Pharmacokinetics and safety of LEAD-452, an EGFR-specific 4-1BB-agonistic trimerbody in non-human primates.

LEAD-452 is a humanized bispecific EGFR-targeted 4-1BB-agonistic trimerbody with a unique trimeric configuration compared to other 4-1BB-specific antibodies that are currently in development. Indeed, enhanced tumor-specific costimulation and very remarkable safety and efficacy profiles have been observed in mouse models. Here, we conducted for the first time a preclinical pharmacokinetic and toxicity study in non-human primates (NHP) (Macaca fascicularis). LEAD-452 exhibits comparable binding affinity for human and macaque targets, indicating its pharmacological significance for safety testing across species. The NHP were administered LEAD-452 in a series of ascending doses, ranging from 0.1 mg/kg to 10 mg/kg, and repeated doses up to 20 mg/kg. The administration of LEAD-452 was found to be clinically well tolerated, with no major related adverse effects observed. Furthermore, there have been no reported cases of liver toxicity, thrombocytopenia, and neutropenia, which are commonly associated with treatments using conventional anti-4-1BB IgG-based antibodies. In addition, neither IgM nor IgG-based anti-drug antibodies were detected in serum samples from NHP during the study, regardless of the dose of LEAD-452 administered. These results support the clinical development of LEAD-452 for the treatment of solid tumors.

Acute calcareous corneal degeneration in a patient with chronic graft-versus-host disease.

Objective: To describe acute calcareous corneal degeneration as a complication of chronic graft-versus-host disease. Materials and methods: Clinical case and review of the literature. Results: We presented a case of bilateral acute calcareous corneal degeneration in a patient with chronic graft-versus-host disease. Conclusions: Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of bone marrow transplantation patients, the most frequent ocular complication being keratoconjunctivitis sicca (KCS). Calcareous corneal degeneration is a type of calcium deposition that can be secondary to chronic ocular inflammation or dry eye, but there are few cases reported of acute calcareous corneal degeneration and recurrent perforation in cGVHD. Abbreviations: GVHD = Chronic graft-versus-host disease, aGVHD = Acute graft-versus-host disease, cGVHD = Chronic graft-versus-host disease, KCS = Keratoconjunctivitis sicca, PKP = Penetrating keratoplasty, AMT = Amniotic membrane transplantation, PRGF = Plasma rich in growth factors, OD = Right eye, OS = Left eye.

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-ß and PD-L1 enhances antitumor responses.

T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-ß play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-ß inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-ß, termed AxF (scFv)2, under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv)2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv)2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-ß by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression.

Novel Titanocene Y derivative with albumin affinity exhibits improved anticancer activity against platinum resistant cells.

The antitumor activity of Ti(IV)-based compounds put them in the spotlight for cancer treatment in the past, but their lack of stability in vivo due to a high rate of hydrolysis has hindered their development as antitumor drugs. As a possible solution for this problem, we have reported a synthesis strategy through which we combined a titanocene fragment, a tridentate ligand, and a long aliphatic chain. This strategy allowed us to generate a titanium compound (Myr-Ti) capable of interacting with albumin, highly stable in water and with cytotoxic activity in tumor cells[1]. Following a similar strategy, now we report the synthesis of a new compound (Myr-TiY) derived from titanocene Y that shows antitumoral activity in a cisplatin resistant model with a 50% inhibitory concentration (IC50) of 41-76 µM. This new compound shows high stability and a strong interaction with human serum albumin. Myr-TiY has a significant antiproliferative and proapoptotic effect on the tested cancer cells and shows potential tumor selectivity when assayed in non-tumor human epithelial cells being more selective (1.3-3.8 times) for tumor cells than cisplatin. These results lead us to think that the described synthesis strategy could be useful to generate compounds for the treatment of both cisplatin-sensitive and cisplatin-resistant cancers.

Lived experiences of mental health nurses who care for clients who are parents: An approximation of Tronto's definition of care.

WHAT IS KNOWN ON THE SUBJECT: Adult psychiatric services typically focus on the mental health needs of the client but they do not support his or her parenting role. Many authors highlight the importance of a non-judgmental approach when providing support and care to clients with mental illness who are parents. Assessments frequently focus on the negative aspects while the strengths of these families were often overlooked. There is a lack of scientific literature exploring nurses' experiences when caring for parents with mental illness and their families. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE: Trust is the basis that helps clients to be open to receiving care and answering parenting-related questions. Therefore, without adequate professional-client trust, some care and interventions addressed to parents with mental illness could be poorly received by the client. Tronto's phases of care facilitated the collection of data and exploration of mental health nurses' experiences of care. WHAT ARE THE IMPLICATIONS FOR PRACTICE: Mental health nurses should be aware of the potential needs of these families, as described in the scientific literature, so they can include them in their assessments. They also should consider the need to individualize each care since each situation of a family with parental mental illness is unique. Mental health nurses must take the person's environment into account (family, social and political aspects and different forms of stigma) since all these factors may influence how parents with mental illness receive and provide care. ABSTRACT: Introduction Many authors highlight the importance of a non-judgmental approach when providing care to parents with mental illness. However, assessments frequently focus on the negative aspects while the strengths of such families were often overlooked. Aim To explore the lived experiences of mental health nurses who care for clients who are parents. Method We conducted a qualitative phenomenological study. The main data collection technique was in-depth interviews. Data were analysed according to Colaizzi model, subsequently, the main categories that arised were compared and related to the five phases of Tronto's care. Results The main categories identified from the analysis of the interviews were: (1) individualized care, (2) continuity of care, (3) psychoeducation and counselling, (4) trust and (5) context of the client. Discussion Trust is the basis that helps parents with mental illness to be open to receiving care and answering parenting-related questions. Without trust, some interventions could be poorly received by the client. Implications for Practice Mental health nurses should be aware of the potential needs of these families, so they can include them in their assessments. They also should consider the need to individualize each care since each situation of a family with parental mental illness is unique.

Sperm Toolbox-A selection of small molecules to study human spermatozoa.

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2.

Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT , are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT , the bispecific trimerbody TNT DNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNT DNGR-1, but not TNT , protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.

Nanobody-Based EGFR-Targeting Immunotoxins for Colorectal Cancer Treatment.

Immunotoxins (ITXs) are chimeric molecules that combine the specificity of a targeting domain, usually derived from an antibody, and the cytotoxic potency of a toxin, leading to the selective death of tumor cells. However, several issues must be addressed and optimized in order to use ITXs as therapeutic tools, such as the selection of a suitable tumor-associated antigen (TAA), high tumor penetration and retention, low kidney elimination, or low immunogenicity of foreign proteins. To this end, we produced and characterized several ITX designs, using a nanobody against EGFR (VHH 7D12) as the targeting domain. First, we generated a nanoITX, combining VHH 7D12 and the fungal ribotoxin α-sarcin (αS) as the toxic moiety (VHHEGFRαS). Then, we incorporated a trimerization domain (TIEXVIII) into the construct, obtaining a trimeric nanoITX (TriVHHEGFRαS). Finally, we designed and characterized a bispecific ITX, combining the VHH 7D12 and the scFv against GPA33 as targeting domains, and a deimmunized (DI) variant of α-sarcin (BsITXαSDI). The results confirm the therapeutic potential of α-sarcin-based nanoITXs. The incorporation of nanobodies as target domains improves their therapeutic use due to their lower molecular size and binding features. The enhanced avidity and toxic load in the trimeric nanoITX and the combination of two different target domains in the bispecific nanoITX allow for increased antitumor effectiveness.

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies.

Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and another three molecules in regulatory review. T cell engagers will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens. The field is thriving, with a plethora of different formats and targets, and around 100 bispecific T cell engagers more are already in clinical trials. Bispecific NK cell engagers are also in early-stage clinical studies and may offer similar efficacy with milder side effects. Trispecific antibodies (engaging either T cell or NK cell receptors) raise the game even further with a third binding moiety, which allows either the targeting of an additional tumor-associated antigen to increase specificity and avoid immune escape or the targeting of additional costimulatory receptors on the immune cell to improve its effector functions. Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies.

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening.

Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome ( https://clinicaltrials.gov , ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.

A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response.

Immune checkpoint blockade (ICB) with antibodies has shown durable clinical responses in a wide range of cancer types, but the overall response rate is still limited. Other effective therapeutic modalities to increase the ICB response rates are urgently needed. New bispecific antibody (bsAb) formats combining the ICB effect and a direct action on cancer cells could improve the efficacy of current immunotherapies. Here, we report the development of a PD-L1/EGFR symmetric bsAb by fusing a dual-targeting tandem trimmer body with the human IgG1 hinge and Fc regions. The bsAb was characterized in vitro and the antitumor efficacy was evaluated in humanized mice bearing xenografts of aggressive triple-negative breast cancer and lung cancer. The IgG-like hexavalent bsAb, designated IgTT-1E, was able to simultaneously bind both EGFR and PD-L1 antigens, inhibit EGF-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of IgTT-1E in two different humanized mouse models were observed, where tumor growth control was associated with a significantly increased proportion of CD8+ T cells. These results support the development of IgTT-1E for the treatment of EGFR+ cancers.

Reflective based learning for nursing ethical competency during clinical practices.

BACKGROUND: A combination of theoretical and practical approaches is required to learn and acquire ethical competencies in caring. Occasionally, reflection on practical action differs from theoretical learning. In the context of reflective learning, issues such as ethical values can be discussed since they evoke conflict among nursing students. AIM: To identify ethical conflicts encountered by nursing students during clinical placements and to determine their cooperation strategies. RESEARCH DESIGN: Qualitative study with a content analysis according to Elo and Kinglas framework. PARTICIPANTS AND RESEARCH CONTEXT: Students enrolled in a nursing program at a Spanish university aged between 22 and 35, mainly women. METHODOLOGY: The study includes 134 ethical reflections from nursing students in the last year of the nursing program, written during their clinical practices in a variety of learning environments. The research team analyzed the reflections using an inductive content analysis method. ETHICAL CONSIDERATIONS: Ethical permission was obtained by the management center according to Law 3/2028, and all the participants accepted to participate through the informed consent form. FINDINGS: Three main categories emerged from the analysis of the ethical reflections: (1) evaluation of professional performance and patient care; (2) the student as the protagonist of the dilemma; (3) student coping. Student dilemmas and concerns are related to ignorance, student-patient communication, mistakes made and self-confidence. Some situations conflict with the autonomy of patients and their rights, and can contribute to stressful situations for patients. Stress factors include hospital routines, which the patient cannot modify, and asymmetric relationships with staff, which encourage passivity. CONCLUSION: All ethical problems detected by the students begin with the professional-patient relationship, including issues related to bad news, errors or malpractice. Reflection on the ethical values of nursing, both in the classroom and in clinical practices, allows students to develop a greater ethical awareness of care, enhancing their decision-making skills in ethical dilemmas.

Myositis autoantibodies detected by line blot immunoassay: clinical associations and correlation with antibody signal intensity.

The aim of this study is to assess the relationship between myositis specific (MSA) and myositis associated (MAA) antibodies and diagnosis (including idiopathic inflammatory myopathies [IIM] and other systemic autoimmune diseases [SAID]), and to explore the impact of antibody signal intensity in diagnostic accuracy. We retrospectively reviewed all the serum samples obtained from patients tested for MSA/MAA by line immunoassay (LIA) between 01/01/2018 and 31/12/2020 in Ramón y Cajal University Hospital (Spain). Clinical true positive (CTP) MSAs and MAAs were defined as those patients with IIM or SAID with phenotypes expected of that MSA/MAA. Patients who did not have a phenotype compatible with that antibody were classified as clinical false positive (CFP). One hundred and thirty positive samples were analysed. Forty-six patients (33.38%) were classified as IIM, forty-two (32.3%) as SAID and forty-two (32.3%) as non-IIM/SAID. Among these 130 patients, 164 MSA/MAA were detected. Eighty-five (51.8%) positive MSA/MAA were classified as CTP, and seventy-nine (48.2%) as CFP. Strongly positive antibodies were more frequently CTP (35/47, 74.5%) than weak positives (54/68, 36.8%), (p ˂ 0.001). Antibodies classified as CTP had a higher signal intensity than CFP (36.77 AU vs 20.00 AU, CI95% 7.79-22.09, p ˂ 0.001). The probability of a CFP was associated to negative ANA, low ANA titer, and multiple positive MSA/MAA (p Ë‚ 0.001). In this study, we confirmed that CFP results using LIA are frequent, and are associated with low signal intensity MSA/MAA, negative ANA, lower titer ANA, and with multiple positive samples.

When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy.

Despite the clinical success of the first bispecific antibody approved by the FDA against B cell malignancies (blinatumomab), many obstacles remain such as dosing, treatment resistance, and modest efficacy in solid tumors. To overcome these limitations, considerable efforts have been dedicated to the development of multispecific antibodies, opening up new avenues to address both the complex biology of cancer and the onset of anti-tumoral immune responses. Simultaneous targeting of two tumor-associated antigens is presumed to enhance cancer cell selectivity and reduce immune escape. Co-engagement of CD3, along with agonists of co-stimulatory molecules or antagonists of co-inhibitory immune checkpoint receptors in a single molecule, may revert T cell exhaustion. Similarly, targeting of two activating receptors in NK cells may improve their cytotoxic potency. And these are only examples of the potential of antibody-based molecular entities engaging three (or more) relevant targets. From the perspective of health care costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies. Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.

The presence of activating IgG Fc receptors in macrophages aggravates the development of experimental abdominal aortic aneurysm. / La presencia de receptores Fc de IgG activadores en macrófagos agrava el desarrollo de aneurisma aórtico abdominal experimental.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA. METHODS: In the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, mouse macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes. RESULTS: Macrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNF-α and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by immune complexes in macrophages. CONCLUSIONS: Activation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment.

Business intelligence for the visualization and data analysis of Telepharmacy activity indicators in a hospital pharmacy service scorecard.

OBJECTIVE: The consolidation of Telepharmacy during the COVID-19 pandemic  has raised the need for managing large volumes of real-time activity data  through data analysis. The aim of this project was to design a dynamic, user- friendly, customizable scorecard in a hospital pharmacy service for the  visualization and analysis of Telepharmacy activity indicators through the use  of advanced business intelligence technology. METHOD: The software tool was developed by a multidisciplinary team between  April and May 2021, driven from the hospital pharmacy service. Once the Telepharmacy indicators of interest were established,  datasets were extracted from raw databases (administrative databases,  Telepharmacy database, outpatient dispensing software, drug catalogues)  through data analysis. The different data sources were integrated in a  scorecard using PowerBI®. The criteria for processing missing and duplicated  data were defined, and data pre-processing, normalization and transformation were performed. Once the pilot scorecard was validated by  different profiles of users, the structure was designed for the panels to  automatically update as databases were updated. RESULTS: Design and implementation of a scorecard of Telepharmacy activity:  general descriptive panel (demographic profile of patients, count and delivery  conditions, program and medical service); geolocation of destination;  pharmacological profile; relative analysis of patients involved in the  Telepharmacy program with respect to the total of outpatients. In the last  updating as of January 2022, data from 16,000 dispensations to more than  4,000 patients had been collected. This means that 21.93% of outpatients had  benefited at some time point from the Telepharmacy service. Filters enable the  visualization of timeline progress and patient characterization, and  measure Telepharmacy activity by program. CONCLUSIONS: The processing of large Telemedicine datasets from various  sources through Business Intelligence in a hospital pharmacy service makes it  possible to synthesize information, generate customized reports, and visualize  information in a dynamic and attractive format. The application of this new  technology will help us improve strategic clinical and management decision  making.

OBJETIVO: La consolidación de la Telefarmacia en el contexto de la pandemia por la COVID-19 exige manejar a tiempo real un gran volumen de datos de actividad mediante análisis de datos. El objetivo de este trabajo fue diseñar un cuadro de mando ágil, personalizable y dinámico para la visualización y análisis de indicadores de actividad en Telefarmacia en un servicio de farmacia de hospital, mediante el empleo de herramientas  avanzadas de inteligencia empresarial (business intelligence).Método: Un equipo de trabajo multidisciplinar desarrolló una herramienta de  software entre abril y mayo de 2021 impulsado desde el servicio de farmacia  de hospital. Una vez consensuados los indicadores de interés en Telefarmacia,  se extrajeron los datos a partir de bases de datos brutas (base de datos de  Telefarmacia, programa de dispensación de pacientes externos, bases de datos  administrativas, catálogos de fármacos) mediante análisis de datos. La  integración de las diferentes fuentes de datos en el cuadro de mando se realizó mediante PowerBI®. Se definió el manejo de los datos perdidos y duplicados y  se aplicó preprocesamiento, normalización y transformación de los datos. Una  vez  validado el piloto por diferentes tipos de usuarios, se diseñó la estructura para actualización automática de los paneles con las sucesivas actualizaciones de las fuentes de datos. RESULTADOS: Diseño e implementación de un cuadro de mando de la actividad  en Telefarmacia: panel descriptivo general (perfil demográfico de pacientes,  recuento y condiciones de envíos, programa y servicio médico); geolocalización  de destino; perfil farmacológico; análisis relativo de los  pacientes beneficiarios de Telefarmacia respecto del total de pacientes  externos. En el último corte, a enero de 2022, se habían incluido datos de  16.000 dispensaciones con entrega informada a más de 4.000 pacientes, lo  que supone que el 21,93% de los pacientes externos han estado en algún momento en el programa de Telefarmacia. La aplicación de filtros permite  visualizar la evolución temporal, caracterizar grupos de pacientes y  dimensionar la actividad por programas. CONCLUSIONES: El procesamiento de paquetes de datos de Telemedicina, de  gran volumen, difícil manejo y procedentes de diversas fuentes relativas a Telefarmacia mediante inteligencia empresarial, en un servicio de farmacia  de hospital, permite sintetizar la información y proporcionar informes  personalizados y visualizaciones dinámicas y atractivas. La aplicación de estas  nuevas tecnologías puede ayudarnos a mejorar la toma de decisiones  estratégicas, tanto clínicas como de gestión.

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation.

The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.

Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity.

Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies (mAbs) has shown anti-tumor activity in human trials, but can be associated with significant off-tumor toxicities involving FcγR interactions. Here, we introduce albumin-fused mouse and human bispecific antibodies with clinically favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. These Fc-free 4-1BB agonists consist of an EGFR-specific VHH antibody, a 4-1BB-specific scFv, and a human albumin sequence engineered for high FcRn binding connected in tandem (LiTCo-Albu). We demonstrate in vitro cognate target engagement, EGFR-specific costimulatory activity, and FcRn-driven cellular recycling similar to non-fused FcRn high-binding albumin. The mouse LiTCo-Albu exhibited a prolonged circulatory half-life and in vivo tumor inhibition, with no indication of 4-1BB mAb-associated toxicity. Furthermore, we show a greater therapeutic effect when used in combination with PD-1-blocking mAbs. These findings demonstrate the feasibility of tumor-specific LiTCo-Albu antibodies for safe and effective costimulatory strategies in cancer immunotherapy.