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Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.
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Desamino Arginina Vasopresina/administración & dosificación , Hemorragia/tratamiento farmacológico , Hemostáticos/administración & dosificación , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Desamino Arginina Vasopresina/efectos adversos , Desamino Arginina Vasopresina/farmacocinética , Hemorragia/metabolismo , Hemostáticos/efectos adversos , Hemostáticos/farmacocinética , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias del Recto/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Desmopressin (DDAVP), a synthetic peptide analog of vasopressin, is a safe antidiuretic and hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor. It is known that DDAVP can inhibit progression of residual metastatic cells and also improves chemotherapy effects in preclinical breast cancer models. Here, we explored the effects of DDAVP on tumor angiogenesis using the aggressive F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of the compound (2 µg/kg) markedly decreased vascularization of growing subcutaneous tumors, as well as inhibited the early angiogenic response around intradermal inoculation sites. In vitro studies confirmed the presence of vasopressin V2 receptors on F3II cells and a modest antiproliferative activity of DDAVP. Interestingly, conditioned media from F3II monolayers exposed to low doses of DDAVP (100 nM) significantly increased angiostatin formation in the presence of purified plasminogen. Such increase was associated with an enhancement of tumor-secreted urokinase-type plasminogen activator, suggesting the proteolytic conversion of plasminogen to angiostatin in vitro. Similar results were observed with the MCF-7 human breast carcinoma, a cell line known to express the vasopressin V2 receptor. No direct effects of DDAVP (100 nM1 µM) were found on capillary-like tube formation by human microvascular cells HMVEC. Our studies showed that DDAVP induces anti-angiogenic effects that may be associated with the generation of angiostatin by tumor cells. Further preclinical studies with DDAVP and other vasopressin analogs are warranted to determine their potential in cancer management.
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Inhibidores de la Angiogénesis/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Desamino Arginina Vasopresina/farmacología , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Angiostatinas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desamino Arginina Vasopresina/administración & dosificación , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Ratones , Proteolisis/efectos de los fármacos , Receptores de Vasopresinas/metabolismo , Carga Tumoral/efectos de los fármacosRESUMEN
The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.g. MAPK, CDK, or GSK3) and thus regulates cell proliferation and cell survival. For these reasons, PIN1 inhibitors are interesting since they may have therapeutic implications for cancer. Several authors have already reported that the non-structural point mutation Trp34Ala prevents PIN1 from interacting with its downstream effector proteins. In this work, we characterized PIN1 structurally, intending to explore new inhibition targets for the rational design of pharmacological activity compounds. Through a conformational diversity analysis of PIN1, we identified and characterized a highly specific druggable pocket around the residue Trp34. This pocket was used in a high-throughput docking screening of 450,000 drug-like compounds, and the top 10 were selected for re-docking studies on the previously used conformers. Finally, we evaluated the binding of each compound by thermal shift assay and found four molecules with a high affinity for PIN1 and potential inhibitory activity. Through this strategy, we achieved novel drug candidates with the ability to interfere with the phosphorylation-dependent actions of PIN1 and with potential applications in the treatment of cancer.Communicated by Ramaswamy H. Sarma.
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Antineoplásicos , Inhibidores Enzimáticos , Peptidilprolil Isomerasa de Interacción con NIMA , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacología , Detección Precoz del Cáncer , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosforilación , Prolina/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to assess the immune response after a third dose of SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA) with undetectable antibody titers after the primary regimen of 2 doses. METHODS: Patients with RA with no seroconversion after 2 doses of SARS-CoV-2 vaccine and who received a third dose of either an mRNA or vector-based vaccine were included. Anti-SARS-CoV-2 IgG antibodies, neutralizing activity, and T cell responses were assessed after the third dose. RESULTS: A total of 21 nonresponder patients were included. At the time of vaccination, 29% were receiving glucocorticoids and 85% biologic disease-modifying antirheumatic drugs (including 6 taking abatacept [ABA] and 4 taking rituximab [RTX]). The majority (95%) received the BNT162b2 vaccine and only one of them received the ChAdOx1 nCoV-19 vaccine. After the third dose, 91% of the patients presented detectable anti-SARS-CoV-2 IgG and 76% showed neutralizing activity. Compared to other treatments, ABA and RTX were associated with the absence of neutralizing activity in 4 out of 5 (80%) patients and lower titers of neutralizing antibodies (median 3, IQR 0-20 vs 8, IQR 4-128; P = 0.20). Specific T cell response was detected in 41% of all patients after the second dose, increasing to 71% after the third dose. The use of ABA was associated with a lower frequency of T cell response (33% vs 87%, P = 0.03). CONCLUSION: In this RA cohort, 91% of patients who failed to seroconvert after 2 doses of SARS-CoV-2 vaccine presented detectable anti-SARS-CoV-2 IgG after a third dose. The use of ABA was associated with a lower frequency of specific T cell response.
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Artritis Reumatoide , COVID-19 , Vacunas , Humanos , Vacunas contra la COVID-19 , ChAdOx1 nCoV-19 , Vacuna BNT162 , COVID-19/prevención & control , SARS-CoV-2 , Artritis Reumatoide/tratamiento farmacológico , Abatacept , Inmunoglobulina G , Vacunación , Rituximab , Anticuerpos Antivirales , InmunidadRESUMEN
Heterologous vaccination against coronavirus disease 2019 (COVID-19) provides a rational strategy to rapidly increase vaccination coverage in many regions of the world. Although data regarding messenger RNA (mRNA) and ChAdOx1 vaccine combinations are available, there is limited information about the combination of these platforms with other vaccines widely used in developing countries, such as BBIBP-CorV and Sputnik V. Here, we assess the immunogenicity and reactogenicity of 15 vaccine combinations in 1,314 participants. We evaluate immunoglobulin G (IgG) anti-spike response and virus neutralizing titers and observe that a number of heterologous vaccine combinations are equivalent or superior to homologous schemes. For all cohorts in this study, the highest antibody response is induced by mRNA-1273 as the second dose. No serious adverse events are detected in any of the schedules analyzed. Our observations provide rational support for the use of different vaccine combinations to achieve wide vaccine coverage in the shortest possible time.
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COVID-19 , Vacunas Virales , Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Antivirales , COVID-19/prevención & control , Humanos , Inmunización , ARN Mensajero/genética , SARS-CoV-2 , VacunaciónRESUMEN
BACKGROUND: A first-dose of various vaccines provides acceptable protection against infections by SARS-CoV-2 and evolution to the most severe forms of COVID-19. The recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), was proven efficacious but information about effectiveness in the real-world setting is lacking. The aim of our study was to investigate the association between the rollout of the first component (rAd26) of Gam-COVID-Vac and PCR-positive tests, hospitalisations and deaths. METHODS: We conducted a retrospective cohort study which analyzed individuals aged 60-79 who self-registered in the online vaccination system of the Province of Buenos Aires, Argentina, from December 29, 2020 to March 21, 2021. Exclusion criteria were having a previous positive RT-PCR or antigen tests for SARS-CoV-2, having received other vaccines, or two doses of any vaccine.Proportions of new laboratory-confirmed SARS-CoV-2 infections, hospitalisations and deaths until 83 days of vaccination were compared between vaccinated and unvaccinated subjects. Vaccine effectiveness for the three outcomes was calculated as (1-OR) × 100. Kaplan-Meier cumulative incidence curves were constructed. FINDINGS: During the study period 415995 registered subjects received the first component of Gam-COVID-Vac; 40387 belonged to the 60-79 age group, and were compared to 38978 unvaccinated. Vaccine effectiveness for preventing laboratory-confirmed infections was 78â¢6% [CI95% 74·8 - 81·7]; and for reducing hospitalizations and deaths was, respectively, 87·6% [CI95% 80·3 - 92·2] and 84·8% [CI95% 75·0 - 90·7]. Effectiveness was high across all subgroups. INTERPRETATION: Similarly to other vaccines, the administration of one dose of Gam-COVID-Vac was effective for a wide range of COVID-19-related outcomes. FUNDING: This study did not receive any funding.
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Massive vaccination offers great promise for halting the global COVID-19 pandemic. However, the limited supply and uneven vaccine distribution create an urgent need to optimize vaccination strategies. We evaluate SARS-CoV-2-specific antibody responses after Sputnik V vaccination of healthcare workers in Argentina, measuring IgG anti-spike titers and neutralizing capacity after one and two doses in a cohort of naive or previously infected volunteers. By 21 days after receiving the first dose of the vaccine, 94% of naive participants develop spike-specific IgG antibodies. A single Sputnik V dose elicits higher antibody levels and virus-neutralizing capacity in previously infected individuals than in naive ones receiving the full two-dose schedule. The high seroconversion rate after a single dose in naive participants suggests a benefit of delaying administration of the second dose to increase the number of people vaccinated. The data presented provide information for guiding public health decisions in light of the current global health emergency.
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Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Argentina/epidemiología , COVID-19/inmunología , Chlorocebus aethiops , Células HEK293 , Personal de Salud , Humanos , Pandemias , SARS-CoV-2/patogenicidad , Seroconversión , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación , Vacunas , Células VeroRESUMEN
Since its discovery, arginine vasopressin (AVP) was subjected to several modifications with the aim of obtaining novel derivatives with increased potency and selectivity for biomedical use. Desmopressin (dDAVP) is a first generation synthetic analog of AVP with hemostatic and antimetastatic activity. dDAVP acts as a selective agonist of the arginine vasopressin type 2 receptor (AVPR2) present in microvascular endothelium and cancer cells. Considering its selective effects on AVPR2-expressing malignant and vascular tissue, and interesting antitumor profile, dDAVP was used as a lead compound for the development of novel peptide analogs with enhanced anticancer efficacy. After conducting different structure-activity relationship studies to determine key aminoacidic positions for its antitumor activity against AVPR2-expressing malignant cells, dDAVP was rationally modified and a wide panel of synthetic analogs with different sequence and structural modifications was assessed. As a result of this structure-based drug derivatization novel AVP analog [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine-8-d-arginine vasopressin) was selected as the most active candidate and further developed. [V4Q5]dDAVP was evaluated in highly aggressive and metastatic cancer preclinical models deploying enhanced cytostatic, antimetastatic and angiostatic effects in comparison to parental peptide dDAVP. In addition, novel compound demonstrated good tolerability as evaluated in several toxicological studies, and cooperative therapeutic effects after combination with standard-of-care chemotherapy. In summary, due to its ability to inhibit growth and tumor-associated angiogenesis, as well as impairing progression of metastatic disease, AVP analogs such as novel [V4Q5]dDAVP are promising compounds for further development as coadjuvant agents for the management of advance or recurrent cancers.
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Antineoplásicos/farmacología , Desamino Arginina Vasopresina/farmacología , Neoplasias/tratamiento farmacológico , Receptores de Vasopresinas/agonistas , Animales , Modelos Animales de Enfermedad , RatonesRESUMEN
PURPOSE: Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4 Q5 ]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of arginine vasopressin type 2 membrane receptor (AVPR2) present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. MATERIALS AND METHODS: Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. RESULTS: In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained intravenous treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-fluorouracil resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. CONCLUSION: The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging. RESULTS: suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.
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Inhibidores de la Angiogénesis/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Desamino Arginina Vasopresina/farmacología , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Desamino Arginina Vasopresina/análogos & derivados , Desamino Arginina Vasopresina/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The characterization of murine cell lines is of great importance in order to identify preclinical models that could resemble human diseases. Aberrant glycosylation includes the loss, excessive or novel expression of glycans and the appearance of truncated structures. MB49 and MB49-I are currently the only two murine cell lines available for the development of preclinical bladder cancer models. The glycans Lewis X (LeX), Sialyl lewis X (SLeX) and Sialyl Tn (STn) have previously been associated with aggressiveness, dissemination and poor prognosis in human bladder cancer, additionally N-glycolyl GM3 (NGcGM3) is a neo-antigen expressed in many types of tumors; however, to the best of our knowledge, its expression has not previously been assessed in this type of cancer. Taking into account the relevance of glycans in tumor biology and considering that they can act as targets of therapies and biomarkers, the present study evaluated the expression of LeX, SLeX, STn and NGcGM3 in MB49 and MB49-I cells, in different growth conditions such as monolayer cultures, three-dimensional multicellular spheroids and mouse heterotopic and orthotopic tumors. The expression of LeX was not detected in either cell line, whereas SLeX was expressed in monolayers, spheroids and orthotopic tumors of both cell lines. STn was only identified in MB49 monolayers and spheroids. There are no reports concerning the expression of NGcGM3 in human or murine bladder cancer. In our hands, MB49 and MB49-I expressed this ganglioside in all the growth conditions evaluated. The assessment of its expression in cancer cell lines and patient tumors is of great importance, considering the relevance of this ganglioside in tumor biology. The data obtained by the present study demonstrates that glycan expression may be substantially altered depending on the growth conditions, highlighting the importance of the characterization of murine cancer models. To the best of our knowledge, the present study is the first to examine the expression of cancer-associated glycans, in the two murine cell lines available for the development of preclinical studies in bladder cancer.
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AIM: Development of compounds with therapeutic application requires the interaction of different disciplines. Several tumors express vasopressin (AVP; arginine vasopressin) receptors with contrasting effects depending on receptor subtype. Desmopressin (dDAVP) is an AVP-selective analog with antiproliferative properties. In this work, an evolutionary approach and a rational strategy were applied in order to design novel AVP analogs. RESULTS: We designed two novel analogs; dDInotocin (dDINT, insect analog), and [V4Q5]dDAVP, and demonstrated the importance of the dDAVP conformational loop for its antiproliferative activity. [V4Q5] dDAVP showed major cytostatic effect on lung cancer cells than dDAVP and its cytostatic effect was abolished by V2R blockade. CONCLUSION: Combination of these strategies could provide the basis for future studies for the development of improved compounds with potential therapeutic applications.
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Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Vasopresinas/química , Vasopresinas/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Receptores de Vasopresinas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/metabolismoRESUMEN
Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that express neuropeptides as synaptophysin, chromogranin A (CgA), and specific neuronal enolase (NSE), among others. Vasopressin (AVP) is a neuropeptide with an endocrine, paracrine, and autocrine effect in normal and pathological tissues. AVP receptors are present in human lung, breast, pancreatic, colorectal, and gastrointestinal tumors. While AVP V1 receptors are associated with stimulation of cellular proliferation, AVP V2 receptor (V2r) is related to antiproliferative effects. Desmopressin (dDAVP) is a synthetic analog of AVP that acts as a selective agonist for the V2r, which shows antitumor properties in breast and colorectal cancer models. Recently, we developed a derivative of dDAVP named [V4Q5]dDAVP, which presents higher antitumor effects in a breast cancer model compared to the parental compound. The goal of present work was to explore the antitumor properties of the V2r agonist dDAVP and its novel analog [V4Q5]dDAVP on aggressive human lung (NCI-H82) and prostate cancer (PC-3) cell lines with neuroendocrine (NE) characteristics. We study the presence of specific NE markers (CgA and NSE) and V2r expression in NCI-H82 and PC-3. Both cell lines express high levels of NE markers NSE and CgA but then incubation with dDAVP diminished expression levels of both markers. DDAVP and [V4Q5]dDAVP significantly reduced proliferation, doubling time, and migration in both tumor cell cultures. [V4Q5]dDAVP analog showed a higher cytostatic effect than dDAVP, on cellular proliferation in the NCI-H82 cell line. Silencing of V2r using small interfering RNA significantly attenuated the inhibitory effects of [V4Q5]dDAVP on NCI-H82 cell proliferation. We, preliminarily, explored the in vivo effect of dDAVP and [V4Q5]dDAVP on NCI-H82 small cell lung cancer xenografts. Treated tumors (0.3 µg kg-1, thrice a week) grew slower in comparison to vehicle-treated animals. In this work, we demonstrated that the specific agonists of V2r, dDAVP, and [V4Q5]dDAVP displays antitumor capacity on different human models of lung and prostate cancers with NE features, showing their potential therapeutic benefits in the treatment of these aggressive tumors.
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[V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 µg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of the compound for the management of aggressive breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/prevención & control , Desamino Arginina Vasopresina/análogos & derivados , Neoplasias Pulmonares/prevención & control , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Desamino Arginina Vasopresina/farmacología , Quimioterapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica , Receptores de Vasopresinas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RESUMEN INTRODUCCIÓN : La vacunación en la provincia de Buenos Aires inició con personal de salud (PS). El objetivo de este trabajo es evaluar el impacto de la vacunación sobre la evolución de los casos de infección por SARS-CoV-2 en el PS, comparado con la de la población general (PG). MÉTODOS : Estudio obsewacional descriptivo de series temporales de casos confirmados de COVID-19, entre abril de 2020 y marzo de 2021. Se utilizó el sistema de información VacunatePBA y el SNVS. Se tomó el grado de inmunización a 14 días de la aplicación de la vacuna. RESULTADOS : A partir de septiembre de 2020, el número de casos disminuyó en el PS, en comparación con la PG. Para fines de febrero de 2021 estaba inmunizado con primera dosis (PD) el 42% del PS y con segunda dosis (SD) el 24%, mientras que en PG solo estaba inmunizado el 0,06% con PD y nadie SD. En marzo de 2021 mientras la cantidad de casos en PG (con 2% inmunizada) aumentó un 10% con respecto a febrero, en PS disminuyó un 35% (95% de esa población inmunizada). Esto indica una disminución significativa entre los nuevos casos de febrero y de marzo en PS (p <0,00001). DISCUSIÓN : A partir del inicio de la vacunación contra COVID-19 a finales de diciembre 2020, se muestra una disminución de casos nuevos de COVID-19 en PS. Este trabajo describe una disminución relativa de los casos en PS luego de la vacunación en la provincia de Buenos Aires y aporta los primeros datos del país sobre el impacto de las vacunas contra COVID-19.
ABSTRACT INTRODUCTION : The vaccination in the province of Buenos Aires has initiated with the health care workers (HCW). The present work aims to evaluate the impact of vaccination on the evolution of confirmed SARS- CoV2 cases in HCW compared to that of the general population (GP). METHODS : The study design is descriptive observational of series were developed confirmed cases, period April 2020 to March 2021. The Sistema Nacional de Vigilancia en Salud (SNVS), and VacunatePBA were used. The grade immunization was estimated at 14 days from the application of the first dose. RESULTS : As of September, the number of cases begins to decrease more sharply in HCW than in the general population. By February 2021, 42% of the HCW had been immunized with the first dose (FD) and 24% with the second dose (SD), while in GP only 0.06% had been immunized with FD and 0% of SD. In March, while the number of GP cases increased by 10% compared to February (only 2% immunized), HCW decreased by 35% (95% immunized). This indicates a significant decrease between the new cases of February and March in HCW (p-value <0.00001). DISCUSSION: Since the introduction of COVID-19 vaccines at the end of December in different countries, a decrease in new cases of COVID-19 in HCW has begun to be reported. The present work describes a relative decrease in HCW cases in a post-vaccination context in the province of Buenos Aires, providing the first data in the country on the impact of COVID-19 vaccines on HCW.
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INTRODUCCIÓN: La vacunación en la provincia de Buenos Aires inició con personal de salud (PS). El objetivo de este trabajo es evaluar el impacto de la vacunación sobre la evolución de los casos de infección por SARS-CoV-2 en el PS, comparado con la de la población general (PG). MÉTODOS: Estudio observacional descriptivo de series temporales de casos confirmados de COVID-19, entre abril de 2020 y marzo de 2021. Se utilizó el sistema de información VacunatePBA y el SNVS. Se tomó el grado de inmunización a 14 días de la aplicación de la vacuna. RESULTADOS: A partir de septiembre de 2020, el número de casos disminuyó en el PS, en comparación con la PG. Para fines de febrero de 2021 estaba inmunizado con primera dosis (PD) el 42% del PS y con segunda dosis (SD) el 24%, mientras que en PG solo estaba inmunizado el 0,06% con PD y nadie SD. En marzo de 2021 mientras la cantidad de casos en PG (con 2% inmunizada) aumentó un 10% con respecto a febrero, en PS disminuyó un 35% (95% de esa población inmunizada). Esto indica una disminución significativa entre los nuevos casos de febrero y de marzo en PS (p <0,00001). DISCUSIÓN: A partir del inicio de la vacunación contra COVID-19 a finales de diciembre 2020, se muestra una disminución de casos nuevos de COVID-19 en PS. Este trabajo describe una disminución relativa de los casos en PS luego de la vacunación en la provincia de Buenos Aires y aporta los primeros datos del país sobre el impacto de las vacunas contra COVID-19
Asunto(s)
Argentina , Vacunas , Personal de Salud , COVID-19 , InmunidadRESUMEN
INTRODUCCIÓN: La morbimortalidad por la enfermedad por el nuevo coronavirus (COVID-19) constituye un problema de salud pública en la Provincia de Buenos Aires y en el resto de Argentina. Las poblaciones con vulnerabilidad social están expuestas a riesgos de manera potenciada. OBJETIVO: Describir la evolución de los casos confirmados de COVID-19 en el Gran Buenos Aires, localizados en zonas con diferentes características sociales categorizadas por vulnerabilidad socioterritorial, desde el inicio de la pandemia hasta el 15 de julio de 2020. MÉTODOS: Estudio descriptivo de corte transversal. Las variables analizadas fueron sexo, edad, evolución de la enfermedad y domicilio categorizado por medio del índice de vulnerabilidad socioterritorial (IVST). RESULTADOS: La mayor cantidad de casos positivos para COVID-19 se encontró en el grupo etario de 20 a 59 años, y el 48% fueron mujeres. El 47% de los casos estudiados residían en zonas vulnerables. El 28% de los casos confirmados requirieron internación. Se internaron en unidades de cuidados intensivos el 3,8% del total de los casos confirmados. Los casos de residentes en zonas no vulnerables tuvieron mayor requerimiento de cuidados intensivos. La letalidad fue de 3,5%, mayor en los varones, y más elevada en residentes de zonas no vulnerables, con una diferencia estadísticamente significativa respecto a los pertenecientes a zonas vulnerables. En la distribución por grupos etarios, se observó un exceso de letalidad estadísticamente significativo en menores de 60 años. DISCUSIÓN: Se observó un número mayor de internaciones en UCI y en la letalidad del grupo de población residente en territorio no vulnerable.
Asunto(s)
Argentina , Evolución Clínica , Infecciones por Coronavirus , Vulnerabilidad SocialRESUMEN
Resumen La detección de SARS-CoV-2 y su implicancia en el diagnóstico de COVID-19 han sido muy debatidas en la pandemia. El objetivo de este estudio fue evaluar el costo/beneficio de la detección de SARS-CoV-2 en contactos estrechos asintomáticos (CE) mediante el uso de distintas pruebas de diagnóstico molecular. Se estudiaron 51 CE de personas con diagnóstico de SARS-CoV-2 confirmado por RTqPCR, clasificadas por el umbral de ciclos (Ct) (<20, entre 20 y 30 y >30) en hospitales públicos de la provincia de Buenos Aires. Del total de contactos estudiados el 15,7% resultó confirmado para SARS-CoV-2; no hubo contactos positivos de casos con Ct>30. La cantidad de contactos positivos de casos con Ct<20 fue significativamente mayor que la de casos con Ct>20. Las muestras con Ct<20 se asociaron a una carga viral estimada de entre uno a cuatro órdenes de magnitud de diferencia con los rangos de Ct>20. Un 13,7% de contactos positivos fueron casos con Ct<20. De las muestras positivas confirmadas por PCR, correspondientes a la semana epidemiológica 1 de 2021 (SE1), sólo un 19,35% correspondían a muestras con Ct<20 y un 50,7% con Ct entre 20 y 30. Estos datos muestran un incremento de sólo un 3,7% de casos detectados. El esfuerzo por parte del sistema de salud pública para esta estrategia, con bajo poder predictivo, puede tener un efecto negativo para el cumplimiento del aislamiento de los contactos y podría generar una demora en los resultados de los casos sospechosos, sin aportar significativamente en el control de la pandemia.
Abstract The detection of SARS-CoV-2 and its implication in the diagnosis of COVID-19 have been highly debated in the pandemic. The objective of this study was to evaluate the cost/benefit of detecting SARS-CoV-2 in asymptomatic close contacts (CC) using different molecular diagnostic tests. A total of 51 CC of people with a diagnosis of SARS-CoV-2 confirmed by RTqPCR, classified by the cycle threshold (Ct) (<20, between 20 and 30 and >30), were studied in public hospitals in the Province of Buenos Aires. Of the total contacts studied, 15.7% were confirmed for SARS-CoV-2; there were no positive contacts of cases with Ct>30 positive. The number of positive contacts of cases with Ct<20 was significantly higher than that of cases with Ct>20. Samples with Ct<20 were associated with an estimated viral load of one to four orders of magnitude difference with Ct ranges >20. A total of 13.7% of positive close contacts were from cases with Ct<20. When studying positive samples with confirmed diagnosis by PCR, corresponding to 1 epidemiological week of 2021 (EW1), only 19.35% corresponded to samples with Ct<20 and 50.7% with Ct between 20 and 30. From these data it is shown that with the CC test only 3.7% of the cases were detected. The effort by the public health system for this strategy, with low predictive power, may have a negative effect on the fulfillment of the isolation of contacts and could generate a delay in the results of suspected cases, without contributing significantly to controlling the pandemic.
Resumo A detecção do SARS-CoV-2 e seu envolvimento no diagnóstico da COVID-19 têm sido muito discutidos durante a pandemia. O objetivo desse estudo foi avaliar a relação custo/benefício na detecção de SARSCoV- 2 em casos de contatos próximos assintomático (CP), por meio do uso de diferentes testes de diagnóstico molecular. Foram estudados 51 casos de CP de pessoas com diagnóstico de SARS-CoV-2 confirmado pelo RTqPCR, sendo classificados pelo limiar de ciclos (Ct) (<20, entre 20 e 30 e >30), em hospitais públicos da província de Buenos Aires. Do total de contatos estudados, 15,7% foram confirmados para SARS-CoV-2, não houve contatos positivos de casos com Ct>30. O número de contatos positivos de casos com Ct<20, foi significativamente maior que os casos com Ct>20. As amostras com Ct<20 foram associadas a uma carga viral estimada de uma a quatro ordens de magnitude de diferença com os intervalos de Ct>20. Dos casos positivos, 13,7% foram com Ct<20. Das amostras positivas confirmadas por PCR, correspondentes à semana epidemiológica 1 de 2021 (SE1), apenas 19,35% correspondiam a amostras com Ct>20 e 50,7% com Ct entre 20 e 30. Esses dados mostram incremento de apenas 3,7% de casos detectados. O esforço por parte do sistema de saúde pública para essa estratégia, com baixo poder preditivo, pode ter um efeito negativo no cumprimento do isolamento dos contatos e poderia gerar uma demora nos resultados dos casos suspeitos, sem contribuir significativamente para o controle da pandemia.
Asunto(s)
Virología , SARS-CoV-2 , Aislamiento de Pacientes , Salarios y Beneficios , Sistemas de Salud , Poder Psicológico , Portador Sano , Reacción en Cadena de la Polimerasa , Salud Pública , Carga Viral , Técnicas y Procedimientos Diagnósticos , Costos y Análisis de Costo , Escala de Richter , Técnicas de Diagnóstico Molecular , Diagnóstico , Patología Molecular , Pandemias , Procrastinación , COVID-19 , Hospitales Públicos , PersonasRESUMEN
Desmopressin (dDAVP) is a safe haemostatic agent with previously reported antitumour activity. It acts as a selective agonist for the V2 vasopressin membrane receptor (V2r) present on tumour cells and microvasculature. The purpose of this study was to evaluate the novel peptide derivative [V4Q5]dDAVP in V2r-expressing preclinical mouse models of breast cancer. We assessed antitumour effects of [V4Q5]dDAVP using human MCF-7 and MDA-MB-231 breast carcinoma cells, as well as the highly metastatic mouse F3II cell line. Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. In order to study the effect of intravenously administered [V4Q5]dDAVP on tumour growth and angiogenesis, breast cancer xenografts were generated in athymic mice. F3II cells were injected into syngeneic mice to evaluate the effect of [V4Q5]dDAVP on spontaneous and experimental metastatic spread. In vitro cytostatic effects of [V4Q5]dDAVP against breast cancer cells were greater than those of dDAVP, and associated with V2r-activated signal transduction and partial cell cycle arrest. In MDA-MB-231 xenografts, [V4Q5]dDAVP (0.3 µg/kg, thrice a week) reduced tumour growth and angiogenesis. Treatment of F3II mammary tumour-bearing immunocompetent mice resulted in complete inhibition of metastatic progression. [V4Q5]dDAVP also displayed greater antimetastatic efficacy than dDAVP on experimental lung colonisation by F3II cells. The novel analogue was well tolerated in preliminary acute toxicology studies, at doses ≥ 300-fold above that required for anti-angiogenic/antimetastatic effects. Our data establish the preclinical activity of [V4Q5]dDAVP in aggressive breast cancer, providing the rationale for further clinical trials.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Desamino Arginina Vasopresina/análogos & derivados , Receptores de Vasopresinas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desamino Arginina Vasopresina/administración & dosificación , Desamino Arginina Vasopresina/farmacología , Femenino , Humanos , Células MCF-7 , Ratones , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCCIÓN: en el contexto de pandemia por el nuevo coronavirus (COVID-19), la situación del personal de salud (PS) constituye un foco de interés, tanto por su alta exposición como por la posibilidad de convertirse en diseminadores de la infección en la comunidad. Estos trabajadores enfrentan un riesgo laboral de morbimortalidad sin precedentes. El objetivo fue estimar la seroprevalencia de infección por el nuevo coronavirus (SARS-CoV-2) en el PS de la Región Sanitaria VIII, provincia de Buenos Aires, durante junio de 2020. MÉTODOS: se utilizó un diseño transversal. Se realizó un muestreo probabilístico por conglomerados bietápico. Se recabaron datos a partir de un cuestionario autoadministrado y una muestra de sangre para determinación de anticuerpos. Se utilizó el test COVIDAR IgG e IgM®. RESULTADOS: se incluyeron 738 trabajadores de la salud, la tasa de respuesta general fue del 73,80 %. El 71,83% fueron mujeres, el 46,39% tenía entre 35 y 49 años. Enfermeros y médicos representaron más de la mitad del personal. El 75,86% refirió usar siempre el equipo de protección personal. El 5,61% tuvo contacto estrecho con un caso confirmado de COVID-19. El 4,60% tenía un hisopado nasofaríngeo previo, con resultado negativo. Se encontraron cinco trabajadores con IgG positiva para SARS-CoV-2 (cuatro mujeres y un varón) e IgM negativa. La edad media de los casos fue de 35 años, dos fueron asintomáticos, en ninguno se había tomado muestra de hisopado. La seroprevalencia general fue de 0,75%, sin diferencias significativas entre estratos. DISCUSIÓN: la seroprevalencia hallada fue baja, con una gran proporción de trabajadores susceptibles a la infección. Se refuerza la necesidad de complementar las estrategias de vigilancia epidemiológica pasiva con el monitoreo serológico en personal de salud