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Background: Hypoxia is the bottleneck that affects the response of conventional photon radiotherapy, but it does not seem to have much effect on carbon ion radiotherapy (CIRT). This study aimed to evaluate the changes of hypoxia before and after CIRT in patients with non-small cell lung cancer (NSCLC) and whether 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT) imaging could predict the response to CIRT in NSCLC patients. Methods: A total of 29 patients with NSCLC who received CIRT were retrospectively included. 18F-FMISO PET/CT imaging was performed before and after treatment, and chest CT was performed after radiotherapy. Radiation response within 1 week after radiotherapy and at the initial follow-up were defined as the immediate response (IR) and early response (ER), respectively. The tumor-to-muscle ratio (TMR), hypoxia volume (HV), and the ΔTMR and ΔHV values of 18F-FMISO uptake were collected. Fisher's exact test, Mann-Whitney U test, Wilcoxon signed-rank test, and binary logistic regression were used to analyze data. Results: (I) Baseline TMR could predict the IR to CIRT with a baseline TMR cut-off value of 2.35, an area under the curve (AUC) of 0.85 [95% confidence interval (CI): 0.62-1.00], a sensitivity of 80.0%, a specificity of 87.5%, and an accuracy of 85.7%. Taking the baseline TMR =2.35 as the cut-off value of high-hypoxia and low-hypoxia group, the IR rate of the high-hypoxia group [66.7% (4/6)] and the low-hypoxia group [6.7% (1/15)] was statistically different (P=0.01). (II) ΔTMR could predict early treatment response after CIRT at initial follow-up, with a cut-off value of ΔTMR =36.6%, AUC of 0.80 (95% CI: 0.61-1.00), sensitivity of 72.7%, specificity of 90.0% and accuracy of 71.4%. Conclusions: A higher degree of tumor hypoxia may be associated with a better IR to CIRT. ΔTMR could predict early treatment response after CIRT.
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In order to improve the wound repair environment, this research has successfully developed a new multifunctional hydrogel dressing, which has strong adaptability and can accelerate wound healing. Pioneering the development of metal-ion-controlled hydrogel dressings, this research integrates dopamine and imidazole double crosslinked networks with metal-ion coordination. The resulting hydrogel dressing exhibits a notable antibacterial effect and exceptional mechanical properties, withstanding pressures of up to 12 kPa, tensions of 25 kPa, and maintaining skin adhesion at 6 kPa. Furthermore, the dressing can self-heal within only 7-8 s post-injection. Impressively, the hydrogel achieves complete biodegradation within a short timeframe (37 h). Notably, the use of various metal ions facilitates painless peeling during the degradation period, perfectly aligning with the requirements of an ideal wound dressing. This study has made significant progress in the fields of trauma repair and materials, providing strong solutions for dealing with harsh post-traumatic environments.
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Objective. To assess the dosimetric consequences and the normal tissue complication probability (NTCP) for the organs at risk (OARs) in intensity-modulated particle radiotherapy of proton (IMPT) and carbon-ion (IMCT) using a fixed-beam delivery system when compared with intensity-modulated photon radiotherapy (IMRT) for locally advanced small-cell lung cancer.Approach. The plans were all designed under the same total relative biological effectiveness (RBE)-weighted prescription dose, in which the planning target volume (PTV) of the internal gross target volume(IGTV) and the PTV of the clinical target volume was irradiated with 69.3 Gy (RBE) and 63 Gy (RBE), respectively, using a simultaneously integrated boosting (SIB) technique. NTCPs were estimated for heart, lung, esophagus and spinal cord by Lyman-Kutcher-Burman (LKB) and logistic models. Dose escalation was simulated under the desired NTCP values (0.05, 0.10 and 0.50) of the three radiation techniques.Main results. Under the similar target coverage, almost all OARs were significantly better spared (p< 0.05) when using the particle radiotherapy except for D1cc (the dose to 1 cm3of the volume) of the proximal bronchial tree (p> 0.05). At least 57.6% of mean heart dose, 28.8% of mean lung dose and 19.1% of mean esophageal dose were reduced compared with IMRT. The mean NTCP of radiation-induced pneumonitis (RP) in the ipsilateral lung was 0.39 ± 0.33 (0.39 ± 0.31) in IMPT plans and 0.36 ± 0.32 (0.35 ± 0.30) in IMCT plans compared with 0.66 ± 0.30 (0.64 ± 0.28) in IMRT plans by LKB (logistic) models. The target dose could be escalated to 78.3/76.9 Gy (RBE) in IMPT/IMCT plans compared with 61.7 Gy (RBE) in IMRT plans when 0.50 of NTCP in terms of RP in the ipsilateral lung was applied.Significance. This study presents the potential of better control of the side effects and improvement of local control originating from the dosimetric advantage with the application of IMPT and IMCT with the SIB technique for locally advanced lung cancer, even with limited beam directions.
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Neoplasias Pulmonares , Terapia de Protones , Neumonitis por Radiación , Radioterapia de Intensidad Modulada , Humanos , Neoplasias Pulmonares/radioterapia , Protones , Rayos X , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Probabilidad , Neumonitis por Radiación/etiología , Órganos en Riesgo/efectos de la radiaciónRESUMEN
BACKGROUND: Concurrent chemoradiotherapy has been standard of care for unresectable esophageal carcinoma. There were no reports on proton radiotherapy (PRT) plus carbon-ion radiotherapy (CIRT) with pencil beam scanning (PBS) for esophageal carcinoma. This study evaluated the tolerability and efficiency of proton and sequential carbon-ion boost radiotherapy for esophageal carcinoma. METHODS: From April 2017 to July 2020, 20 patients with primary esophageal carcinoma at stages II-IV were treated with PRT plus sequential CIRT with PBS. A median relative biological effectiveness-weighted PRT dose of 50 Gy in 25 fractions, and a sequential CIRT dose of 21 Gy in 7 fractions were delivered. Respiratory motion management was used if the tumor moved > 5 mm during the breathing cycle. A dosimetric comparison of photon intensity-modulated radiotherapy (IMRT), PRT, and CIRT was performed. The median times and rates of survivals were estimated using the Kaplan-Meier method. Comparison of the dose-volume parameters of the organs at risk employed the Wilcoxon matched-pairs test. RESULTS: Twenty patients (15 men and 5 women, median age 70 years) were included in the analysis. With a median follow-up period of 25.0 months, the 2-year overall survival and progression-free survival rates were 69.2% and 57.4%, respectively. The patients tolerated radiotherapy and chemotherapy well. Grades 1, 2, 3, and 4 acute hematological toxicities were detected in 25%, 30%, 10%, and 30% of patients, respectively. Grades 3-5 acute non-hematological toxicities were not observed. Late toxicity events included grades 1, 2, and 3 in 50%, 20%, and 10% (pulmonary and esophageal toxicity in each) of patients. Grades 4-5 late toxicities were not noted. PRT or CIRT produced lower doses to organs at risk than did photon IMRT, especially the maximum dose delivered to the spinal cord and the mean doses delivered to the lungs and heart. CONCLUSIONS: PRT plus CIRT with PBS appears to be a safe and effective treatment for esophageal carcinoma. PRT and CIRT delivered lower doses to organs at risk than did photon IMRT. Further investigation is warranted.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Radioterapia de Iones Pesados , Radioterapia de Intensidad Modulada , Masculino , Humanos , Femenino , Anciano , Protones , Estudios Retrospectivos , Radioterapia de Iones Pesados/efectos adversos , Neoplasias Esofágicas/patología , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Carcinoma de Células Escamosas/patología , Carbono , Dosificación RadioterapéuticaRESUMEN
Stroke is a group of cerebrovascular diseases with high prevalence and mortality rate. Stroke can induce many impairments, including motor and cognitive dysfunction, aphasia/dysarthria, dysphagia, and mood disorders, which may reduce the quality of life among the patients. Constraint-induced therapy has been proven to be an effective treatment method for stroke rehabilitation. It has been widely used in the recovery of limb motor dysfunction, aphasia, and other impairment like unilateral neglect after stroke. In recent years, constraint-induced therapy can also combine with telehealth and home rehabilitation. In addition, constraint-induced therapy produces significant neuroplastic changes in the central nervous system. Functional magnetic resonance imaging, diffusion tensor imaging, and other imaging/electrophysiology methods have been used to clarify the mechanism and neuroplasticity. However, constraint-induced therapy has some limitations. It can only be used under certain conditions, and the treatment time and effectiveness are controversial. Further research is needed to clarify the mechanism and effectiveness of CI therapy.
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Pyroptosis is accompanied by immunogenic mediators' release and serves as an innovative strategy to reprogram tumor microenvironments. However, damaged mitochondria, the origin of pyroptosis, are frequently eliminated by mitophagy, which will severely impair pyroptosis-elicited immune activation. Herein, black phosphorus nanosheets (BP) are employed as a pyroptosis inducer delivery and mitophagy flux blocking system since the degradation of BP could impair lysosomal function by altering the pH within lysosomes. The pyroptosis inducer of lonidamine (LND) was precoupled with the mitochondrial target moiety of triphenylphosphonium to facilitate the occurrence of pyroptosis. The mitochondria-targeting LND-modified BP (BPTLD) were further encapsulated into the macrophage membrane to endow the BPTLD with blood-brain barrier penetration and tumor-targeting capability. The antitumor activities of membrane-encapsulated BPTLD (M@BPTLD) were investigated using a murine orthotopic glioblastoma model. The results demonstrated that the engineered nanosystem of M@BPTLD could target the mitochondria, and induce as well as reinforce pyroptosis via mitophagy flux blocking, thereby boosting the release of immune-activated factors to promote the maturation of dendritic cells. Furthermore, upon near-infrared (NIR) irradiation, M@BPTLD induced stronger mitochondrial oxidative stress, which further advanced robust immunogenic pyroptosis in glioblastoma cells. Thus, this study utilized the autophagy flux inhibition and phototherapy performance of BP to amplify LND-mediated pyroptosis, which might greatly contribute to the development of pyroptosis nanomodulators.
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Glioblastoma , Animales , Ratones , Glioblastoma/metabolismo , Piroptosis , Fósforo/farmacología , Mitocondrias/metabolismo , Microambiente TumoralRESUMEN
Stroke and spinal cord injury are common neurological disorders that can cause various dysfunctions. Motor dysfunction is a common dysfunction that easily leads to complications such as joint stiffness and muscle contracture and markedly impairs the daily living activities and long-term prognosis of patients. Orthotic devices can prevent or compensate for motor dysfunctions. Using orthotic devices early can help prevent and correct deformities and treat muscle and joint problems. An orthotic device is also an effective rehabilitation tool for improving motor function and compensatory abilities. In this study, we reviewed the epidemiological characteristics of stroke and spinal cord injury, provided the therapeutic effect and recent advances in the application of conventional and new types of orthotic devices used in stroke and spinal cord injury in different joints of the upper and lower limbs, identified the shortcomings with these orthotics, and suggested directions for future research.
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A highly sensitive dual-gas sensor based on a two-channel multipass cell (MPC) was designed and developed for simultaneous detection of atmospheric methane (CH4) and carbon dioxide (CO2) by using two distributed feedback lasers emitting at 1653 nm and 2004 nm. The nondominated sorting genetic algorithm was applied to intelligently optimize the MPC configuration and accelerate the dual-gas sensor design process. A compact and novel two-channel MPC was used to achieve two optical path lengths of 27.6 m and 2.1 m in a small volume of 233 cm3. Simultaneous measurements of CH4 and CO2 in the atmosphere were performed to demonstrate the stability and robustness of the gas sensor. According to the Allan deviation analysis, the optimal detection precision for CH4 and CO2 was 4.4 ppb at an integration time of 76 s and 437.8 ppb at an integration time of 271 s, respectively. The newly developed dual-gas sensor exhibits superior characteristics of high sensitivity and stability, cost-effectiveness and simple structure, which make it well-suited for multiple trace gas sensing in various applications, including environmental monitoring, safety inspections and clinical diagnosis.
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Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbon-ion radiotherapy is a radical nonsurgical treatment with high local control rates and no serious adverse events. N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNA (mRNA) and has important effects on the stability, splicing, and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbon-ion radiotherapy of non-small-cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of methyltransferase-like 3 (METTL3) and its mediated m6A modification were elevated in NSCLC cells with carbon-ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3-mediated m6A modification of mRNA inhibited the decay of H2A histone family member X (H2AX) mRNA and enhanced its expression, which led to enhanced DNA damage repair and cell survival.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , CarbonoRESUMEN
PURPOSE: Lymphopenia is a common adverse effect of radiation therapy (RT). Little is known about the difference in lymphopenia between intensity modulated (photon) radiation therapy (IMRT) and proton and carbon ion radiation therapy (PCIRT). This study aimed to investigate lymphopenia differences between IMRT and PCIRT in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Clinical and dosimetric parameters were collected from 343 patients who received definitive IMRT or PCIRT for NSCLC. Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) ≤0.5 × 103 cells/µL. Overall survival (OS) was analyzed using the Kaplan-Meier method. Propensity score matching was performed between the IMRT and PCIRT groups. Least absolute shrinkage and selection operator analysis was used to select appropriate dosimetric parameters. Univariate and multivariate logistic regression analyses were conducted to identify the predictors of SRL. RESULTS: Compared with the IMRT group, the PCIRT group was less likely to develop SRL (P < .001). Compared with the non-SRL group, the SRL group showed significant association with poorer OS, with a median survival time of 29.2 versus 15.0 months (P = .046). IMRT was an independent risk factor of SRL (P = .004). A lower ALC before RT (P = .030) and larger planning target volume (PTV) (P = .002) were also significant independent risk factors for SRL. Moreover, the majority of dosimetric parameters of organs at risk in PCIRT were lower than those in IMRT (P < .001). Thoracic vertebra V5 (P = .002) and aorta V5 (P = .026) were identified as independent risk predictors of SRL after adding dosimetric parameters to the regression model. CONCLUSIONS: Compared with IMRT, PCIRT could reduce SRL incidence, possibly by limiting thoracic vertebra and aortic doses, and SRL was associated with poor outcomes in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Radioterapia de Iones Pesados , Neoplasias Pulmonares , Linfopenia , Terapia de Protones , Radioterapia de Intensidad Modulada , Humanos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Protones , Linfopenia/etiología , Radioterapia de Iones Pesados/efectos adversos , Columna Vertebral , Dosificación Radioterapéutica , Terapia de Protones/efectos adversosRESUMEN
BACKGROUND: The dose distribution of carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LANSCLC) is highly sensitive to anatomical changes. PURPOSE: To demonstrate the dosimetric benefits of adaptive CIRT for LANSCLC and compare the differences between patients with and without adaptive plans based on dosimetry and clinical effect factors. MATERIALS AND METHODS: Of the 98 patients with LANSCLC receiving CIRT, 31 patients underwent replanning following re-evaluations that revealed changes that would have compromised the dose coverage of the target volume or violated dose constraints. Dosimetric parameters and clinical factors were compared between patients with and without adaptive plans. Multivariate analysis identified factors influencing the adaptive planning. RESULTS: The median number of fractions delivered using adaptive plans was eight (range: 2-18). Adaptive plans ensured target coverage, and the maximum spinal cord dose was significantly decreased (p = 0.02). The median reduction in the maximum spinal cord dose was 10.4 Gy (relative biological effectiveness). Patients with adaptive plans had larger tumor volumes (p < 0.001); the median initial internal gross tumor volumes (iGTVs) of patients with adaptive and nonadaptive plans were 125.9 and 49.79 cm3 , respectively. Tumor volumes of patients with adaptive plans were altered to a greater extent (p < 0.001); the median absolute percentage of volume changes in patients in the adaptive and in nonadaptive groups were 20.76% and 3.63%, respectively, while the median movements of iGTV centers were 5.75 and 2.44 mm, respectively. Binary logistic regression analysis revealed that the iGTV volume change and iGTV center movements were significantly different between the groups. CONCLUSIONS: An adaptive plan can effectively ensure target area coverage and protect normal tissues, especially in patients with large tumor volumes and substantial changes. iGTV volume changes and iGTV center movements are the main factors influencing adaptive planning. Weekly simulation computed tomography scans are necessary for treatment evaluation in patients with LANSCLC treated with CIRT.
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Carcinoma de Pulmón de Células no Pequeñas , Radioterapia de Iones Pesados , Neoplasias Pulmonares , Radioterapia de Intensidad Modulada , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Órganos en Riesgo , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/métodosRESUMEN
OBJECTIVES: This study aimed to investigate the tolerance and effect of proton plus carbon-ion radiotherapy with concurrent chemotherapy in limited-stage small cell lung cancer using the pencil beam scanning technique. MATERIALS AND METHODS: From March 2017 to April 2020, 25 patients with limited-stage small cell lung cancer treated with combined proton and carbon-ion radiotherapy were analyzed. The primary lesions and involved lymph nodes were irradiated using 2-4 portals. Proton and sequential carbon-ion beams were delivered with a median dose of 67.1 (range, 63-74.8) GyE as fraction doses of 2.0-2.2 GyE with proton beams in 20-23 fractions and 3.0-3.8 GyE with carbon ions in 5-8 fractions. Chemotherapy was delivered concurrently with radiotherapy in all patients. RESULTS: At the last follow-up, the 2-year overall and locoregional progression-free survival rates were 81.7% and 66.7%, respectively. Radiochemotherapy was well tolerated, with grade 1, 2, and 3 acute toxicities occurring in 12.0%, 68.0%, and 20.0% of patients, respectively. All grade 3 acute toxicities were hematologically related changes. One patient experienced grade 3 acute non-hematological toxicity in the esophagus, and one other patient had grade 3 bronchial obstruction accompanied by obstructive atelectasis as a late side effect. CONCLUSION: Proton plus carbon-ion radiotherapy using pencil beam scanning yielded promising survival rates and tolerability in patients with limited-stage small cell lung cancer. A prospective clinical study is warranted to validate the therapeutic efficacy of particle radiotherapy in combination with chemotherapy in limited-stage small cell lung cancer.
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BACKGROUND: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC. METHODS: The inclusion criteria were as follows: 1) age 18-80 years; 2) Eastern Cooperative Oncology Group Performance Status 0-2; 3) histologically confirmed TACC; 4) stage III-IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66-72.6 GyE/22-23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Eighteen patients with a median age of 48 (range 30-73) years were enrolled. The median follow-up time was 20.7 (range 5.8-44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2-41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed. CONCLUSIONS: CIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.
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Neoplasias de los Bronquios/radioterapia , Carcinoma Adenoide Quístico/radioterapia , Traqueítis/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Radioterapia de Iones Pesados/métodos , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: To evaluate the safety and efficacy of particle therapy (PT) using pencil beam scanning (PBS) technique for early stage non-small cell lung cancer (NSCLC). METHODS: From 08/2014 to 03/2018, 31 consecutive patients with sum of the longest diameters of primary tumor and hilar lymph node < 5 cm, N0-1, M0 NSCLC treated with PT were retrospectively analyzed. Gating/active breathing control techniques were used to control tumor motion in 20 and 7 patients. PBS-based proton radiotherapy (PRT) or carbon ion radiotherapy (CIRT) plans were designed via Syngo® planning system. PRT, PRT + CIRT boost, and CIRT were used in 6, 6 and 19 patients, respectively. Prescriptions were categorized to 3 levels: 5-7.5 GyE * 8-10 Fx, 4-5 GyE * 15-16 Fx and 2.25-3.5 GyE * 20-31 Fx. RESULTS: Thirty-one patients (20 males and 11 females) with a median age of 71 (50-80) years were enrolled with a median follow-up time of 12.1 (2.9-45.2) months. Fourteen were adenocarcinomas, 7 squamous cell carcinomas, 4 non-specified NSCLC and 6 had no histological diagnosis (4/6 had previous resected lung cancer). The median tumor size was 3.1 (1.1-4.7) cm. No grade 4-5 toxicities were observed. One patient experienced grade 3 (per the Common Terminology Criteria for Adverse Events version 4.03) radiation-induced lung injury (RILI) at 6.7 months from radiation started. Grade 2 acute toxicities included hematological toxicities (5 cases), RILI (2), plural pain (1) and dermatitis (1). Grade 2 late toxicities included RILI (3) and asymptomatic rib fracture (1). Three patients had progressed disease at 4.0~10.6 months after the initiation of PT. One experienced local failure with simultaneous distant failure and died of brain metastasis at 10.8 months; one developed regional and distant failure and died of lung infection at 8.7 months; the other experienced isolated distant failure only and his disease was well controlled after salvage systemic therapy. The estimated rates of progression-free survival, local control, cause-specific survival and overall survival at 1, 2 years were 85.5% and 85.5%, 95.2% and 95.2%, 95.0% and 95.0%, 90.7% and 90.7%, respectively. CONCLUSIONS: PBS-based PT appears safe and effective for early stage NSCLC. Further follow-up and investigation is warranted. TRIAL REGISTRATION: ISRCTN, ISRCTN78973763. Registered 14 August 2018- Retrospectively registered, http://www.isrctn.com/ISRCTN78973763 .
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Adenocarcinoma/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Células Escamosas/radioterapia , Radioterapia de Iones Pesados , Neoplasias Pulmonares/radioterapia , Terapia de Protones , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Seguridad , Tasa de SupervivenciaRESUMEN
BACKGROUND: The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α). METHODS: TCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. RESULTS: Pancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis. CONCLUSION: The present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.
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BACKGROUND This study aimed to evaluate differences in the radiosensitivities of triple-negative breast cancer (TNBC) and luminal-type breast cancer cells and to investigate the effects of estrogen receptor (ER) expression on the biological behaviors of the cells. MATERIAL AND METHODS Colony-forming assays were performed to detect differences in radiosensitivities in breast cancer cell lines. Gene transfection technology was used to introduce the expression of ERα in TNBC cells to compare the difference in radiosensitivity between the TNBC cells and ERα transfected cells. CCK-8 assays were used to observe changes in the proliferation of TNBC cells after ERα transfection. Immunofluorescence was used to detect the number of γH2AX foci in nuclei. Flow cytometry was used to detect changes in cell cycle distribution and apoptosis. Western blotting was used to detect changes in autophagy-associated proteins. RESULTS The radioresistance of the TNBC cell line MDA-MB-231 (231 cells) was greater than that of ERα-positive luminal-type breast cancer cell line MCF-7. Moreover, 231 cell proliferation and radioresistance decreased after ERα transfection. Interestingly, ERα-transfected 231 cells showed increased double-stranded breaks and delayed repair compared with 231 cells, and ERα-transfected 231 cells showed increased G2/M phase arrest and apoptosis after irradiation compared with those in 231 cells. ERα transfection in 231 cells reduced autophagy-related protein expression, suggesting that autophagy activity decreased in 231 ER-positive cells after irradiation. CONCLUSIONS TNBC cells were more resistant to radiation than luminal-type breast cancer cells. ERα expression may have major roles in modulating breast cancer cell radiosensitivity.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/radioterapia , Regulación Neoplásica de la Expresión Génica , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/radioterapia , Apoptosis , Proteínas Relacionadas con la Autofagia/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Relación Dosis-Respuesta en la Radiación , Receptor alfa de Estrógeno/metabolismo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Células MCF-7 , Tolerancia a Radiación , Sincalida/metabolismo , TransfecciónRESUMEN
BACKGROUND We assessed the role of adjuvant intensity-modulated radiotherapy (IMRT) in combination with chemotherapy for pancreatic carcinomas after curative resection and identified prognostic factors related to pancreatic carcinoma after multidisciplinary treatment strategies. MATERIAL AND METHODS Pancreatic carcinoma patients (n=61) who received adjuvant radiotherapy after resection (median dose, 50.4 Gy) between 2010 and 2016 were retrospectively identified. Sixty patients received chemotherapy, including concurrent chemoradiotherapy (CCRT), systemic chemotherapy, and regional intra-arterial infusion chemotherapy (RIAC). The Kaplan-Meier method was used to measure the 3-year overall survival (OS) and disease-free survival (DFS) rates. Log-rank univariate analysis and multivariate Cox regression model analysis were used to identify prognostic factors. RESULTS Median follow-up time was 25.5 (range, 4.9-59.7) months. The 3-year OS and DFS rates were 31.0% and 16.1%, respectively. The median OS and DFS were 27.4 and 16.7 months, respectively. Multivariate analysis indicated that independent favorable predictors for OS were CCRT (p=0.039) and postoperative RIAC (p=0.044). Moreover, postoperative RIAC (p=0.027), and pre-radiotherapy CA19-9 ≤37 U/mL (p=0.0080) were independent favorable predictors for DFS. The combination of radiotherapy and chemotherapy was tolerated well by the patients, and no treatment-related death occurred. CONCLUSIONS Combined IMRT and adjuvant chemotherapy appeared safe and effective for pancreatic carcinoma. CCRT was associated with improved survival with acceptable toxicity. We propose that radiotherapy could be a part of postoperative treatment, but it should be administered concurrently with chemotherapy. Adding RIAC was associated with improved OS and DFS and it could be integrated into the postoperative treatment regimen.
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Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Radioterapia de Intensidad Modulada/métodos , Adenocarcinoma/patología , Adulto , Anciano , Quimioradioterapia/métodos , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Femenino , Humanos , Infusiones Intraarteriales/métodos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Dosificación Radioterapéutica , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5 mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by γ-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study.
Asunto(s)
Daño del ADN , Reparación del ADN , Puntos de Control de la Fase G2 del Ciclo Celular , Metformina/farmacología , Neoplasias Pancreáticas/terapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Apoptosis/efectos de la radiación , Proteína Quinasa CDC2 , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Quimioradioterapia , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Mitosis/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/patología , Fosforilación , Biosíntesis de Proteínas/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Recombinasa Rad51/metabolismo , Tolerancia a RadiaciónRESUMEN
BACKGROUND: To evaluate the role of intensity modulated radiotherapy (IMRT) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC), and the prognostic factors in the setting of multidisciplinary approach strategies. METHODS: 63 patients with LAPC and MPC receiving IMRT in our institution were retrospectively identified. Information on patient baseline, treatment characteristics and overall survival (OS) time were collected. Data of pain relief and toxicity were evaluated. Univariate and multivariate analyses were conducted to investigate the prognostic factors. RESULTS: All patients received IMRT with a median dose of 46.0 Gy. The median OS for LAPC and MPC patients were 15.7 months and 8.0 months, respectively (p = 0.029). Symptomatic improvements were observed in the 44 patients with abdominal/back pain after radiotherapy (RT) or concurrent chemoradiotherapy (CCRT), particularly in those with severe pain. Only 13.9% and 14.8% cases presented Grade ≥ 3 hematologic toxicities in RT and CCRT group, while no cases developed Grade ≥ 3 non-hematologic toxicities in both groups. Multivariate analysis indicated that tumors located in pancreas body/tail (HR 0.28, p = 0.008), pretreatment CA19-9 < 1000 U/mL (HR 0.36, p = 0.029) and concurrent chemotherapy (HR 0.37, p = 0.016) were independent favorable predictors for OS. CONCLUSIONS: CCRT further improved OS for LAPC and MPC with acceptable toxicities, and use of RT markedly alleviated pain. Tumors located in pancreas body/tail, pretreatment CA19-9 level of < 1000 U/mL and CCRT were associated with better OS. However, regional intra-arterial chemotherapy did not show any survival benefit in our study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Neoplasias Pancreáticas/radioterapia , Radioterapia de Intensidad Modulada/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/secundario , Pronóstico , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
AIMS: Recent epidemiological studies indicated that use of metformin might decrease the risk of various cancers among patients with type 2 diabetes mellitus (T2DM). However, its influence on pancreatic cancer was controversial. Therefore, we did a meta-analysis of currently available observational studies on the issue. METHODS: We did a PubMed and ISI Web of Science search for observational articles. The pooled relative risk (RR) was estimated using a random-effect model. Heterogeneity was evaluated using I(2) statistic. Subgroup analysis was performed to explore the source of heterogeneity and confirm the overall estimates. Publication bias was also examined. RESULTS: The analysis included 11 articles (13 studies) comprising 10 cohort studies and 3 case-control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer [RR 0.63, 95% confidence internal (CI) 0.46-0.86, p=0.003]. In a total 11 subgroup analyses, 5 provided the consistent result with pooled effect estimates of overall analysis. No publication bias was detected by Begg's (Z=-0.79, p=0.428) and Egger's test (t=-0.92, p=0.378). CONCLUSIONS: From present observational studies, use of metformin appears to be associated with a reduced risk of pancreatic cancer in patients with T2DM. Further investigation is needed.