20,110 research outputs found

    Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS)

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    Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders.Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs.Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib.Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention

    Exposure to harmful drugs during pregnancy in France between 2013 and 2019.

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    A. Exposure to teratogenic drugs during the preconceptional period (PC) or the first trimester (T1). Antineoplastic and Immunomodulating drugs: fingolimod, leflunomide, lenalidomide, methotrexate, mycophenolic acid, thalidomide, teriflunomide. Retinoids for systemic use: acitretin (for psoriasis treatment), alitretinoin agents for dermatitis, etretinate, isotretinoin for systemic use, tretinoin. Retinoids for topical use: adapalene, alitretinoin antineoplastic agent, isotretinoin, tifarotene, tretinoin. Antiepileptic drugs: carbamazepine, fosphenytoin, oxcarbazepine, phenytoin, topiramate, valproic acid. Treatment of affective disorders: divalproate, lithium, valpromide. Antithyroid preparations: carbimazole, thiamazole. Vitamin K antagonists: acenocoumarol, fluindione, warfarin. HMG Coa reductase inhibitors: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin. Other drugs acting as teratogens: acetazolamide, antiglaucoma preparation. B. Exposure to fetotoxic drugs during the second (T2) or the third trimester (T3). Non-steroids anti-inflammatory drugs for systemic use: acetic acid derivatives and related substances, oxicams, propionic acid derivatives, fenamates, coxibs, other anti-inflammatory and antirheumatic agents, non-steroids, acetylsalicylic acid ≥ 250mg. Non-steroids anti-inflammatory drugs for topical use. Agents acting on the renin-angiotensin system: Angiotensin Converting Enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors. Contraceptives: hormonal contraceptives for systemic use, emergency contraceptives, contraceptives for topical use. Sex hormones: androgens, estrogens, progestogens, anti-androgen, hormone replacement therapy, gonadotropins and other ovulation stimulants, antigonadotropins and similar agents, sex hormones for systemic disease. For details regarding specific drugs, refer to Supplementary, S2 Table.</p

    Idiopathic inflammatory myopathies and cancer : familial risk, genetics and consequences

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    Idiopathic inflammatory myopathies (IIMs) are a group of rare rheumatic inflammatory diseases (RIDs), characterised by a diverse range of clinical, serological and histopathological characteristics, with muscle weakness as a shared hallmark. While advancements in disease management have improved the survival rates of patients with IIM, the mortality rate among patients with IIM is still higher than the general population, mainly due to association with comorbidities such as cancer. The pathogenesis of IIM, the pathological link between IIM and cancer and the impact of cancer on the survival of patients with IIM remain a subject of uncertainty. The rarity and heterogeneity inherent in IIM pose significant challenges in filing these knowledge gaps. This thesis encompasses five studies, which aimed at addressing research questions concerning the genetic contribution to IIM and its link with other autoimmune diseases and cancer, as well as the disease burden in the context of cancer in a large representative population of patients with IIM. Study I was a population-based case-control family study including 7,615 first-degree relatives of 1,620 patients with IIM diagnosis between 1997 and 2016 and 37,309 first-degree relatives of 7,797 matched comparators without IIM. Patients with IIM were four times more likely to have at least one first-degree relative affected by IIM compared to matched comparators without IIM. The heritability of IIM, a proportion of the phenotypic variance that can be explained by additive genetic variance, was 22% in the Swedish population. Study II, with the same study population as in Study I, analysed the familial associations between IIM and a variety of autoimmune diseases under a causal framework. We found shared familial factors between IIM and other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease. Study III, with a similar study population and analytical approach as in Study II, comprehensively investigated the familial co-aggregation of IIM and cancer. We did not observe a familial association between IIM and cancer overall but modification effect by sex was noted: there was a modest familial association (adjusted odds ratio=1.39) with cancer in male first-degree relatives of patients with IIM. We also found that offspring of patients with IIM were more likely to have a cancer diagnosis at age younger than 50 years compared to those of matched comparators without IIM. In the exploratory analysis by specific cancer types, findings suggest that IIM shared familial factors with myeloid malignancies and liver cancer. Study IV explored genetic correlation between IIM and B-cell lymphomas via a cross-trait secondary analysis using summary statistics from genome-wide associations studies of IIM and four common B-cell lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We detected a limited number of genomic loci, predominantly within the human leukocyte antigen region, demonstrating significant genetic correlations between IIM and common Bcell lymphoma subtypes. Study V, a cohort study, followed 1,826 patients to (first and second) cancer and death (overall and cause-specific death) events since IIM diagnosis for more than 20 years. Compared to patients with no cancer diagnosis after IIM, patients with a first cancer diagnosis after IIM faced a greater five-year mortality (22% versus 49%). This excessive risk was due to an increased risk of death from cancer. In patients with a first cancer diagnosis after IIM, the one-year risk of having a second primary cancer was 11% and having a second cancer diagnosis slightly increased the risk of death. We also reported several prognostic factors associated with increased risks of cancer and death (overall, from cancer and from other causes). This thesis offers useful insight into the role of genetics in IIM pathogenesis and its connections with other autoimmune diseases and cancer, as well as the impact of cancer on the survival of patients with IIM. The observed familial aggregation of IIM and familial associations between IIM and other autoimmune diseases suggest genetic involvement in the development of IIM. Family history of IIM, other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease may serve as indicators pointing towards an IIM diagnosis. Missing heritability is suggested by the discrepancy between our family-based heritability and the SNP-based heritability, implying yet-to-be discovered genetic variants associated with IIM. The acquired knowledge of shared familial factors between IIM and other autoimmune diseases may inform future genetic studies aiming to uncover novel IIMassociated genetic variants. There is a limited shared familial/genetic susceptibility between IIM and cancer. The human leukocyte antigen region plays an important role in the limited shared genetic susceptibility between IIM and common B-cell lymphoma subtypes. IIM concomitant with cancer leads to a substantial increase in mortality, mainly due to cancer. Future research should focus on reducing cancer-related disease burden in patients with IIM

    Purification of 3×Myc PKG-Puro-Poly A Gene for Bacterial Transformation

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    Dysregulation of the oncoprotein c-Myc (Myc) is involved in many types of cancer. Myc is a sequence-specific transcription factor that regulates the transcription of genes involved in the control of cell proliferation and apoptosis through mechanisms that are not well understood. The method of this research is experimental. The experiment result will be described.  Some processes will be done by polymerase chain reaction (PCR) to amplify the gene and then it will be extracted to pure the targeted gene. This research has been succesful to purify 3×Myc PKG-Puro-Poly A gene. c-MYC (hereinafter MYC) is an oncoprotein consisting of 439 amino acids contains a well-characterized C-terminal DNA compound and an N-terminal transactivation domain (TAD). The C-terminal region »100 residues comprises a basic leucine zipper-helix-loop-helix (bHLH-LZ) segment that regulates heterodimerization between MYC and its partner bHLH-LZ MAX mediate in their binding to gene promoters

    The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

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    Introduction: Bone metastasis of breast cancer (BC) is a process in which the disruption of the bone homeostatic microenvironment leads to an increase in osteoclast differentiation. Ailanthus altissima shows an inhibitory effect on osteoclast differentiation. Ailanthone (AIL) refers to a natural compound isolated from Ailanthus altissima, a Chinese herbal medicine, and has effective anti-tumor activity in numerous cell lines. Its impact on bone metastases for BC is yet unclear.Methods: We measured the effect of AIL on MDA-MB-231 cells by wound healing experiments, Transwell and colony formation experiment. Using the Tartrate-resistant Acid Phosphatase (TRAP) staining tests, filamentous (F-actin) staining and bone resorption test to detect the effect of AIL on the osteoclast cell differentiation of the Bone Marrow-derived Macrophages (BMMs), activated by the MDA-MB-231 cell Conditioned Medium (MDA-MB-231 CM) and the Receptor Activator of Nuclear factor-κB Ligand (RANKL),and to explore its possibility Mechanisms. In vivo experiments verified the effect of AIL on bone destruction in breast cancer bone metastasis model mice.Results:In vitro, AIL significantly decrease the proliferation, migration and infiltration abilities of MDA-MB-231 cells at a safe concentration, and also reduced the expression of genes and proteins involved in osteoclast formation in MDA-MB-231 cells. Osteoclast cell differentiation of the BMMs, activated by MDA-MB-231 CM and RANKL, were suppressed by AIL in the concentration-dependent manner. Additionally, it inhibits osteoclast-specific gene and protein expression. It was noted that AIL inhibited the expression of the osteoclast differentiation-related cytokines RANKL and interleukin-1β (IL-1β) that were secreted by the MDA-MB-231 cells after upregulating the Forkhead box protein 3 (FOXP3) expression. Furthermore, AIL also inhibits the expression of the Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Nuclear factor-κB Ligand (NF-κB) signaling pathways, which then suppresses the MDA-MB-231CM-induced development of Osteoclasts.Conclusion: Our study shows that AIL blocks osteoclast differentiation in the bone metastasis microenvironment by inhibiting cytokines secreted by BC cells, which may be a potential agent for the treatment of BC and its secondary bone metastasis

    Predictors of Hypersensitivity Reactions to Platinum-Based Chemotherapy in a Tertiary Hospital in Oman: A case-control study

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    Objectives: Platinum-based compounds (PBC) play an important role in cancer therapy. However, one of the drawbacks of PBC is the occasional occurrence of hypersensitivity reactions (HSR) which can lead to serious consequences. The aim of the study is to estimate the prevalence and evaluate risk factors of HSR to PBC in cancer patients. Methods: A case-control study of patients who received any PBC for the management of non-haematological cancers from 2013 to 2020 at Sultan Qaboos University Hospital, Oman. Data regarding demographic features and diseases and treatment details were collected from the hospital’s electronic patients record. We quantitatively described the data, and Student’s t-test and Wilcoxon Man-Whittney tests were used to detect significant differences. Results: A total of 38 cases and 148 matched controls were studied. The prevalence of HSR to PBC in our cohort was 4.7% (95% confidence interval: 3.33%-6.37%), more with carboplatin compared to cisplatin and oxaliplatin. In our study, female gender (p=0.032), concomitant taxanes (p=0.002) and concurrent radiation (p&lt;0.001) were significant predictors of HSR to PBC. The majority of reactions were of mild to moderate severity and the rechallenge rate after HSR development was 13%. Conclusion: HSR to PBC impact therapy decisions and understanding the risk factors are important to improve treatment outcomes in cancer patients. Keywords: Hypersensitivity; Platinum; Anti-neoplastic; Oncology; Oman

    Contaminação residual em embalagens de medicamentos antineoplásicos

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    Introdução: o manuseio de medicamentos antineoplásicos deve seguir cuidados e regras rígidas de segurança com o intuito de reduzir os riscos de exposição ocupacional aos profissionais envolvidos no preparo. A contaminação da superfície externa dos frascos de medicamentos é reconhecida como um risco a saúde. Objetivo: avaliar a contaminação de frascos e embalagens dos medicamentos antineoplásicos ciclofosfamida e doxorrubicina, através da análise por cromatografia líquida de alta eficiência/espectrometria de massas. Método: Estudo transversal. As amostras foram coletadas em papel filtro Whatman umedecido com 1 mL de metanol e mantidas em tubo de ensaio até a análise. As amostras foram preparadas por extração sólido-líquido. Cinco mL de metanol e acetato de etila (1:1, v/v) foram adicionados ao tubo contendo o papel de filtro e homogeneizados em vórtex por 30 minutos à temperatura ambiente. Após centrifugação, 2 mL do sobrenadante foram filtrados para um novo tubo e evaporados a 60ºC. O extrato seco foi retomado com 200 μL de água com 0,1% de ácido fórmico e metanol (1:1, v/v). Após a homogeneização, uma alíquota de 10 μL foi injetada no sistema UHPLC-MS/MS. Resultados: Foi analisado um total de 209 amostras, 66 de ciclofosfamida de um mesmo fabricante e 143 de doxorrubicina de 3 fabricantes diferentes. Os níveis de ciclofosfamida foram detectados em 9 amostras (13,63%), 3 estavam abaixo do limite inferior de quantificação (LLQ) e as outras 6 tinham níveis de contaminação que variavam entre 1,24 e 28,04 ng/filtro. Os níveis de doxorrubicina foram detectados em 36 amostras (25,17%), 2 estavam abaixo do LLQ e as outras tinham níveis entre 1,32 e 664,84 ng/patch. 80% das amostras com contaminação residual eram provenientes de frascos. Conclusão: Os resultados revelam a presença de contaminação residual dos medicamentos ciclofosfamida e doxorrubicina. Embora a quantidade de resíduos encontrados em cada amostra seja pequena, deve-se ter um cuidado especial no manuseio e descarte desses medicamentos. Sugerimos a realização de mais estudos com diferentes metodologias a fim de possibilitar criação de estratégias de prevenção com intuito de minimizar o risco de exposição aos profissionais.Introduction: The handling of antineoplastic drugs should follow strict care and safety rules in order to reduce the risks of occupational exposure for the professionals involved in the preparation. Contamination of the external surface of drug vials is recognized as a health risk. Objective: To evaluate the contamination of vials and packaging of the antineoplastic drugs cyclophosphamide and doxorubicin, through analysis by high-performance liquid chromatography/mass spectrometry. Method: Cross-sectional study. Samples were collected on Whatman filter paper moistened with 1 mL of methanol and kept in a test tube until analysis. Samples were prepared by solid-liquid extraction. Five mL of methanol and ethyl acetate (1:1, v/v) were added to the tube containing the filter paper and homogenized by vortex for 30 minutes at room temperature. After centrifugation, 2 mL of supernatant was filtered to a new tube and evaporated at 60 °C. The dried extract was recovered with 200 μL of water with 0.1% formic acid and methanol (1:1, v/v). After homogenization, a 10 μL aliquot was injected on UHPLC-MS/MS system. Results: A total of 209 samples were analyzed, 66 of cyclophosphamide from the same manufacturer and 143 of doxorubicin from 3 different manufacturers Cyclophosphamide levels were detected in 9 samples (13.63%), 3 were below the lower limit of quantification (LLQ) and the other 6 had contamination levels ranging from 1.24 to 28.04 ng/patch. Doxorubicin levels were detected in 36 samples (25.17%), 2 were below the LLQ and the others had levels between 1.32 and 664.84 ng/patch. 80% of the samples with residual contamination were from vials. Conclusion: The results reveal the presence of residual contamination of the drugs cyclophosphamide and doxorubicin. Although the amount of residues found in each sample is small, special care should be taken in the handling and disposal of these drugs. We suggest that further studies with different methodologies be carried out in order to enable the creation of prevention strategies to minimize the risk of exposure for professionals

    Dibenzylideneacetone Induces Apoptosis in Cervical Cancer Cells through Ros-Mediated Mitochondrial Damage

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    Cervical cancer is a health problem among women worldwide. Considering the limitations of prevention and antineoplastic chemotherapy against cervical cancer, research is needed to discover new, more effective, and safe antitumor agents. In the present study, we investigated the in vitro cytotoxicity of a new synthetic dibenzylideneacetone derived from 1,5-diaryl-3-oxo-1,4-pentadienyl (A3K2A3) against cervical cancer cells immortalized by HPV 16 (SiHa), and 18 (HeLa) by MTT assay. Furthermore, we performed spectrofluorimetry, flow cytometry, and Western blot analyzes to explore the inhibitory mechanism of A3K2A3 in cervical cancer cells. A3K2A3 showed cytotoxic activity against both cell lines. Mitochondrial depolarization and reduction in intracellular ATP levels were observed, which may be dependent on the redox imbalance between increased ROS and reduced levels of the antioxidant defense. In addition, damage to the cell membrane and DNA, and effective blocking of cell division in the G2/M phase were detected, which possibly led to the induction of apoptosis. This result was further confirmed by the upregulation of apoptosis-related proteins Bax, cytochrome C, and caspases 9 and 3. Our results provided the first evidence that A3K2A3 contributes to the suppression of cervical cancer in vitro, showing promise as a possible alternative for the treatment of this cancer

    Peripheral arterial disease

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    The role of granulocyte-colony stimulating factor biosimilars for supportive cancer care : a year in review

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    This year-in-review article provides insights into clinical updates relating to granulocyte-colony stimulating factor (G-CSF) biosimilars research presented at five key congresses in 2022. These include the American Society of Clinical Oncology (ASCO) 55th Annual Meeting (3rd–7th June 2022, Chicago, Illinois, USA), European Society for Medical Oncology (ESMO) Congress (9th–13th September 2022, Paris, France), ESMO Asia Congress (2nd–4th December 2022, Singapore), San Antonio Breast Cancer Symposium (SABCS; 6th–10th December 2022, Texas, USA), and American Society of Hematology (ASH) 64th Annual Meeting and Exposition (10th–13th December 2022, New Orleans, Louisiana, USA). Alongside reviewing the current research presented at these key congresses, with a focus on the use of G-CSF agents and biosimilars in patients undergoing treatment for breast, colorectal, and gynaecological cancers, this article provides an overview of current guidelines on the use of G-CSF in supportive cancer care to manage chemotherapy-induced febrile neutropenia and explores trends in G-CSF biosimilars research
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