient area, but with interesting potential. Interestingly, the stage of inside the brain, was the stage with the lowest amount of drug targets, which places it as a priority for research and drug development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Although consensus guidelines have been proposed in 2010 for the diagnostic screening of paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry (FCM), so far no study has investigated the efficiency of such medical indications in multicentric vs. reference laboratory settings., Methods: Here we evaluate the efficiency of consensus medical indications for PNH testing in 3,938 peripheral blood samples submitted to FCM testing in 24 laboratories in Spain and one reference center in Brazil., Results: Overall, diagnostic screening based on consensus medical indications was highly efficient (14% of PNH + samples) both in the multicenter setting in Spain (10%) and the reference laboratory in Brazil (16%). The highest frequency of PNH + cases was observed among patients screened because of bone marrow (BM) failure syndrome (33%), particularly among those with aplastic anemia (AA; 45%) and to a less extent also a myelodysplastic syndrome (MDS; 10%). Among the other individuals studied, the most efficient medical indications for PNH screening included: hemolytic anemia (19%), hemoglobinuria (48%) and unexplained cytopenias (9%). In contrast, only a minor fraction of the patients who had been submitted for PNH testing because of unexplained thrombosis in the absence of cytopenia, were positive (0.4%)., Conclusions: In summary, our results demonstrate that the current medical indications for PNH screening by FCM are highly efficient, although improved screening algorithms are needed for patients presenting with thrombosis and normal blood cell counts. © 2016 International Clinical Cytometry Society., (© 2016 International Clinical Cytometry Society.)

Pediatric posterior fossa tumor (PFT) survivors who have been treated with cranial radiation therapy often suffer from cognitive impairments that might relate to IQ decline. Radiotherapy (RT) distinctly affects brain regions involved in different cognitive functions. However, the relative contribution of regional irradiation to the different cognitive impairments still remains unclear. We investigated the relationships between the changes in different cognitive scores and radiation dose distribution in 30 children treated for a PFT. Our exploratory analysis was based on a principal component analysis (PCA) and an ordinary least square regression approach. The use of a PCA was an innovative way to cluster correlated irradiated regions due to similar radiation therapy protocols across patients. Our results suggest an association between working memory decline and a high dose (equivalent uniform dose, EUD) delivered to the orbitofrontal regions, whereas the decline of processing speed seemed more related to EUD in the temporal lobes and posterior fossa. To identify regional effects of RT on cognitive functions may help to propose a rehabilitation program adapted to the risk of cognitive impairment.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease resulting from variants in the WAS gene, characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Despite the fact that WAS is traditionally differentiated from immune thrombocytopenia (ITP) by small size of WAS platelets, in practice, microthrombocytopenia may occasionally not be present, and in certain cases, WAS patients exhibit some parallelism to ITP patients. We characterized one patient presenting with the classic form of the disease but increased mean platelet volume. Molecular studies revealed a novel hemizygous 1-bp deletion in WAS gene, c.802delC, leading to a frameshift and stop codon at amino acid 308 (p.Arg268Glyfs*40). Next-generation sequencing of a total of 70 additional genes known to harbor variants implicated in inherited platelet disorders did not identify additional defects. The pathogenesis of macrothrombocytopenia in this case is not known, but probably the coexistence of a still unidentified additional genetic variant might be involved.

Background: Data mining publications and patent data can provide decision support for scientists, inventors and industry in the field of cancer research., Objective: The main objective of this article it to identify trends of research and patent generation productivity originating from Latin American countries in the field of cancer., Method: Publications were collected from the Scopus, Web of Science, PubMed database; and patents were collected from Latipat Espacenet databases. Data from January 1, 2000 until December 31, 2014 were searched for documents with specific words in cancer as a ''topic'' and a list of 20 Latin American countries as affiliation country., Results: A total of 12,989 items published and 244 patent applications including "cancer" were retrieved. Brazil, Mexico, Argentina, Chile and Peru were highest contributors in cancer research, while Brazil, Mexico, Cuba and Argentina were highest contributors in cancer patent applications., Conclusion: The analysis of the data from this study provides an overview of research and patent activity in Latin America in the cancer field, which can be useful to help health policy makers and people in academia to shape up cancer research in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)