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Metabolic derivatives of numerous microorganisms inhabiting the human gut can participate in regulating physiological activities and immune status of the lungs through the gut-lung axis. The current well-established microbial metabolites include short-chain fatty acids (SCFAs), tryptophan and its derivatives, polyamines (PAs), secondary bile acids (SBAs), etc. As the study continues to deepen, the critical function of microbial metabolites in the occurrence and treatment of lung cancer has gradually been revealed. Microbial derivates can enter the circulation system to modulate the immune microenvironment of lung cancer. Mechanistically, oncometabolites damage host DNA and promote the occurrence of lung cancer, while tumor-suppresive metabolites directly affect the immune system to combat the malignant properties of cancer cells and even show considerable application potential in improving the efficacy of lung cancer immunotherapy. Considering the crosstalk along the gut-lung axis, in-depth exploration of microbial metabolites in patients' feces or serum will provide novel guidance for lung cancer diagnosis and treatment selection strategies. In addition, targeted therapeutics on microbial metabolites are expected to overcome the bottleneck of lung cancer immunotherapy and alleviate adverse reactions, including fecal microbiota transplantation, microecological preparations, metabolite synthesis and drugs targeting metabolic pathways. In summary, this review provides novel insights and explanations on the intricate interplay between gut microbial metabolites and lung cancer development, and immunotherapy through the lens of the gut-lung axis, which further confirms the possible translational potential of the microbiome metabolome in lung cancer treatment.
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Microbioma Gastrointestinal , Inmunoterapia , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Ácidos Grasos Volátiles/metabolismo , Animales , Triptófano/metabolismo , Pulmón/microbiología , Pulmón/inmunología , Pulmón/metabolismoRESUMEN
PURPOSE: Hematologic toxicities (HTs) are among the most common toxicities of combined immunotherapy and radiation therapy (RT). It remains essential to prevent RT-induced HTs because they can cause treatment discontinuation (influencing antitumoral effects) and because lymphopenia might dampen the effects of immunotherapy. To date, there are no studies examining the effect of thoracic vertebral body (TVB) RT dose on HTs in patients with non-small cell lung cancer receiving combined lung RT and programmed cell death (ligand) 1 immunotherapy. METHODS AND MATERIALS: For standardization, all doses were reported as 2-Gy equivalents (EQD2). Mirroring publications before the immunotherapy era, TVB volumes referred to T1-T10, and specific dosimetric parameters (DmeanEQD2, V5EQD2-V60EQD2) were analyzed. Logistic regression estimated associations between grade ≥3 HTs (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability (NTCP) models were constructed by logistic regression analysis modeling for HT3+. Receiver operating characteristic (ROC) analysis delineated TVB dosimetric thresholds, the stratification of which was able to evaluate post-RT absolute lymphocyte count and immunotherapy responses. Areas under the curve (AUCs) for NTCP models were corroborated by bootstrapping (optimism-corrected) methodology. RESULTS: In 132 patients, there were 26 (19.7%) instances of HT3+. On multivariate analysis, DmeanEQD2 and V5EQD2 to V20EQD2 were associated with HT3+ (P < .05 for all). The NTCP models illustrated a 50% probability of HT3+ at a DmeanEQD2 = 39.8 Gy, V5EQD2 = 87.4%, V10EQD2 = 77.0%, and V20EQD2 = 68.4%. ROC analysis delineated optimal thresholds of HT3+ with DmeanEQD2 ± 30.2 Gy, V5EQD2 ± 69.1%, V10EQD2 ± 64.6%, and V20EQD2 ± 53.5%. Patients treated with values above those cutoffs had over double the risk of HT3+, with significant differences in post-RT absolute lymphocyte count and immunotherapy responses (P < .05 for all). AUCs for each individual parameter ranged from 0.743 to 0.798, and combining all 4 aforementioned cutoffs into a ROC curve resulted in a qualitatively higher AUC (0.836). CONCLUSIONS: This hypothesis-generating work suggests that TVB dosimetry may equate with HT3+ in patients with non-small cell lung cancer undergoing combined lung RT/immunotherapy. Applying TVB dose constraints in this population could reduce HT3+ and avoid dampening of immunotherapy responses, but prospective validation is required.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/radioterapia , Cuerpo Vertebral , Inmunoterapia/métodos , Pulmón , Estudios Retrospectivos , Dosificación RadioterapéuticaRESUMEN
At present the efficacy of immune checkpoint inhibitors (ICIs) remains limited. The lack of responsiveness in certain patients may be attributed to CD8+ T cell exhaustion within the tumor microenvironment (TME). Hematopoietic progenitor kinase 1 (HPK1) has been identified as a mediator of T cell dysfunction, leading to our hypothesis that HPK1 positive exhausted CD8+ T cells could serve as a predictor for ICIs' efficacy in NSCLC patients, and potentially indicate key cellular subset causing ICIs resistance. Here, we retrospectively collected tumor tissue samples from 36 NSCLC patients who underwent first-line immunotherapy. Using multiplex immunohistochemistry, we visualized various PD-1+CD8+ T cell subsets and explore biomarkers for response. The analysis endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS), correlating them with levels of cell infiltration or effective density. We found that the proportion of PD-1+CD8+ T cell subsets did not align with predictions for ORR, PFS, and OS. Conversely, a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells was identified as an independent risk factor for both PFS (P = 0.019) and OS (P = 0.03). These cells were found to express the highest levels of Granzyme B, and the secretion of Granzyme B in CD8+ T cell subsets was related to TCF-1. In conclusion, these data suggest that a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells correlates with poor clinical outcomes in NSCLC patients receiving immunotherapy. These cells may represent terminally exhausted T cells that fail to respond to ICIs, thereby laying the groundwork for the potential integration of HPK1 inhibitors with immunotherapy to enhance treatment strategy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinasas , Humanos , Linfocitos T CD8-positivos , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1 , Granzimas , Receptor 2 Celular del Virus de la Hepatitis A , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Supervivencia sin Progresión , Inmunoterapia , Pronóstico , Microambiente TumoralRESUMEN
BACKGROUND: Numerous studies have explored the association between fear of missing out and mobile phone addiction, but there are different viewpoints and the results are inconsistent. This study intends to estimate the strength of the correlation between fear of missing out and mobile phone addiction in general through a meta-analysis, and to analyze the influencing factors of the inconsistent results of previous studies. METHODS: We Searched China National Knowledge Infrastructure Database, Wan fang Database, CQVIP Journal DatabaseãWeb of Science Core Collection, Elsevier SD, Springer Online Journals, Medline, EBSCO-ERIC, SAGE Online Journals, PsycINFO, PsycArticles and ProQuest Dissertations and Thesesã85 studies (90 independent effect size) were included from 2016 to 2023ãThe pooled correlation coefficient of the association between fear of missing out and mobile phone addiction was calculated by a random effects model using Comprehensive Meta-Analysis(Version 3.3). RESULTS: The main effect analysis revealed a high positive correlation between fear of missing out and mobile phone addiction (r = 0.47, 95%CI [0.44, 0.50]). Furthermore, the measurements of mobile phone addiction moderated the strength of the association between fear of missing out and mobile phone addiction, with the highest correlation measured using MPATS and the lowest correlation measured using MPDQ. The age, gender, year of publication, cultural background, and the measurements of fear of missing out had no significant effect on the correlation between fear of missing out and mobile phone addiction. CONCLUSION: The results indicated that fear of missing out was closely related to mobile phone addiction, which complied with the I-PACE model. Psychological services and mental health services should be developed to reduce the emergence of fear of missing out in the digital age and thus alleviate dependence on devices.
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Teléfono Celular , Servicios de Salud Mental , Humanos , Adicción a la Tecnología , Miedo , ChinaRESUMEN
BACKGROUND: Although preoperative radiotherapy (PORT) is a promising therapeutic option for stage III non-small cell lung cancer (NSCLC), the efficacy of this treatment remains controversial. The positive lymph node ratio (PLNR) is recognized as an independent prognostic factor for survival. However, no previous studies have focused on the association between PLNR and PORT in stage III NSCLC. METHODS: Data were collected from the Surveillance, Epidemiology and End Results (SEER) database, and all patients enrolled in this analysis were diagnosed during 2010-2015. The primary endpoint was overall survival (OS). Univariate and multivariate Cox regression analysis was used to identify factors associated with survival before and after case-control matching. PLNR was defined as the ratio of the number of positive lymph nodes to the total number of retrieved or examined lymph nodes. A cutoff value for PLNR was calculated using an X-tile model. RESULTS: Overall, 391 patients with PORT and 2814 patients without PORT were enrolled in this study. The cohort after 1:1 case-control matching included 322 patients who received PORT and 322 patients without PORT. PORT was not associated with a significant effect on OS (HR = 1.14; 95% CI: 0.91-1.43; P = 0.825). Multivariate Cox regression analysis showed that PLNR (P < 0.001) was independently associated with OS in patients with stage III NSCLC. An X-tile model was used to identify a cutoff value for PLNR: the risk of death was significantly lower in patients with PLNR ≤0.41 who received PORT than in those with PLNR >0.41 who received PORT (HR = 0.59; 95% CI: 0.38-0.91; P = 0.015). CONCLUSION: PLNR may be a prognostic factor for survival in patients with stage III NSCLC who undergo PORT. Lower PLNR is a predictor of better OS and thus warrants further study.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Índice Ganglionar , Pronóstico , Estadificación de Neoplasias , Estudios Retrospectivos , Ganglios Linfáticos/patologíaRESUMEN
Potential cognitive and physiological alterations due to space environments have been investigated in long-term space flight and various microgravity-like conditions, for example, head-down tilt (HDT), confinement, isolation, and immobilization. However, little is known about the influence of simulated microgravity environments on visual function. Contrast sensitivity (CS), which indicates how much contrast a person requires to see a target, is a fundamental feature of human vision. Here, we investigated how the CS changed by 1-h -30° HDT and determined the corresponding mechanisms with a perceptual template model. A quick contrast sensitivity function procedure was used to assess the CS at ten spatial frequencies and three external noise levels. We found that (1) relative to the + 30° head-up tilt (HUT) position, 1-h -30° HDT significantly deteriorated the CS at intermediate frequencies when external noise was present; (2) CS loss was not detected in zero- or high-noise conditions; (3) HDT-induced CS loss was characterized by impaired perceptual template; and (4) self-reported questionnaires indicated that subjects felt less pleasure and more excitement, less comfort and more fatigued by screen light, less comfort in the area around the eye, and serious symptoms such as piercing pain, blur acid, strain, eye burning, and dizziness after HDT. These findings improve our understanding of the negative effects of simulated microgravity on visual function and elucidate the potential risks of astronauts during space flight.
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Inclinación de Cabeza , Vuelo Espacial , Humanos , Inclinación de Cabeza/fisiología , Sensibilidad de Contraste , Vuelo Espacial/métodos , DolorRESUMEN
Background: Recently, immunotherapy (IO) has shown striking survival improvement in unresectable stage III non-small cell lung cancer (NSCLC). However, the role of chemo-radiotherapy (CRT) for improvement in outcomes should not be disregarded. This study aimed to compare the treatment patterns and illustrate the impact of radiotherapy on the cancer-specific survival (CSS) and overall survival (OS) of patients with unresected locally advanced stage III NSCLC. Methods: We retrospectively analyzed the data of patients with stage III NSCLC patients who did not undergo surgery from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database between 2001 and 2016, and three continuous years were regarded as one unit. Using the Kaplan-Meier method, we identified the CSS and OS. Then, a linear regression model was graphed to analyze the correlation between median survival of CSS or OS and calendar years in the radiotherapy alone, chemotherapy alone, and CRT groups. Results: A total of 20986 patients were included in this study. In the overall cohort, CSS and OS improved consistently. To explore the reason for the improved survival, patients were divided into three different cohorts: radiotherapy alone, chemotherapy alone, and CRT. From 2001 to 2015, the median CSS improved persistently, 7, 8, 8, 9, and 11 months in the radiotherapy alone group and 12, 13, 15, 17, 19 months in the CRT group, but improvement in outcomes was less consistent in the chemotherapy alone group (10, 9, 11, 12, 12 months). To better visualize the correlation between CSS and calendar year, linear regression was performed, yielding r2 = 0.8032, P = 0.0395 for the radiotherapy alone group; r2 = 0.7206, P = 0.0689 for the chemotherapy alone group; and r2 = 0.9878, P = 0.0006 for the CRT group. Similar findings were observed in the OS data. In addition to this, we also analyzed different pathological types and also obtained the same results. Conclusions: The survival of patients with unresectable stage III NSCLC has improved substantially, and the most pronounced and consistent improvements were observed in the CRT group. In addition to IO, radiotherapy played an essential role in the treatment of unresectable stage III NSCLC in the past years and should be considered in the design of clinical trials.
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The efficacy of immunotherapy for advanced non-small cell lung cancer (NSCLC) remains unsatisfactory, as the majority of patients either do not experience an objective response or acquire secondary resistance. As a result, several methods to enhance the systemic efficacy of immunotherapy have been investigated, including a large area of active research by combining immunotherapy with radiation therapy (RT). Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit, we review the progress in this field thus far and explore further avenues for enhancing this combination. This review commences with a discussion of the only two existing randomized trials (and a pooled analysis) showing that the addition of RT to immunotherapy improves the abscopal response rate, progression-free survival, and overall survival in metastatic NSCLC patients. We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT, such as low programmed cell death protein ligand 1 (PD-L1) status, tumor mutational burden (TMB), and patient's immune function. Next, the implementation of RT to overcome immunotherapy resistance is discussed, including a mechanistic discussion and methods with which these mechanisms could be exploited. Lastly, the emerging role of low-dose RT is discussed, which may help to overcome inhibitory signals in the tumor stroma that limit T-cell infiltration. Taken together, given the current state of this rapidly expanding realm, these futuristic strategies may be reflected upon to further enhance the efficacy of immunotherapy for a wider group of patients.