RESUMO
In traditional understanding, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are regarded as efflux transporters that can decrease the concentration of their substrates in the testis, thereby reducing reproductive toxicity in males (RTM) and protecting spermatogenesis. However, there is currently no direct pharmacological evidence demonstrating that P-gp and BCRP can reduce the occurrence of drug-induced RTM. In this study, we chose small molecule targeted anti-tumor agents as model drugs and systematically retrieved and collected information on the transporters and RTM for these drugs, followed by correlation analysis. The results showed a lower incidence of RTM for P-gp substrate drugs, which aligns with previous knowledge. Surprisingly, BCRP substrate drugs exhibited higher rates of RTM in various dimensions, contradicting previous notions. This discrepancy may be attributed to the differential distribution and transport directions of P-gp and BCRP on the blood-testis barrier (BTB). For the first time, this study may provide clues that BCRP may facilitate the passage of exogenous compounds across the BTB, increasing the occurrence of RTM, rather than protecting spermatogenesis as traditionally believed. Furthermore, this study provides the first direct verification of the role of P-gp in reducing RTM and protecting spermatogenesis.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos , Barreira Hematotesticular , Masculino , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Barreira Hematotesticular/efeitos dos fármacos , Barreira Hematotesticular/metabolismo , Reprodução/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Espermatogênese/efeitos dos fármacosRESUMO
BACKGROUND: Older adults are at high risk for toxicity due to cancer treatment and increased risk for adverse events related to chemotherapy-induced nausea and vomiting (CINV). Unfortunately, older adults report multiple treatment-related symptoms but use few strategies to self-manage these symptoms due to erroneous beliefs related to the effectiveness of commonly taught self-management strategies. We developed a novel serious game, Managing at Home (MAH), to help older adults learn how to effectively self-manage CINV at home. OBJECTIVE: This study has 2 aims. Aim 1 is to examine changes in CINV severity, self-management behaviors, functioning, quality of life, cognitive representation, and health care use within the intervention group from baseline (T1) to completion of the study (T6). Aim 2 is to determine the efficacy of the MAH intervention by comparing differences in primary outcomes (CINV severity and health care use) and secondary outcomes (self-management behaviors, functioning, and quality of life) between the intervention and control groups at each follow-up visit (T2-T6) and completion of the study (T6). METHODS: This is a longitudinal randomized clinical trial. We will collect data from 500 older adults receiving cancer-related chemotherapy at baseline (T1) and at each treatment cycle until cycle 6 (T6). Participants will be enrolled if they are 60 years or older of age, are newly diagnosed with cancer, being treated with any chemotherapy agent with moderate or high emetic potential, are on a 2-, 3-, or 4-week treatment cycle, are proficient in English, and have a telephone. Previous diagnosis or treatment for cancer, end-stage disease with less than 6 months to live, and uncorrected visual or hearing impairment are exclusion criteria. RESULTS: This study was funded in September 2022 and received institutional review board approval in October 2022. As of July 2023, the enrollment of participants is ongoing and currently has 130 enrolled participants. Data collection and analysis will be complete in 2027. CONCLUSIONS: This study addresses self-management of CINV in older adults using an innovative serious game. The MAH intervention uses simulation and gaming technology to engage older adults in active learning in order to reframe erroneous perceptions about symptom self-management. If shown to be effective, it can easily be adapted to include other cancer-related symptoms or other chronic illnesses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05838638; https://clinicaltrials.gov/study/NCT05838638. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/64673.
Assuntos
Antineoplásicos , Náusea , Neoplasias , Vômito , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Náusea/induzido quimicamente , Náusea/prevenção & controle , Náusea/tratamento farmacológico , Náusea/terapia , Neoplasias/tratamento farmacológico , Qualidade de Vida/psicologia , Autogestão/métodos , Jogos de Vídeo , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This survey aimed to reveal the actual preventing exposure for handling of clothing and sweat of patients treated with anticancer drugs, following the publication of "Guideline for Preventing Occupational Exposure in Cancer Chemotherapy Drugs, 2019 Edition" (Guideline 2019). A survey was conducted among nurses working at 95 hematopoietic stem cell transplantation promotion base hospitals from September 1, 2023 to October 31, 2023. The response rate was 84.2% (80 facilities). Of the respondents, 45% wore gloves when touching patients' skin to administer anticancer drugs. Almost the nurses identified "urine" and "feces" as fluids on contaminated linen, while 14.1% also identified "sweat." For new staff, the results for preventing exposure education on "if touching the patients' skin" and "if handling clothing and linen" were 23.8% and 34.9%, respectively. This survey shows that nurses may not be following the Guideline 2019 for use of personal protective equipment and handling of clothes. Medical institutions handling anticancer drugs need to educate their staff for preventing occupational exposure.
Assuntos
Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Exposição Ocupacional , Suor , Humanos , Antineoplásicos/efeitos adversos , Exposição Ocupacional/prevenção & controle , Inquéritos e Questionários , Suor/química , Equipamento de Proteção Individual , Luvas Protetoras , Fidelidade a Diretrizes , Vestuário , Guias de Prática Clínica como AssuntoRESUMO
Many patients with chronic myeloid leukemia (CML) can now maintain response thanks to the advent of tyrosine kinase inhibitors (TKIs) and STAMP inhibitors, but adverse events associated with prolonged TKI therapy have become a problem. Adequate management of adverse events is key to successful treatment, as some can significantly impact the patient's prognosis. The goal of CML treatment was once to prevent acute transformation, but now that many patients achieve deep remission and long-term survival, the goal has shifted to achieving long-term treatment free remission (TFR). It is essential to carefully consider disease risk, patient background, and adverse events of each therapeutic agent in order to make the appropriate choice. This article reviews the treatment of chronic phase CML (CML-CP) as described in the 2023 edition of the Guidelines for Hematopoietic Tumors, focusing on treatment options for first-line CML-CP, dose optimization of ponatinib, outcomes with the new CML drug asciminib, and TFR.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagemAssuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Difosfonatos/efeitos adversos , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/efeitos adversosRESUMO
Tepotinib is approved for the treatment of patients with non-small-cell lung cancer harboring MET exon 14 skipping alterations. While edema is the most prevalent adverse event (AE) and a known class effect of MET inhibitors including tepotinib, there is still limited understanding about the factors contributing to its occurrence. Herein, we apply machine learning (ML)-based approaches to predict the likelihood of occurrence of edema in patients undergoing tepotinib treatment, and to identify factors influencing its development over time. Data from 612 patients receiving tepotinib in five Phase I/II studies were modeled with two ML algorithms, Random Forest, and Gradient Boosting Trees, to predict edema AE incidence and severity. Probability calibration was applied to give a realistic estimation of the likelihood of edema AE. Best model was tested on follow-up data and on data from clinical studies unused while training. Results showed high performances across all the tested settings, with F1 scores up to 0.961 when retraining the model with the most relevant covariates. The use of ML explainability methods identified serum albumin as the most informative longitudinal covariate, and higher age as associated with higher probabilities of more severe edema. The developed methodological framework enables the use of ML algorithms for analyzing clinical safety data and exploiting longitudinal information through various covariate engineering approaches. Probability calibration ensures the accurate estimation of the likelihood of the AE occurrence, while explainability tools can identify factors contributing to model predictions, hence supporting population and individual patient-level interpretation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Edema , Aprendizado de Máquina , Humanos , Edema/induzido quimicamente , Feminino , Masculino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Adulto , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piperidinas , PiridazinasRESUMO
PURPOSE: We aimed at identifying prevalence, clinical outcomes and prognostic factors in cancer patients with intravenous chemotherapy-induced severe neutropenia (ICISN). METHODS: In this multicenter retrospective cohort study on the clinical data warehouse of Greater Paris University Hospitals (AP-HP), we included all adult patients with solid cancer hospitalized between 2016 and 2021 with intravenous chemotherapy within 30 days prior to severe neutropenia (D70 or D611 ICD-10 codes AND a neutrophil count < 500/mm3). The primary endpoint was referral to intensive care unit (ICU) or death within 30 days. We collected cancer, patient, and treatment characteristics. RESULTS: Among 141,586 cancer inpatients, 40,660 received chemotherapy among whom 661 (1.6%) had ICISN. Median age was 63 years (interquartile range (IQR), 54-70) and 330 patients (49%) were female. The median Charlson score was 10 (IQR, 8-11). Main primary cancers were lung (n = 204, 31%) and breast (n = 87, 13%). Advanced cancers were found in 551 patients (83%), 331 (50%) were in 1st line of chemotherapy, 284 (42%) in the 1st cycle of the current line and 149 (22%) had primary G-CSF. Documented bacterial (mostly gram-negative bacilli) and fungal infections were observed in 113 (17%) and 19 (3%) patients; 58 (9%) were transferred to ICU and 82 (12%) died within 30 days, 372 (56%) patients received subsequent chemotherapy. Independent prognostic factors were the level of monocyte, lymphocyte counts or albuminemia and a documented bacterial infection, while Charlson index and primary prophylactic G-CSF were not associated with patient clinical outcomes. CONCLUSION: Despite the use of primary G-CSF, ICISN remains a frequent event, which leads to ICU death in one on five cases Some prognostic factors of severity have been highlighted and could help clinicians to prevent severe complications.
Assuntos
Antineoplásicos , Neoplasias , Neutropenia , Humanos , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Neoplasias/tratamento farmacológico , Prevalência , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Estudos de Coortes , Prognóstico , Unidades de Terapia Intensiva/estatística & dados numéricos , Fatores de Risco , Índice de Gravidade de Doença , Administração IntravenosaAssuntos
Doenças Autoimunes , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Feminino , Neoplasias/tratamento farmacológico , Masculino , Idoso , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Dermatopatias Vesiculobolhosas/patologia , Pessoa de Meia-Idade , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Piperazinas/uso terapêutico , Piperazinas/efeitos adversos , Comitês Consultivos , Estudos de Coortes , PiridinasRESUMO
The objective of this study was to establish a nausea-free ward model and evaluate the effect of an intervention procedure guided by this model on chemotherapy-induced nausea and vomiting (CINV) in cancer patients. A total of 105 chemotherapy patients from March to September 2022 before the establishment of nausea-free ward in the Chongqing Jiulongpo District People's Hospital were selected as the control group as well as 105 chemotherapy patients from March to September 2023 after the establishment of nausea-free ward as the intervention group. The intervention group was managed by comprehensive standardized CINV management on the basis of the control group. Finally, the Chinese Society of Clinical Oncology grading tool for nausea and vomiting and the Functional Living Index-Emesis were used to evaluate the effect. Under the intervention of the nausea-free ward model, the intervention group exhibited significantly lower ratings of nausea and vomiting compared to the control group (all P-value <.05). The nausea score, vomiting score, and total score of the intervention group were significantly lower than the control group (all P-value <.05). Our study found CINV symptoms and quality of life can be significantly improved by the application of the nausea-free ward model. The nausea-free ward model is instructive in clinical practice and can guide clinical work as well as bring management experience to clinical workers.
Assuntos
Antineoplásicos , Náusea , Neoplasias , Vômito , Humanos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/prevenção & controle , Feminino , Masculino , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Qualidade de Vida , Idoso , Antieméticos/uso terapêutico , ChinaRESUMO
The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.
Assuntos
Antineoplásicos , Cardiotoxicidade , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Sirtuína 1 , Humanos , Sirtuína 1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Cardiotoxicidade/etiologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoAssuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/história , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , História do Século XX , História do Século XXI , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/história , /efeitos adversos , Ensaios Clínicos Fase III como Assunto , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-ß-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.
Assuntos
Cisplatino , MAP Quinase Quinase Quinases , Camundongos Knockout , Transdução de Sinais , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Animais , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de SinalRESUMO
Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.
Assuntos
Injúria Renal Aguda , Cisplatino , Estresse do Retículo Endoplasmático , eIF-2 Quinase , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Animais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/genética , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Masculino , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Antineoplásicos/efeitos adversos , Antineoplásicos/toxicidade , FosforilaçãoRESUMO
Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis, which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Nontargeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCTPAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCTPAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCTinduced PAH in rats by reducing the Warburg effect.
Assuntos
Flavonoides , Glicólise , Monocrotalina , Hipertensão Arterial Pulmonar , Animais , Ratos , Masculino , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Glicólise/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Ratos Sprague-Dawley , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Scutellaria baicalensis/química , Modelos Animais de Doenças , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Efeito Warburg em Oncologia/efeitos dos fármacosRESUMO
The study aims to evaluate the effect of Kaixin Powder(KXP) on the behavior and brain tissue of chemotherapy-treated mice to explore its mechanism in alleviating chemotherapy-induced cognitive impairment in tumor-bearing mice. Thirty female BALB/c mice were inoculated with 4T1 breast cancer cells to establish a tumor-bearing mouse model and randomly divided into the tumor group, a doxorubicin group, and a KXP group. Behavioral tests, including open field test, elevated plus maze test, forced swimming test, tail suspension test, Morris water maze test, and novel object recognition test, were conducted. Pathological examinations, including hematoxylin-eosin staining, Nissl staining, toluidine blue staining, Fluoro-Jade B staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay, immunofluorescence staining, and transmission electron microscopy, were performed. Network pharmacology and whole transcriptome sequencing methods were used to analyze the mechanism of chemotherapy-induced cognitive impairment and the targets of KXP. The results showed that KXP prevented chemotherapy-induced behavioral changes(P<0.001), increased the total movement distance and central zone residence time in the open field test, increased exploration time in the open arm area in the elevated plus maze test, reduced immobility time in the forced swimming test and tail suspension test, reduced escape latency in the Morris water maze test and increased platform crossings, and improved cognitive index in the novel object recognition test. KXP also inhibited chemotherapy-induced neuroinflammation, apoptosis, and autophagy in the prefrontal cortex, and reshaped the RNA expression profile of the prefrontal cortex tissue during chemotherapy(P<0.05). In conclusion, KXP may alleviate chemotherapy-induced cognitive impairment in tumor-bearing mice by reshaping the RNA expression profile of prefrontal cortex tissue, thereby reducing neuronal tissue damage.
Assuntos
Neoplasias da Mama , Medicamentos de Ervas Chinesas , Camundongos Endogâmicos BALB C , Animais , Feminino , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/genética , Disfunção Cognitiva/tratamento farmacológico , Humanos , Comprometimento Cognitivo Relacionado à Quimioterapia/genética , Comprometimento Cognitivo Relacionado à Quimioterapia/tratamento farmacológico , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Transcriptoma/efeitos dos fármacos , Pós/química , Perfilação da Expressão Gênica , Apoptose/efeitos dos fármacos , Antineoplásicos/efeitos adversosRESUMO
Objective: To investigate the impact of exosomes and microRNA (miRNA) from placental mesenchymal stem cells on chemotherapy-damaged ovarian granulosa cells. Methods: Various public databases were searched for miRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene. After miRNA transfection into human ovarian granulosa cells, cell growth and expressions of the target miRNA and PTEN were detected. Cisplatin was utilized to induce damage to human ovarian granulosa cells, which were subsequently co-cultured with human placental mesenchymal stem cells and exosomes generated from mesenchymal stem cells, then apoptosis and expressions of PTEN and the target miRNA were detected. Results: After analyzing several databases, miRNA 139-5p (miR-139-5p) was chosen as the target miRNA for this research. Transfection of miR-139-5p mimics into human ovarian granulosa cells elevated miR-139-5p expression level (9 882.080±1 049.130), reduced PTEN protein expression level (0.78±0.11), and increased cell proliferation absorbance (0.85±0.07). Cisplatin treatment severely damaged human ovarian granulosa cells and increased apoptosis, cisplatin-treated cells had a higher apoptosis ratio compared to untreated cells [ (41.9±1.0)% vs (5.0±0.3)%, P<0.001]. In damaged human ovarian granulosa cells, co-cultured with human placental mesenchymal stem cells and exosomes increased miR-139-5p expression levels (1.31±0.04 and 1.20±0.03, respectively) and decreased apoptosis ratios [(20.0±0.4)% and (22.3±1.1)%, respectively]. Conclusion: Placental mesenchymal stem cell-derived exosomes repair damages of cisplatin-induced ovarian granulosa cell and could target PTEN gene through miR-139-5p, which might be a potential option for the treatment of chemotherapy-induced ovarian dysfunction.
Assuntos
Apoptose , Proliferação de Células , Cisplatino , Exossomos , Células da Granulosa , Células-Tronco Mesenquimais , MicroRNAs , PTEN Fosfo-Hidrolase , Placenta , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Exossomos/metabolismo , Exossomos/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Células da Granulosa/metabolismo , Cisplatino/efeitos adversos , Placenta/metabolismo , Gravidez , Transfecção , Técnicas de Cocultura , Ovário , Antineoplásicos/efeitos adversosRESUMO
PURPOSE: To explore the reliability and validity of clinically-relevant outcome measures for balance (i.e., The Short Physical Performance Battery [SPPB] - Balance Subscale) and sensation (i.e., monofilament threshold testing) for use in clinical trials of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Adult, post-treatment cancer survivors (N = 142) who had reported ≥ 4/10 CIPN symptom severity following neurotoxic chemotherapy were recruited from six National Cancer Institute Community Oncology Research Program (NCORP) sites associated with the University of Rochester Cancer Center NCORP Research Base. Participants completed the monofilament threshold test at the screening and baseline time points (i.e., one week apart), while the Quality of Life Questionnaire-CIPN20, Treatment-Induced Neuropathy Assessment Scale, and SPPB - Balance Subscale were completed at baseline. Test-retest reliability of the monofilament threshold testing scores was assessed using the Intraclass Correlation Coefficient (ICC). The convergent validity among monofilament threshold testing, SPPB - Balance Subscale, and CIPN patient-reported outcome (PRO) scores at baseline was assessed using Spearman's correlation. RESULTS: Ceiling effects were observed for SPPB-Balance Subscale scores as 113 (79.6%) respondents reported the highest score. Agreement between the screening and baseline monofilament threshold testing scores was moderate (ICC = 0.65). Monofilament threshold testing (rs Range: 0.14 - 0.21) and SPPB Balance Subscale scores (rs Range: -0.36 - -0.22) showed largely low correlations with all PRO measures. CONCLUSIONS: Monofilament threshold testing demonstrated moderate test-retest reliability, but low convergent validity with CIPN PROs, while the SPPB - Balance Subscale demonstrated low convergent validity with CIPN PROs and ceiling effects (i.e., highest possible score) among post-treatment cancer survivors with CIPN. Future research is needed to identify promising measures of balance and sensation loss for use in clinical trials that complement CIPN PROs to aid in the identification of clinically relevant treatments for CIPN. TRIAL REGISTRATION: NCT04367490 [April 29, 2020].
Assuntos
Antineoplásicos , Doenças do Sistema Nervoso Periférico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Sobreviventes de Câncer , Neoplasias/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Equilíbrio Postural/efeitos dos fármacos , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Major cancer treatments can cause a wide range of unpleasant symptoms that burden oncology patients. Different symptom clusters (SC) among cancer patients have been reported in the literature. This study determined the prevalence of symptoms patients experience during chemotherapy treatment and identified symptom clusters among them. METHODS: A cross-sectional study was conducted among 213 cancer patients undergoing chemotherapy in three large hospitals in Vietnam. Symptoms were measured by the Memorial Symptom Assessment Scale. RESULTS: The most prevalent symptoms were lack of appetite (65.3%), difficulty sleeping (62.9%), dry mouth (57.7%), numbness (60.1%), hair loss (43.2%), change in the way food tastes (40.8%), and lack of energy (44.1%). Four symptom clusters were identified. Difficult concentration, pain, cough, and dizziness contributed to the first SC. The second one included lack of energy, numbness, change the food taste, and lack of appetite. Dry mouth, nausea, feeling bloated, problems with urination, hair loss, and constipation made up for the third SC. The final SC consisted of psychological symptoms, which were feeling nervous, feeling drowsy, feeling sad, worrying, problems with sexual interest or activity and difficulty sleeping. CONCLUSION: The study demonstrated that respondents experienced various symptoms and symptom clusters during chemotherapy. These findings can be used to develop clinical guidelines for symptom assessment and management in oncology patients for healthcare professionals.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Masculino , Estudos Transversais , Feminino , Pessoa de Meia-Idade , Vietnã/epidemiologia , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Idoso , PrevalênciaRESUMO
BACKGROUND: The optimal duration of preoperative imatinib (IM) remains controversial. This study aimed to evaluate the safety, therapeutic effectiveness, and optimal duration of preoperative IM in patients with locally advanced gastric gastrointestinal stromal tumors (GIST). METHODS: The clinicopathologic data of 41 patients with locally advanced gastric GIST who received preoperative IM and underwent surgical resection from January 2014 and December 2021 were retrospectively analyzed. RESULTS: After a median of 7.0 (IQR: 4.5-10) months of preoperative IM treatment, 30 patients experienced adverse events (AEs), 80% of which were grade 1/2 AEs. The mean tumor size decreased from 12.71 ± 5.34 cm to 8.26 ± 4.00 cm, with a reduction rate of 35%. Setting 8 months as the cut-off value according to the results of ROC analysis. The proportion of laparoscopic surgery was higher in patients with short-term (≤8 months) versus long-term (>8 months) preoperative IM. Compared with the subtotal/total gastrectomy group, patients in the local gastrectomy group exhibited less intraoperative blood loss, shorter length of postoperative hospital stay, and fewer postoperative complications. The 3-year recurrence-free survival (RFS) and overall survival (OS) rates were 82.9% and 97.6%, and the expected 5-year RFS and OS rates were 75.6% and 90.2% respectively. RFS was better in the short-term than in the long-term preoperative IM treatment group, and it was also better in pre- plus postoperative IM treatment group than that in the preoperative IM alone group. Both univariate and multivariate COX analysis showed that a higher mitotic index and long-term preoperative IM treatment were associated with worse RFS, while postoperative IM treatment could significantly improve RFS. CONCLUSIONS: The study suggests that in patients with locally advanced gastric GIST, preoperative short-term (≤8 months) use of IM is associated with higher RFS than long-term use.