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Technology in Cancer Research &... 2024Recurrence after stage III lung cancer treatment usually appears with a poor prognosis, and salvage therapy for these patients is challenging, with limited data for...
Recurrence after stage III lung cancer treatment usually appears with a poor prognosis, and salvage therapy for these patients is challenging, with limited data for reirradiation. Fifteen patients with recurrent stage III lung cancer treated with stereotactic body radiotherapy (SABR) between October 2013 and December 2017 were retrospectively evaluated for local control as a first endpoint; overall survival, disease-free survival, and treatment-related toxicity were secondary endpoints. The median age was 68 (IQR: 50-71) years, and the median tumor size was 3.3 cm (IQR: 3.0-4.5). The radiation field was all within the previous radiation (previous 80%-90% isodose line), and the median dose was 66 Gy/(2 Gy × 33 ) For SABR, the median biologically effective dose at an α/β ratio of 10 (BED) was 60.0 Gy (IQR: 39.38-85.0) and given in 3 to 5 fractions. Three patients experienced grade 3 or 4 toxicity but none experienced grade 5. The median follow-up period was 14 (IQR: 10-23) months. The local control rate was found as 86.7% in the first year, 80% in the second year, and 80% in the third year. The median disease-free survival was 8 (IQR: 6-20) months and the median overall survival was 14 (IQR: 10-23) months. The rate of overall survival was 66.6% for the first year and 33.3% for the second and third years. The disease-free survival rate was 46.6% for the first year and 40% for the second and third years. Nine patients who received doses of BED ≥ 50 Gy developed no local recurrence ( = .044). In local local-regional recurrence of lung cancer, radiosurgery as reirradiation can be used at doses of BED ≥ 50 Gy and above to provide local control for radical or palliative purposes. SABR is an important and relatively safe treatment option in such recurrences.
Topics: Humans; Radiosurgery; Middle Aged; Lung Neoplasms; Aged; Male; Female; Neoplasm Recurrence, Local; Re-Irradiation; Retrospective Studies; Neoplasm Staging; Treatment Outcome; Radiotherapy Dosage; Dose Fractionation, Radiation
PubMed: 38860536
DOI: 10.1177/15330338231208616 -
Biochimica Et Biophysica Acta.... Jun 2024Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells of the...
Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells of the central nervous system (CNS), are key players in this physiological process, demonstrating a remarkable adaptability in responding to various stimuli in the eye and the brain. Within the complex network of neuroinflammatory signals, the fatty acid N-ethanolamines, in particular N-arachidonylethanolamine (anandamide, AEA), emerged as crucial regulators of microglial activity under both physiological and pathological states. In this study, we interrogated for the first time the impact of the signaling of these bioactive lipids on microglial cell responses to a sub-lethal acute UVB radiation, a physical stressor responsible of microglia reactivity in either the retina or the brain. To this end, we developed an in vitro model using mouse microglial BV-2 cells. Upon 24 h of UVB exposure, BV-2 cells showed elevated oxidative stress markers and, cyclooxygenase (COX-2) expression, enhanced phagocytic and chemotactic activities, along with an altered immune profiling. Notably, UVB exposure led to a selective increase in expression and activity of fatty acid amide hydrolase (FAAH), the main enzyme responsible for degradation of fatty acid ethanolamides. Pharmacological FAAH inhibition via URB597 counteracted the effects of UVB exposure, decreasing tumor necrosis factor α (TNF-α) and nitric oxide (NO) release and reverting reactive oxidative species (ROS), interleukin-1β (IL-1β), and interleukin-10 (IL-10) levels to the control levels. Our findings support the potential of enhanced fatty acid amide signaling in mitigating UVB-induced cellular damage, paving the way to further exploration of these lipids in light-induced immune responses.
PubMed: 38857757
DOI: 10.1016/j.bbalip.2024.159524 -
Parkinsonism & Related Disorders Jun 2024Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with...
INTRODUCTION
Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD).
METHODS
We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure.
RESULTS
Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine.
CONCLUSIONS
These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.
PubMed: 38843617
DOI: 10.1016/j.parkreldis.2024.107024 -
Journal of Radiation Research Jun 2024Radioresistance is increasingly developed in esophageal cancer. Increasing radiation sensitivity can reduce the mortality of esophageal cancer. To investigate the effect...
Radioresistance is increasingly developed in esophageal cancer. Increasing radiation sensitivity can reduce the mortality of esophageal cancer. To investigate the effect and mechanism of ozone on the radiotherapy sensitization of esophageal carcinoma. KYSE150 cells were xenografted subcutaneously into nude mice and irradiated with 8 Gy radiation according to different subgroups (sham, radiation, ozone and radiation+ozone group (n = 10 per group)). Half of the mice were used to determine the body weight, tumor size and tumor weight. Half of the mice were used to collect peripheral blood. The serum was centrifuged to detect circulating cell-free DNA (cf-DNA), interleukin-6 (IL-6), interferon-γ (IFN-γ), myeloperoxidase (MPO)-DNA complexes, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9) and hypoxia-inducible factor-1α (HIF-1α) using commercial kits. The levels of phosphorylation AMP-activated protein kinase (p-AMPK) and scavenger receptor-A (SR-A) were measured by immunocytochemistry and Western blotting in the tumor tissues of mice. Ozone alone or combined with radiation therapy significantly reduced the body weight, tumor volume and tumor weight of esophageal cancer compared to the sham group. The ELISA results showed that the levels of cf-DNA, IFN-γ, MPO-DNA complexes, TNF-α, IL-6, HIF-1α and MMP-9 in the peripheral blood of mice treated with ozone combined with radiation were significantly lower compared with the radiation group. Ozone, synergistically with radiation, significantly increased the protein expression of p-AMPK and SR-A. Ozone may increase the radiosensitivity of esophageal cancer by inhibiting neutrophil extracellular traps.
PubMed: 38842109
DOI: 10.1093/jrr/rrae041 -
The EPMA Journal Jun 2024Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint...
Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.
PubMed: 38841620
DOI: 10.1007/s13167-024-00358-4 -
Energy & Environmental Science Jun 2024The technique of alloying FA with Cs is often used to promote structural stabilization of the desirable α-FAPbI phase in halide perovskite devices. However, the precise...
The technique of alloying FA with Cs is often used to promote structural stabilization of the desirable α-FAPbI phase in halide perovskite devices. However, the precise mechanisms by which these alloying approaches improve the optoelectronic quality and enhance the stability have remained elusive. In this study, we advance that understanding by investigating the effect of cationic alloying in CsFAPbI perovskite thin-films and solar-cell devices. Selected-area electron diffraction patterns combined with microwave conductivity measurements reveal that fine Cs tuning (CsFAPbI) leads to a minimization of stacking faults and an increase in the photoconductivity of the perovskite films. Ultra-sensitive external quantum efficiency, kelvin-probe force microscopy and photoluminescence quantum yield measurements demonstrate similar Urbach energy values, comparable surface potential fluctuations and marginal impact on radiative emission yields, respectively, irrespective of Cs content. Despite this, these nanoscopic defects appear to have a detrimental impact on inter-grains'/domains' carrier transport, as evidenced by conductive-atomic force microscopy and corroborated by drastically reduced solar cell performance. Importantly, encapsulated CsFAPbI devices show robust operational stability retaining 85% of the initial steady-state power conversion efficiency for 1400 hours under continuous 1 sun illumination at 35 °C, in open-circuit conditions. Our findings provide nuance to the famous defect tolerance of halide perovskites while providing solid evidence about the detrimental impact of these subtle structural imperfections on the long-term operational stability.
PubMed: 38841317
DOI: 10.1039/d4ee00901k -
Journal of Ethnopharmacology Jun 2024Bronchitis is a respiratory disease characterized by a productive cough. Polygala tenuifolia Willd., commonly known as Yuan zhi, is a traditional Chinese herbal medicine...
Phytochemical determination and mechanistic investigation of Polygala tenuifolia root (Yuanzhi) extract for bronchitis: UPLC-MS/MS analysis, network pharmacology and in vitro/in vivo evaluation.
ETHNOPHARMACOLOGICAL RELEVANCE
Bronchitis is a respiratory disease characterized by a productive cough. Polygala tenuifolia Willd., commonly known as Yuan zhi, is a traditional Chinese herbal medicine used for relieving cough and removing phlegm. Despite its historical use, studies are lacking on the effectiveness of P. tenuifolia in treating bronchitis. Furthermore, the molecular mechanisms underlying the action of its bioactive compounds remain unknown.
AIM OF THE STUDY
This study aims to identify the main bioactive compounds responsible for the effects of P. tenuifolia liquid extract (PLE) in treating bronchitis and to elucidate the associated molecular mechanisms.
MATERIALS AND METHODS
The main chemical compounds in PLE were identified and determined using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The antitussive, expectorant and anti-inflammatory activities of PLE were evaluated in an ammonia-induced mouse cough model, a tracheal phenol red excretion mouse model, and a xylene-induced ear swelling mouse model, respectively. A network pharmacology analysis was conducted to investigate the associated gene targets, gene ontology, and KEGG pathways related to the main bioactives in PLE targeting bronchitis. PLE and its five bioactive compounds were assessed for their potential anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Western blot analysis was conducted to elucidate the associated molecular mechanisms.
RESULTS
Thirty-seven compounds in PLE were identified, and twelve main compounds were further quantified in PLE using UPLC-MS/MS. PLE oral gavage administrations (0.6 and 0.12 mg/kg) for 7 days markedly reduced cough frequency, prolonged latency period of cough, reduced phlegm and inflammation in mice. The network pharmacology analysis identified 57 gene targets of PLE against bronchitis. The PI3K/AKT and MAPK signalling pathways were the top two modulated pathways. In RAW264.7 cells, PLE (12.5-50 μg/mL) significantly reduced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. PLE downregulated LPS-elevated protein targets in both PI3K/AKT and MAPK signaling pathways. In PLE, tenuifolin, polygalaxanthone ⅠⅠⅠ, polygalasaponin ⅩⅩⅤⅢ, tenuifoliside B, and 3,6'-Disinapoyl sucrose, were identified as the top five core components responsible for treating bronchitis. These compounds were also found to modulate the protein targets in the PI3K/AKT and MAPK signalling pathways.
CONCLUSIONS
This study demonstrated the potential therapeutic effects of PLE on bronchitis by reducing cough, phlegm and inflammation. The anti-inflammatory action and molecular mechanisms of the 5 main bioactive compounds in PLE were partly validated through the in vitro assays. The findings provide valuable insights into the mechanisms underlying the traditional use of PLE for bronchitis.
PubMed: 38838926
DOI: 10.1016/j.jep.2024.118418 -
Frontiers in Pharmacology 2024During the past half-century, although numerous interventions for obesity have arisen, the condition's prevalence has relentlessly escalated annually. Obesity represents...
During the past half-century, although numerous interventions for obesity have arisen, the condition's prevalence has relentlessly escalated annually. Obesity represents a substantial public health challenge, especially due to its robust correlation with co-morbidities, such as colorectal cancer (CRC), which often thrives in an inflammatory tumor milieu. Of note, individuals with obesity commonly present with calcium and vitamin D insufficiencies. Transient receptor potential canonical (TRPC) channels, a subclass within the broader TRP family, function as critical calcium transporters in calcium-mediated signaling pathways. However, the exact role of TRPC channels in both obesity and CRC pathogenesis remains poorly understood. This study set out to elucidate the part played by TRPC channels in obesity and CRC development using a mouse model lacking all seven TRPC proteins (TRPC HeptaKO mice). Relative to wild-type counterparts, TRPC HeptaKO mice manifested severe obesity, evidenced by significantly heightened body weights, augmented weights of epididymal white adipose tissue (eWAT) and inguinal white adipose tissue (iWAT), increased hepatic lipid deposition, and raised serum levels of total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C). Moreover, TRPC deficiency was accompanied by an decrease in thermogenic molecules like PGC1-α and UCP1, alongside a upsurge in inflammatory factors within adipose tissue. Mechanistically, it was revealed that pro-inflammatory factors originating from inflammatory macrophages in adipose tissue triggered lipid accumulation and exacerbated obesity-related phenotypes. Intriguingly, considering the well-established connection between obesity and disrupted gut microbiota balance, substantial changes in the gut microbiota composition were detected in TRPC HeptaKO mice, contributing to CRC development. This study provides valuable insights into the role and underlying mechanisms of TRPC deficiency in obesity and its related complication, CRC. Our findings offer a theoretical foundation for the prevention of adverse effects associated with TRPC inhibitors, potentially leading to new therapeutic strategies for obesity and CRC prevention.
PubMed: 38835669
DOI: 10.3389/fphar.2024.1392328 -
Cureus Jun 2024Ulcerative colitis (UC) is an inflammatory disorder affecting the colon, and typically, during the disease course, the condition may exacerbate, relapse, and remit. One... (Review)
Review
Ulcerative colitis (UC) is an inflammatory disorder affecting the colon, and typically, during the disease course, the condition may exacerbate, relapse, and remit. One of the most successful lines for inducing and maintaining clinical remission in subjects with UC is biological therapy with anti-tumor necrosis factor α (anti-TNF) agents, including adalimumab (ADA) and infliximab (IFX). This meta-analysis is an attempt to obtain complementary information driven by real-world experience (RWE) concerning the efficacy and safety of two of the most popular anti-TNFs in treating UC. This is a systematic review and meta-analysis of RWE studies comparing ADA and IFX as naïve anti-TNF agents for the treatment of subjects with UC. Studies were obtained by searching Scopus, Google Scholar, the Cochrane Central Register of Controlled Trials, Embase, and the PubMed Central databases. Patients treated with IFX showed significantly higher induction responses. No statistically significant difference was found in the comparison of response in the maintenance treatment period. Higher overall adverse events were related to IFX treatment, with serious adverse events that were nonsignificantly higher in the ADA-treated group. In conclusion, IFX demonstrated significantly higher induction responses compared to ADA in patients with moderate-to-severe UC. IFX was associated with higher overall adverse events, whereas serious adverse events were non-significantly higher in the ADA-treated group. IFX may be favored as a first-line agent for its induction efficacy, and the choice between IFX and ADA should be individualized based on comprehensive clinical evaluation.
PubMed: 38835557
DOI: 10.7759/cureus.61547 -
Parasites, Hosts and Diseases May 2024Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We...
Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We generated virus-like particles (VLPs) that expressed either apical membrane antigen 1 (AMA1) or microneme-associated antigen (MIC) of Plasmodium berghei and compared their efficacy in BALB/c mice. We found that immune sera acquired from AMA1 VLP- or MIC VLP-immunized mice specifically interacted with the antigen of choice and the whole P. berghei lysate antigen, indicating that the antibodies were highly parasite-specific. Both VLP vaccines significantly enhanced germinal center B cell frequencies in the inguinal lymph nodes of mice compared with the control, but only the mice that received MIC VLPs showed significantly enhanced CD4+ T cell responses in the blood following P. berghei challenge infection. AMA1 and MIC VLPs significantly suppressed TNF-α and interleukin-10 production but had a negligible effect on interferon-γ. Both VLPs prevented excessive parasitemia buildup in immunized mice, although parasite burden reduction induced by MIC VLPs was slightly more effective than that induced by AMA1. Both VLPs were equally effective at preventing body weight loss. Our findings demonstrated that the MIC VLP was an effective inducer of protection against murine experimental malaria and should be the focus of further development.
Topics: Animals; Plasmodium berghei; Mice, Inbred BALB C; Vaccines, Virus-Like Particle; Malaria Vaccines; Malaria; Membrane Proteins; Mice; Protozoan Proteins; Antigens, Protozoan; Female; Antibodies, Protozoan; Parasitemia; CD4-Positive T-Lymphocytes; B-Lymphocytes
PubMed: 38835260
DOI: 10.3347/PHD.24017