44,498 research outputs found

    Valutazione dell'attivita' protettiva di inibitori dell'enzima anidrasi carbonica nei confronti della tossicita' da chemioterapico paclitaxel

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    Le Anidrasi Carboniche sono una famiglia di metalloenzimi che catalizzano l'interconversione tra anidride carbonica e bicarbonato. Diverse isoforme di CA sono state ritrovate in varie specie e in vari tessuti di vertebrati più sviluppati, fra cui l’uomo. In particolare nei mitocondri sono presenti due isoforme, CA VA e CA VB, la cui inibizione ha portato alla luce il ruolo essenziale che esse svolgono nella regolazione della biogenesi mitocondriale. Recentemente è stato osservato che alterazioni della funzione mitocondriale possono essere coinvolte nella patogenesi del dolore neuropatico causato da agenti chemioterapici, tra cui paclitaxel. Tra gli approcci terapeutici più innovativi per il trattamento dei sintomi della neuropatia c’è l’uso di inibitori della CA. A tal proposito, in questa tesi di Laurea si è voluto comprendere il ruolo delle CA mitocondriali. Per questo motivo su encefalo e midollo spinale, provenienti da topi trattati con paclitaxel e con inibitori di CA, AA 20-13, AA 20-16 ed acetazolamide, è stata valutata l’attività dell’enzima citrato sintasi. La citrato sintasi è un enzima mitocondriale ubiquitario. Esso appartiene alla classe delle transferasi e catalizza la condensazione dell’ossalacetato con acetil-CoA, per ottenere citrato. Tale reazione è la prima del ciclo di Krebs, processo chiave della respirazione cellulare. L’attività di questo enzima è quindi associata all’attività metabolica cellulare e riflette eventuali disfunzioni mitocondriali. Carbonic Anhydrases are a family of metalloenzymes that catalyze the interconversion between carbon dioxide and bicarbonate. Different isoforms of CA have been found in various species and in various tissues of more developed vertebrates, including humans. In particular, in mitochondria there are two isoforms, CA VA and CA VB, whose inhibition has brought to light the essential role they play in the regulation of mitochondrial biogenesis. It has recently been observed that alterations in mitochondrial function may be involved in the pathogenesis of neuropathic pain caused by chemotherapeutic agents, including paclitaxel. Among the most innovative therapeutic approaches for treating the symptoms of neuropathy is the use of CA inhibitors. In this thesis we wanted to understand the role of mitochondrial CAs. For this reason, the activity of the enzyme citrate synthase was evaluated on the brain and spinal cord, coming from mice treated with paclitaxel and with CA inhibitors, AA 20-13, AA 20-16 and acetazolamide. Citrate synthase is a ubiquitous mitochondrial enzyme. It belongs to the class of transferases and catalyzes the condensation of oxaloacetate with acetyl-CoA, to obtain citrate. This reaction is the first of the Krebs cycle, a key process of cellular respiration. The activity of this enzyme is therefore associated with cellular metabolic activity and reflects any mitochondrial dysfunctions

    A computational framework for pharmaco-mechanical interactions in arterial walls using parallel monolithic domain decomposition methods

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    A computational framework is presented to numerically simulate the effects of antihypertensive drugs, in particular calcium channel blockers, on the mechanical response of arterial walls. A stretch-dependent smooth muscle model by Uhlmann and Balzani is modified to describe the interaction of pharmacological drugs and the inhibition of smooth muscle activation. The coupled deformation-diffusion problem is then solved using the finite element software FEDDLib and overlapping Schwarz preconditioners from the Trilinos package FROSch. These preconditioners include highly scalable parallel GDSW (generalized Dryja-Smith-Widlund) and RDSW (reduced GDSW) preconditioners. Simulation results show the expected increase in the lumen diameter of an idealized artery due to the drug-induced reduction of smooth muscle contraction, as well as a decrease in the rate of arterial contraction in the presence of calcium channel blockers. Strong and weak parallel scalability of the resulting computational implementation are also analyzed

    Proton pump inhibitors may enhance the risk of digestive diseases by regulating intestinal microbiota

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    Proton pump inhibitors (PPIs) are the most used acid-inhibitory drugs, with a wide range of applications in the treatment of various digestive diseases. However, recently, there has been a growing number of digestive complications linked to PPIs, and several studies have indicated that the intestinal flora play an important role in these complications. Therefore, developing a greater understanding of the role of the gut microbiota in PPI-related digestive diseases is essential. Here, we summarize the current research on the correlation between PPI-related digestive disorders and intestinal flora and establish the altered strains and possible pathogenic mechanisms of the different diseases. We aimed to provide a theoretical basis and reference for the future treatment and prevention of PPI-related digestive complications based on the regulation of the intestinal microbiota

    Clinical Challenges in the Management of Malignant Ovarian Germ Cell Tumours

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    Nonepithelial ovarian cancers (NEOC) are a group of rare malignancies, including germ cell tumours (GCT) and sex cord-stromal tumours (SCST), along with small-cell carcinomas and sarcomas. GCTs represent 2-5% of ovarian cancers, with a yearly incidence of 4:100,000, and they usually affect young women and adolescents. Precursory germ cells of the ovary form the basis of GCT. They are histologically classified into primitive GCT, teratomas, and monodermal and somatic-type tumours associated with dermoid cysts. A primitive GCT can be either a yolk sac tumour (YST), dysgerminoma, or mixed germ cell neoplasm. Teratomas are either mature (benign) or immature (malignant). Given that malignant GCTs occur rarely compared to epithelial ovarian tumours (EOC), greater focus is required in their diagnosis and treatment. In this article, we review the epidemiology, clinical manifestations, diagnosis, and molecular biology, along with the management and therapeutic challenges

    Cost-effectiveness of maintenance niraparib with an individualized starting dosage in patients with platinum-sensitive recurrent ovarian cancer in China

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    Objective: Niraparib improved survival in platinum-sensitive recurrent ovarian cancer (PSROC) patients versus routine surveillance, accompanied by increased costs. Based on the NORA trial, we evaluated for the first time the cost-effectiveness of maintenance niraparib with individualized starting dosage (ISD) in China.Methods: A Markov model was developed to simulate the costs and health outcomes of each strategy. The total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured. One-way and probabilistic sensitivity analysis were performed to estimate model robustness. Scenario analyses were also conducted.Results: Compared to routine surveillance, niraparib additionally increased QALYs by 0.59 and 0.30 in populations with and without germline BRCA (gBRCA) mutations, with incremental costs of 10,860.79and10,860.79 and 12,098.54, respectively. The ICERs of niraparib over routine surveillance were 18,653.67/QALYand18,653.67/QALY and 39,212.99/QALY. At a willingness-to-pay (WTP) threshold of $37,488/QALY, the ISD enhanced the likelihood of cost-effectiveness from 9.35% to 30.73% in the gBRCA-mutated group and from 0.77% to 11.74% in the non-gBRCA mutated population. The probability of niraparib being cost-effective in the region with the highest per capita Gross Domestic Product (GDP) in China was 74.23% and 76.10% in the gBRCA-mutated and non-gBRCA mutated population, respectively. Niraparib was 100% cost-effective for National Basic Medical Insurance beneficiaries under the above WTP thresholds.Conclusion: Compared to routine surveillance, the ISD of niraparib for maintenance treatment of PSROC is cost-effective in the gBRCA-mutated population and more effective but costly in the non-gBRCA mutated patients. The optimized niraparib price, economic status, and health insurance coverage may benefit the economic outcome

    Induction of RIPK3/MLKL-mediated necroptosis by Erigeron breviscapus injection exhibits potent antitumor effect

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    Colorectal cancer (CRC) is the second leading cause of tumor-related deaths worldwide. Resistance of tumor cells to drug-induced apoptosis highlights the need for safe and effective antitumor alternatives. Erigeron breviscapus (Dengzhanxixin in China) injection (EBI), extracted from the natural herb Erigeron breviscapus (Vant.) Hand.-Mazz (EHM), has been widely used in clinical practice for cardiovascular diseases. Recent studies have suggested that EBI’s main active ingredients exhibit potential antitumor effects. This study aims to explore the anti-CRC effect of EBI and elucidate the underlying mechanism. The anti-CRC effect of EBI was evaluated in vitro using CCK-8, flow cytometry, and transwell analysis, and in vivo through a xenograft mice model. RNA sequencing was utilized to compare the differentially expressed genes, and the proposed mechanism was verified through in vitro and in vivo experiments. Our study demonstrates that EBI significantly inhibits the proliferation of three human CRC cell lines and effectively suppresses the migration and invasion of SW620 cells. Moreover, in the SW620 xenograft mice model, EBI markedly retards tumor growth and lung metastasis. RNA-seq analysis revealed that EBI might exert antitumor effects by inducing necroptosis of tumor cells. Additionally, EBI activates the RIPK3/MLKL signaling pathway, a classical pathway of necroptosis and greatly promotes the generation of intracellular ROS. Furthermore, the antitumor effect of EBI on SW620 is significantly alleviated after the pretreatment of GW806742X, the MLKL inhibitor. Our findings suggest that EBI is a safe and effective inducer of necroptosis for CRC treatment. Notably, necroptosis is a non-apoptotic programmed cell death pathway that can effectively circumvent resistance to apoptosis, which provides a novel approach for overcoming tumor drug resistance

    The current consensus for the diagnostic and treatment of extramammary Paget’s disease

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    Extramammary Paget's disease is a slow-growing cutaneous intraepithelial adenocarcinoma of the apocrine glands in the anogenital and axillary regions. The disease is extremely rare, affects predominantly postmenopausal women, and has nonspecific clinical caracteristics, so that it can take 210 years from the first clinical signs to diagnosis. The vulva and the perianal region are the most affected zones. Extramammary Pagets disease is clinically manifested as well-defined erythematous plaques with secondary changes, such as scaling, ulceration and even bleeding. Differential diagnosis is made between primary and secondary forms of Extramammary Pagets disease, candidiasis, contact dermatitis, Crohn's disease, eczema, erosive lichen planus, hydradenitis suppurativa, Langerhans cell histiocytosis, sclerosing lichen, psoriasis, squamous cell carcinoma in situ, amelanotic melanoma and mycosis fungoide. Treatment mainly includes the surgical component, as well as the use of photodynamic therapy, cytostatic agents, and, depending on the stage, systemic chemotherapy

    Efficacy and safety of pembrolizumab with preoperative neoadjuvant chemotherapy in patients with resectable locally advanced head and neck squamous cell carcinomas

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    BackgroundThis study aimed to explore the efficacy and safety of pembrolizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinomas (LA-HNSCCs).MethodsIn this prospective, single-arm, single-centre clinical trial, patients meeting the inclusion criteria were treated with preoperative neoadjuvant therapy with 200 mg pembrolizumab combined with 75 mg/m2 cisplatin and 175 mg/m2 paclitaxel. This was followed by surgery and postoperative adjuvant therapy. The primary endpoint was the postoperative pathological complete response (pCR) rate. All statistical analyses were performed using SPSS 26.ResultsA total of 22 patients were enrolled. The location of primary lesion showed: hypopharynx were 15 (68.2%), oropharynx were 6 (27.3%) and oral cavity was 1 (4.5%). The postoperative pCR rate, was 36.4% (8/22), and there was no delay to surgery due to adverse drug reactions. The rate of laryngeal function preservation was 90.9% (20/22). Delayed wound healing was the main surgical complication, with an incidence of 22.7% (5/22). The median follow-up time was 9.5 months, and only 1 patient (4.55%) suffered a regional recurrence.ConclusionPreoperative treatment with pembrolizumab and chemotherapy in resectable LA-HNSCC has a high pCR rate with no significant impact on surgical safety. This treatment was found to increase the rate of laryngeal function preservation. However, the effects of neoadjuvant immunotherapy on long-term prognosis in LA-HNSCCs require further study
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