RESUMO
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma cells and correlated with increased tumor growth and poor prognosis. In vitro tests on MP41 (BAP1 positive) and MP46 (BAP1 negative) cancer cell lines using inhibitors pamiparib (PARP1) and Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined treatment had synergistic effects in MP41 and additive in MP46 cell lines, reducing cell proliferation and inhibiting the mTOR signaling pathway. Furthermore, the applied inhibitors in combination decreased cell motility and migration speed, especially for BAP1-negative cell lines. Our hypothesis of the double hit into tumoral DNA metabolism as a possible therapeutic option in uveal melanoma was confirmed since combined targeting of DTYMK and PARP1 affected all tested cytophysiological parameters with the highest efficiency. Our in vitro findings provide insights into novel therapeutic avenues for managing uveal melanoma, warranting further exploration in preclinical and clinical settings.
Assuntos
Proliferação de Células , Melanoma , Poli(ADP-Ribose) Polimerase-1 , Neoplasias Uveais , Humanos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologia , Neoplasias Uveais/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/metabolismo , Linhagem Celular Tumoral , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Kidney graft failure is not a homogenous disease and the Banff classification distinguishes several types of graft rejection. The maintenance of a transplant and the treatment of its failure require specific medications and differ due to the underlying molecular mechanism. As a consequence, patients suffering from different rejection types will experience distinct side-effects upon therapy. The review is focused on comparing treatment regimens as well as presenting the latest insights into innovative therapeutic approaches in patients with an ongoing active ABMR, chronic active ABMR, chronic ABMR, acute TCMR, chronic active TCMR, borderline and mixed rejection. Furthermore, the profile of cardiovascular adverse effects in relation to the applied therapy was subjected to scrutiny. Lastly, a detailed assessment and comparison of different approaches were conducted in order to identify those that are the most and least detrimental for patients suffering from kidney graft failure.
RESUMO
BACKGROUND: Myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, is a rare disease entity characterized by the emergence of an extramedullary tumor, which may be antecedent, coexisting, or manifest secondarily to an ongoing malignancy of lymphoid origin. Owing to its low prevalence, scientific reports addressing this matter comprise mainly retrospective studies with a limited number of participants, rather low-quality research, and only few case reports. Despite MS's rarity, the need for enhancing their diagnostic tools and refinement of their therapeutic regimens is broadly recognized among physicians. CASE SUMMARY: In this case series, we present the clinical histories of two patients diagnosed with MS. The former (Case 1) exhibited MS of the sternum alongside chronic myeloid leukemia (CML), while in case of the latter (Case 2) MS presented as the initial manifestation of a current acute myeloid leukemia (AML). Treatment for both patients included chemotherapy (CHTH) and radiation (RT); however, patient 1 with CML died due to cardiorespiratory insufficiency secondary to an infection, while patient 2 is in clinical remission (CR) for 16 months since their MS diagnosis. Furthermore, a comprehensive analysis of previously reported cases was conducted which incorporated MS in patients with AML and CML. CONCLUSION: The objective of this report was to emphasize the heterogeneity among the clinical manifestations of MS, to underline the relevance of the histopathological and molecular diagnostic tools in opting for the appropriate therapy, and that, in spite of it occurring rather uncommonly, physicians should think of MS in the presence of pathological masses in patients under risk of hematological malignancies.
RESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment modality, frequently used for patients suffering from haematological malignancies. In the last two decades, there have been multiple randomised controlled trials (RCTs), review articles, and meta-analyses addressing the efficacy of rabbit anti-thymocyte globulin (r-ATG) as a graft-versus-host disease (GvHD) prophylaxis. Nevertheless, only a few aimed to compare the effectiveness of different r-ATG formulations. Since the last article we retrieved comparing different r-ATGs in GvHD prophylaxis dates back to 2017, we performed a systematic literature review of articles published since 2017 to this day, utilising PubMed, Scopus, Cochrane, and MEDLINE, with the main endpoints being prophylaxis of acute GvHD (aGvHD) and chronic GvHD (cGvHD). We subjected to scrutiny a total of five studies, of which four compared the differences between Thymoglobulin (ATG-T) and Grafalon (ATG-G), and one discussed the impact of ATG-T dose. Overall, cGvHD, aGvHD grades II-IV, TRM, OS, NRM, LFS, relapse, overall infections, and EBV reactivation do not seem to be affected by the type of utilised rATG. However, data on aGvHD grades III-IV, GRFS, moderate-severe cGvHD, and CMV reactivation is conflicting. Through our research, we sought to summarise the most recent findings concerning r-ATGs in allo-HCT, and provide insight into the differences between the targets and origin of various ATG formulations.
RESUMO
Anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) are two frequently utilised strategies in graft-versus-host disease (GvHD) prophylaxis following allogeneic hematopoietic cell transplantation (allo-HCT), currently approved for different recipient-donor settings. In addition, being efficacious in preventing GvHD owing to their T-cell depleting capacity, the employment of these two agents increases the risk of infections, including CMV reactivation, which stands as one of the most common and serious infections following allo-HCT. We performed a systematic literature review of articles published until 1 September 2023, through PubMed, MEDLINE, and Scopus, with the main endpoint being CMV reactivation after PTCy or ATG allo-HCT. The majority of the studies included in the analysis provide supporting evidence for a reduced risk of CMV reactivations following the use of PTCy compared to ATG, although not all findings reached statistical significance. Additionally, it appears that utilising a haploidentical donor leads to a higher incidence of CMV infections and clinically significant CMV infections (CS-CMVis) compared to other donor settings in PTCy allo-HCT. This study aims to compare the risk of CMV infections following allo-HCT in patients who have received either ATG or PTCy as GvHD prophylaxis and discuss other factors that could influence the infectious outcomes of patients who have undergone allo-HCT.
RESUMO
Deep brain stimulation (DBS) is a relatively dated treatment procedure that emerged in the late 1980s. Nonetheless, numerous studies are being carried out to examine its influence on the human brain and develop new treatment indications. This systematic review aims to summarize the current state of knowledge referring to DBS, investigate novel insights into its indications, and discuss the technical aspects and rationale behind DBS application. In particular, we sought to subject to scrutiny the application of DBS specifically in anorexia nervosa (AN), various addiction types, depression, and obsessive-compulsive disorders (OCDs). The method is supposed to offer promising results, especially in pharmacologically resistant forms of the upper-mentioned psychiatric disorders. Moreover, further insight has been provided into the historical notions of the method and differences in the surgical approach in specific disease entities. Furthermore, we mark the possible influence of comorbidities on treatment results. Our review consists of articles and studies found on PubMed, Google Scholar, Cochrane, and Scopus, which were then analyzed with scrutiny in the identification process, including the most resourceful ones. After methodological quality and risk of bias assessment, a total of 53 studies were included. To this date, DBS's usefulness in the treatment of AN, OCDs, depression, and addictions has been proven, despite an ongoing debate concerning the technical aspects and parameters when applying DBS. To the best of our knowledge, we have not found any paper that would recapitulate the current state of DBS in the context of psychiatric disorders with an addition of technical insights.
RESUMO
This case report describes a 59-year-old male patient after heart and kidney transplantation, subsequently diagnosed with refractory hypertension since implemented antihypertensive pharmacotherapy consisting of six agents did not provide a substantial therapeutic response. Elevated blood pressure and its impact on a hypertrophied transplanted heart and impaired renal graft function have led to a significant deterioration in the patient's cardiovascular risk profile. To address this issue, a native renal arteries denervation was performed. It resulted in a noteworthy decrease in both systolic and diastolic pressure values, thus manifesting a positive hypotensive effect. Furthermore, a sustainable reduction of left ventricular mass and stabilization in kidney graft function were noticed. The presented case provides evidence that renal denervation can be an efficacious complementary treatment method in individuals who received kidney and heart grafts as it leads to a decrease in cardiovascular risk.
RESUMO
The purpose of this article is to assess the present knowledge about chronic active (CA) T-cell mediated rejection (TCMR) of a kidney. In the research authors review current Banff diagnostic criteria used in kidney rejection, focus on their possible future evolution, and investigate the role of currently available molecular methods that could be implemented into the diagnostic scheme. Research also points out previously and currently available treatment methods applied to CA TCMR and takes into account possible side effects consequent upon the therapy. Moreover, attention is being paid to the CA TCMR coincidence with other kidney rejection types such as antibody-mediated rejection (ABMR) and its influence on the treatment approach. Authors also mark the possibility of non-HLA antibodies coexistence in patients with CA TCMR and describe its possible resonance on kidney allograft function. Nonetheless, it seems that current knowledge about CA TCMR is not sufficient and requires further investigation.