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Cancer Immunology, Immunotherapy : CII Jul 2024Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph...
INTRODUCTION
Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph nodes. Early detection of lymph node metastasis via biomarkers could enhance the therapeutic strategy for OSCC. Here, we explored dendritic cells (DCs) and cytotoxic T-cells in tumour-draining lymph nodes (TDLNs) as potential biomarkers.
METHOD
Dendritic cells and cytotoxic T-cells in 33 lymph nodes were analyzed with multi-parameter flow cytometry in TDLNs, regional non-TDLNs surgically excised from 12 OSCC patients, and compared to 9 lymph nodes from patients with benign conditions.
RESULTS
Our results displayed a higher proportion of conventional cDC1s with immunosuppressive features in TDLN. Further, high PD-L1 expression on cDC1 in TDLNs was associated with metastasis and/or recurrent disease risk. Also, elevated levels of memory CD8 T-cells and terminally exhausted PD-1TCF-1CD8 T-cells were observed in TDLNs and non-TDLNs compared to healthy lymph nodes.
CONCLUSIONS
We conclude that TDLNs contain cells that could trigger an anti-tumor adaptive response, as evidenced by activated cDC1s and progenitor-like TCF-1 T-cells. The detection of high PDL1 expression on cDC1s was indicative of TDLN metastasis and an adverse prognosis, proposing that PD-L1 on dendritic cells in TDLN could serve as a predictive biomarker of OSCC patients with a worse prognosis.
Topics: Humans; Dendritic Cells; Mouth Neoplasms; Prognosis; Female; Male; Lymph Nodes; B7-H1 Antigen; Middle Aged; Aged; Lymphatic Metastasis; Carcinoma, Squamous Cell; Biomarkers, Tumor; Adult
PubMed: 38954023
DOI: 10.1007/s00262-024-03754-x -
Langenbeck's Archives of Surgery Jul 2024The mortality rate for non-occlusive mesenteric ischemia remains high even after patients survive the acute postoperative period with tremendous treatment efforts,...
PURPOSE
The mortality rate for non-occlusive mesenteric ischemia remains high even after patients survive the acute postoperative period with tremendous treatment efforts, including emergency surgery, which is challenging. The aim of this study was to explore the preoperative risk factors for 90-day postoperative mortality in patients with non-occlusive mesenteric ischemia.
METHODS
This single-center, retrospective cohort study included patients diagnosed with non-occlusive mesenteric ischemia who underwent emergency surgery between August 2014 and January 2023. All patients were divided into survival-to-discharge and mortality outcome groups at the 90-day postoperative follow-up. Preoperative factors, including comorbidities, preoperative status of vital signs and consciousness, blood gas analysis, blood test results, and computed tomography, were compared between the two groups.
RESULTS
Twenty patients were eligible, and 90-day mortality was observed in 10 patients (50%). The mortality outcome group had significantly lower HCO3- (20.9 vs. 14.6, p = 0.006) and higher lactate (4.4 vs. 9.4, p = 0.023) levels than did the survival outcome group. The median postoperative time to death was 19 [2-69] days, and five patients (50%) died after postoperative day 30, mainly because hemodialysis was discontinued because of hemodynamic instability in patients requiring hemodialysis.
CONCLUSION
Low preoperative HCO3- and high lactate levels may be preoperative risk factors for 90-day postoperative mortality in patients with non-occlusive mesenteric ischemia. However, patients on hemodialysis die from discontinuing hemodialysis even after surviving the acute postoperative phase. Therefore, indications for emergency surgery in patients with risk factors for postoperative mortality should be carefully determined.
Topics: Humans; Male; Female; Mesenteric Ischemia; Retrospective Studies; Aged; Risk Factors; Middle Aged; Postoperative Complications; Aged, 80 and over; Cohort Studies; Preoperative Period
PubMed: 38954011
DOI: 10.1007/s00423-024-03391-z -
Cancer Immunology, Immunotherapy : CII Jul 2024Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)/CD141 (BDCA-3) myeloid dendritic cells in solid tumors.
BACKGROUND
Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.
METHODS
In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)/CD141(BDCA-3) myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).
RESULTS
Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.
CONCLUSION
SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.
TRIAL REGISTRATION NUMBER
Clinicaltrials.gov: NCT04571632 (09 AUG 2020).
EUDRACT
2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.
Topics: Humans; Antibodies, Monoclonal, Humanized; Female; Male; Aged; Middle Aged; Radiosurgery; Dendritic Cells; Ipilimumab; Adult; Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Thrombomodulin; Aged, 80 and over; Combined Modality Therapy; Myeloid Cells; Glycoproteins; Antigens, CD1
PubMed: 38954010
DOI: 10.1007/s00262-024-03751-0 -
American Journal of Physiology.... Jul 2024Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by...
Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to to derive the correlation of the expression levels between and multiple genes and the survival prognosis based on expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assays, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of was positively correlated with glycolysis-related genes and , lipogenesis-related genes and , and . FOXM1 appeared to modulate AKT/mTOR signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.
PubMed: 38953837
DOI: 10.1152/ajpgi.00032.2024 -
Melanoma Research Jun 2024Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and...
Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and a low response rate to approved treatments. We retrospectively analyzed the clinical features, treatments, and outcomes of patients diagnosed with mucosal melanoma treated with axitinib ± anti-programmed cell death protein 1 (PD-1) therapy at a single US referral center between 2018 and 2021. Radiologic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Twenty-three patients were included in this study. In all, 78% were females with a median age of 62 years. The originating site of mucosal melanoma was the sinonasal (35%), genitourinary (35%), and gastrointestinal (30%) tracts. Sixty-five percent of patients had M1c or M1d disease and 0% had BRAF V600 mutations detected. The majority (96%) had prior treatment inclusive of anti-PD-1, with a median of 2 prior lines, and 78% of patients received a combination of axitinib and PD-1 and the median duration of treatment was 3.2 months. The overall response rate was 13% and the disease control rate was 26%. The median progression-free survival was 3.2 months, and the median overall survival was 8.2 months. Overall, the regimen was well tolerated with 39% of patients requiring dose reduction and 9% requiring treatment cessation. Axitinib with anti-PD-1 therapy has modest clinical activity in heavily pretreated patients with mucosal melanoma outside of Asia, including some with long-term benefits. This data supports the worldwide clinical trials evaluating this combination and the role of incorporating vascular endothelial growth factor-based therapy in the therapeutic paradigm for patients with mucosal melanoma.
PubMed: 38953532
DOI: 10.1097/CMR.0000000000000988 -
Cancer Medicine Jul 2024Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these... (Comparative Study)
Comparative Study
BACKGROUND
Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B.
METHODS
Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis.
RESULTS
Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001).
CONCLUSIONS
In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quinolines; Phenylurea Compounds; Male; Female; Middle Aged; Sorafenib; Retrospective Studies; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Progression-Free Survival; Bevacizumab; Treatment Outcome; Immunotherapy
PubMed: 38953381
DOI: 10.1002/cam4.7415 -
MBio Jul 2024pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for...
pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30%-60% mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed neutrophil extracellular trap (NET) presence in the lungs of the -infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with . Isolated NETs compromised viability , highlighting the potential role of neutrophils in controlling fungal growth and promoting inflammation during pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with .IMPORTANCE pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30%-60% mortality rate, underscoring the need for deeper insight into PjP's inflammatory responses. Past research focused on macrophages in managing infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in -infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues. Understanding the behavior of neutrophils in infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.
PubMed: 38953359
DOI: 10.1128/mbio.01409-24 -
Chinese Medical Sciences Journal =... Jul 2024Objective To explore the influence of Linggui Zhugan Decoction (LGZGD) on high glucose induced podocyte autophagy Methods LGZGD containing serum were prepared by...
Objective To explore the influence of Linggui Zhugan Decoction (LGZGD) on high glucose induced podocyte autophagy Methods LGZGD containing serum were prepared by intragastric administation of 4.2 g·kglow dose, 8.4 g·kg (medium dose), and 12.6 g·kg (high dose) LGZGD into SD rats respectively. MPC5 and AB8/13 cells were treated with 60 mmol/L glucose to establish diabetic nephropathy podocyte model in vitro. Podocytes, MPC5 and AB8.13, were divided into control group, high glucose group, low dose LGZGD group, medium dose LGZGD group, and high dose LGZGD group, respectively. For the three LGZGD groups, before LGZGD intervention, podocytes were treated with 60 mmol/L glucose for 3 days. After treated with LGZGD containing serum, cells were collected to analyze cell migration using Transwell assay, proliferation using CCK8, apoptosis and cell cycle using flow cytometry,, autophagosome formation using transmission electron microscopy, and expression levels of Beclin-1, Atg5, LC3II/I, and P62 proteins using western blot.Results Compared with the control group, the proliferation and migration of MPC5 and AB8.13 cells in high glucose group showed slightly decreased, whereas these parameters restored after intervention with low and medium concentrations of LGZGD, with the medium dose LGZGD having the best effect. Flow cytometry analysis showed that the medium dose LGZGD group had a lower apoptosis rate (P < 0.05) and higher survival rate (P > 0.05) compared to the high dose group. High glucose arrested podocytes in G1 phase, whereas LGZGD shifted podocytes from being predominant in G1 phase to increasing into G2. High dose LGZGD significanly reduced increased autophagosome formation due to high glucose in both podocytes (P < 0.05). Western blot analysis showed that Beclin-1, Atg5, LC3Ⅱ/Ⅰ, and P62 expressions were increased in MPC5 cells treated with high glucose, and reversed after adminstration of low and medium doses of LGZGD (P < 0.05). Conclusion LGZGD reduced apoptosis and enhanced autophagy in high glucose treated podocytes via regulating Beclin-1/LC3II/I/Atg5 expression.
PubMed: 38953223
DOI: 10.24920/004330 -
PeerJ 2024The aim of this study was threefold. Firstly, it aimed to introduce and detail a novel method for chemically etching the bases of stainless-steel orthodontic brackets.... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Comparative bond failure rate of orthodontic brackets when bracket base is treated with micro-abrasive blasting . acid etching: eighteen month randomized control trial and scanning electron microscope study.
BACKGROUND
The aim of this study was threefold. Firstly, it aimed to introduce and detail a novel method for chemically etching the bases of stainless-steel orthodontic brackets. Secondly, the study sought to investigate the structural alterations within the brackets' microstructure following chemical etching compared to those with sandblasted bases, using electron microscopy analysis. Lastly, the study aimed to evaluate and compare the long-term durability and survivability of orthodontic brackets with chemically etched bases those with sandblasted bases, both bonded using the conventional acid etch technique with Transbond XT adhesive, over an 18-month follow-up period.
METHODS
The study was a randomized clinical control trial with triple blinding and split-mouth study design and consisted of two groups. The brackets in the sandblasted group were prepared by sandblasting the intaglio surface of the base of the bracket with 50 µm SiO particles. Hydrofluoric acid was used to roughen the base in the acid-etched group. The bases of the brackets were viewed under an electron microscope to analyze the topographical changes.
RESULTS
A total of 5,803 brackets (3,006 acid-etch, 2,797 sandblasted) in 310 patients were bonded, in a split-mouth design by the same operator. The patients were followed for 18 months. The failure rate of 2.59% and 2.7% was noted in an acid-etched and sandblasted group, respectively. There was a close approximation of curves in the Kaplan-Meier plot, and the survival distribution of the two groups in the log-rank (Mantel-Cox) test was insignificant; x2 = 0.062 ( value = 0.804).
CONCLUSION
Acid etching if the bases of the brackets can be used as an alternative to sandblasting furthermore acid etching can be performed on the chair side.
Topics: Orthodontic Brackets; Humans; Acid Etching, Dental; Microscopy, Electron, Scanning; Female; Male; Dental Bonding; Adolescent; Surface Properties; Adult; Resin Cements; Young Adult; Stainless Steel; Dental Etching
PubMed: 38952970
DOI: 10.7717/peerj.17645 -
Frontiers in Public Health 2024Studies have analyzed the effects of industrial installations on the environment and human health in Taranto, Southern Italy. Literature documented associations between...
INTRODUCTION
Studies have analyzed the effects of industrial installations on the environment and human health in Taranto, Southern Italy. Literature documented associations between different variables and dementia mortality among both women and men. The present study aims to investigate the associations between sex, environment, age, disease duration, pandemic years, anti-dementia drugs, and death rate.
METHODS
Data from the regional medication registry were used. All women and men with an anti-dementia medication between 2015 and 2021 were included and followed-up to 2021. Bayesian mixed effects logistic and Cox regression models with time varying exposures were fitted using integrated nested Laplace approximations and adjusting for patients and therapy characteristics.
RESULTS
A total of 7,961 person-years were observed. Variables associated with lower prevalence of acetylcholinesterase inhibitors (AChEIs) medication were male sex (OR 0.63, 95% CrI 0.42-0.96), age 70-79 years (OR 0.17, 95% CrI 0.06-0.47) and ≥ 80 years (OR 0.08, 95% CrI 0.03-0.23), disease duration of 2-3 years (OR 0.43, 95% CrI 0.32-0.56) and 4-6 years (OR 0.21, 95% CrI 0.13-0.33), and pandemic years 2020 (OR 0.50, 95% CrI 0.37-0.67) and 2021 (OR 0.47, 95% CrI 0.33-0.65). Variables associated with higher mortality were male sex (HR 2.14, 95% CrI 1.75-2.62), residence in the contaminated site of national interest (SIN) (HR 1.25, 95% CrI 1.02-1.53), age ≥ 80 years (HR 6.06, 95% CrI 1.94-18.95), disease duration of 1 year (HR 1.50, 95% CrI 1.12-2.01), 2-3 years (HR 1.90, 95% CrI 1.45-2.48) and 4-6 years (HR 2.21, 95% CrI 1.60-3.07), and pandemic years 2020 (HR 1.38, 95% CrI 1.06-1.80) and 2021 (HR 1.56, 95% CrI 1.21-2.02). Variables associated with lower mortality were therapy with AChEIs alone (HR 0.69, 95% CrI 0.56-0.86) and in combination with memantine (HR 0.54, 95% CrI 0.37-0.81).
DISCUSSION
Male sex, age, disease duration, and pandemic years appeared to be associated with lower AChEIs medications. Male sex, residence in the SIN of Taranto, age, disease duration, and pandemic years seemed to be associated with an increased death rate, while AChEIs medication seemed to be associated with improved survival rate.
Topics: Humans; Male; Female; Italy; Aged; Bayes Theorem; Dementia; Aged, 80 and over; Sex Factors; Cholinesterase Inhibitors; Survival Analysis; Cohort Studies; COVID-19; Middle Aged; Registries
PubMed: 38952726
DOI: 10.3389/fpubh.2024.1380609