-
European Journal of Pharmaceutical... May 2024Drug resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a primary factor affecting their therapeutic efficacy in human...
Drug resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a primary factor affecting their therapeutic efficacy in human non-small cell lung cancer (NSCLC). NSCLC cells can undergo epithelial-mesenchymal transition (EMT) induced by many factors in the tumour microenvironment (TME), which plays a crucial role in tumour drug resistance. In this study, a multicellular lung-on-a-chip that can realise the cell co-culture of the human non-small cell lung cancer cell line HCC827, human foetal lung fibroblasts (HFL-1), and human umbilical vein endothelial cells (HUVECs) is prepared. The TME was simulated on the chip combined with perfusion and other factors, and the drug evaluation of osimertinib was performed to explore the drug resistance mechanism of EGFR-TKIs. In the early stages, a two-dimensional static cell co-culture was achieved by microchip, and the results showed that HFL-1 cells could be transformed into cancer-associated fibroblasts (CAFs), and HCC827 cells could undergo EMT, both of which were mediated by Interleukin-6 (IL-6). Vimentin (VIM) and Alpha Skeletal Muscle Actin (a-SMA) expression of HFL-1 was upregulated, whereas E-cadherin (E-cad) expression of HCC827 was down-regulated. Further, N-cadherin (N-cad) expression of HCC827 was upregulated. In both the static cell co-culture and multicellular lung-on-a-chip, HCC827 cells with CAFs co-culture or IL-6 treatment developed resistance to osimertinib. Further use of the IL-6 antibody inhibitor tocilizumab could reverse EGFR-TKI resistance to a certain extent. Combination therapy with tocilizumab and EGFR-TKIs may provide a novel therapeutic strategy for overcoming EGFR-TKI resistance caused by EMT in NSCLC. Furthermore, the lung-on-a-chip can simulate complex TME and can be used for evaluating tumour resistance and exploring mechanisms, with the potential to become an important tool for personalised diagnosis, treatment, and biomedical research.
PubMed: 38763450
DOI: 10.1016/j.ejps.2024.106805 -
Cell Communication and Signaling : CCS May 2024While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly...
BACKGROUND
While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood.
METHODS
We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses.
RESULTS
Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy.
CONCLUSIONS
Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.
Topics: Colorectal Neoplasms; Humans; Squalene Monooxygenase; NF-kappa B; Drug Resistance, Neoplasm; Animals; Fluorouracil; Mice; Cell Line, Tumor; Mice, Nude; Mice, Inbred BALB C; Female; Male; Cell Proliferation; NF-KappaB Inhibitor alpha; Xenograft Model Antitumor Assays
PubMed: 38762737
DOI: 10.1186/s12964-024-01649-z -
BMC Cardiovascular Disorders May 2024Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence...
BACKGROUND
Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting.
METHODS
A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms "cardiac surgery" and "hemoadsorption". The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view.
RESULTS
The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability.
CONCLUSIONS
The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy.
Topics: Humans; Cardiac Surgical Procedures; Treatment Outcome; Risk Factors; Postoperative Complications; Cardiopulmonary Bypass; Male; Female; Risk Assessment; Aged; Middle Aged
PubMed: 38762715
DOI: 10.1186/s12872-024-03938-4 -
Scientific Reports May 2024There are some discrepancies about the superiority of the off-pump coronary artery bypass grafting (CABG) surgery over the conventional cardiopulmonary bypass (on-pump).... (Comparative Study)
Comparative Study
There are some discrepancies about the superiority of the off-pump coronary artery bypass grafting (CABG) surgery over the conventional cardiopulmonary bypass (on-pump). The aim of this study was estimating risk ratio of mortality in the off-pump coronary bypass compared with the on-pump using a causal model known as collaborative targeted maximum likelihood estimation (C-TMLE). The data of the Tehran Heart Cohort study from 2007 to 2020 was used. A collaborative targeted maximum likelihood estimation and targeted maximum likelihood estimation, and propensity score (PS) adjustment methods were used to estimate causal risk ratio adjusting for the minimum sufficient set of confounders, and the results were compared. Among 24,883 participants (73.6% male), 5566 patients died during an average of 8.2 years of follow-up. The risk ratio estimates (95% confidence intervals) by unadjusted log-binomial regression model, PS adjustment, TMLE, and C-TMLE methods were 0.86 (0.78-0.95), 0.88 (0.80-0.97), 0.88 (0.80-0.97), and 0.87(0.85-0.89), respectively. This study provides evidence for a protective effect of off-pump surgery on mortality risk for up to 8 years in diabetic and non-diabetic patients.
Topics: Humans; Male; Coronary Artery Bypass, Off-Pump; Female; Middle Aged; Aged; Likelihood Functions; Coronary Artery Bypass; Iran; Coronary Artery Disease; Treatment Outcome; Propensity Score; Cardiopulmonary Bypass
PubMed: 38762564
DOI: 10.1038/s41598-024-61846-1 -
Immunity & Ageing : I & A May 2024Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune...
BACKGROUND
Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.
METHODS
Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.
RESULTS
Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.
CONCLUSIONS
In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.
PubMed: 38762550
DOI: 10.1186/s12979-024-00432-5 -
BMC Surgery May 2024Because the cases are quite scarce, we aimed to review cases of foreign body impaction penetrating the neck through the esophagus to analyze the characteristics of these...
BACKGROUND
Because the cases are quite scarce, we aimed to review cases of foreign body impaction penetrating the neck through the esophagus to analyze the characteristics of these cases. The open surgery skills of the surgeon, the treatment procedure and the surgeons' experience in the rare diseases were analyzed.
METHODS
We collected and analyzed all cases from 2015-2020 in our hospital. Surgical skills and procedures for fasting and anti-infection treatment were reviewed retrospectively. Follow-up was telephone communication.
RESULTS
Our series included 15 cases. Tenderness in the pre-cervical site was a physical sign for screening. Thirteen cases underwent a lateral neck open surgery with the incision including the left side of neck and only two cases were incised from the right side of the neck. Pus was found 3 days after the impaction in one case, the shortest time observed in our series. The esophageal laceration was only sutured primarily in 5 cases (33.33%) among all fifteen cases. After sufficient drainage (average more than 9 days), antibiotic treatment and fasting (normally 2-3 weeks), patients gradually began to switch to solid foods from fluids after complete blood counts and confirmations from esophageal radiography result. No severe complications occurred, and all the patients have no swallowing dis-function and recovered well.
CONCLUSION
Surgery should be performed as soon as possible after impaction. Lateral neck approach surgery and the therapeutic procedure described in this article are safe and effective treatments.
Topics: Humans; Foreign Bodies; Male; Female; Adult; Retrospective Studies; Middle Aged; Esophagus; Neck; Young Adult; Adolescent; Aged
PubMed: 38762478
DOI: 10.1186/s12893-024-02449-5 -
Journal of Translational Medicine May 2024Neoadjuvant immunochemotherapy (NICT) plus esophagectomy has emerged as a promising treatment option for locally advanced esophageal squamous cell carcinoma (LA-ESCC)....
BACKGROUND
Neoadjuvant immunochemotherapy (NICT) plus esophagectomy has emerged as a promising treatment option for locally advanced esophageal squamous cell carcinoma (LA-ESCC). Pathologic complete response (pCR) is a key indicator associated with great efficacy and overall survival (OS). However, there are insufficient indicators for the reliable assessment of pCR.
METHODS
192 patients with LA-ESCC treated with NICT from December 2019 to October 2023 were recruited. According to pCR status, patients were categorized into pCR group (22.92%) and non-pCR group (77.08%). Radiological features of pretreatment and preoperative CT images were extracted. Logistic and COX regressions were trained to predict pathological response and prognosis, respectively.
RESULTS
Four of the selected radiological features were combined to construct an ESCC preoperative imaging score (ECPI-Score). Logistic models revealed independent associations of ECPI-Score and vascular sign with pCR, with AUC of 0.918 in the training set and 0.862 in the validation set, respectively. After grouping by ECPI-Score, a higher proportion of pCR was observed among the high-ECPI group and negative vascular sign. Kaplan Meier analysis demonstrated that recurrence-free survival (RFS) with negative vascular sign was significantly better than those with positive (P = 0.038), but not for OS (P = 0.310).
CONCLUSIONS
This study demonstrates dynamic radiological features are independent predictors of pCR for LA-ESCC treated with NICT. It will guide clinicians to make accurate treatment plans.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Neoadjuvant Therapy; Male; Female; Middle Aged; Esophageal Neoplasms; Treatment Outcome; Immunotherapy; Aged; Kaplan-Meier Estimate; Tomography, X-Ray Computed; Prognosis; Esophagectomy
PubMed: 38762454
DOI: 10.1186/s12967-024-05291-8 -
Asian Journal of Surgery May 2024
PubMed: 38762411
DOI: 10.1016/j.asjsur.2024.05.017 -
Vaccine May 2024Tetanus is a non-communicable disease, preventable with vaccination. Despite the implemented vaccination strategy, a certain number of tetanus cases per year continue to...
BACKGROUND
Tetanus is a non-communicable disease, preventable with vaccination. Despite the implemented vaccination strategy, a certain number of tetanus cases per year continue to occur. The aim of the study was to evaluate the seroprevalence of anti-tetanus antibodies in the Italian population by age, sex and geographical area.
METHODS
To determine the level of tetanus-specific antibodies, an immunoenzymatic assay was used.
RESULTS
A total of 3,821 serum samples were collected in the years 2019-20 from healthy subjects aged 6-90 years residing in 13 Italian regions. Overall, 85 % of the tested subjects resulted positive. The rate of subjects protected against tetanus showed a gradual decrease from the younger age groups to the older ones (6-12 years: 93.6 %, 13-24 years: 91.8 %, 25-39 years: 91.0 %, 40-64 years: 78.2 %, ≥ 65 years: 45.3 %); this is particularly evident in the Southern regions and Islands. Moreover, the prevalence of subjects with low protection (<0.1 IU/ml) was significantly higher in the ≥ 65 age group (10.3 %). Males and females' prevalence showed a significant difference only in the oldest age group (M: 60.8 %, F: 30.4 %). In general, a higher prevalence was observed for Northern (90.8 %) and Central regions (87.3 %) than Southern regions and Islands (80.0 %).
CONCLUSION
These data, compared with epidemiological ones which showed a high number of cases in the elderly, confirmed that the population with lower protection has a greater risk of contracting the disease, demonstrating the need for adequate immunization through both primary vaccination and boosters for all ages and both sexes, in order to provide lifelong protection.
PubMed: 38762356
DOI: 10.1016/j.vaccine.2024.05.015 -
International Journal of Infectious... May 2024To resolve an exceptional clustering of Cutibacterium avidum prosthetic valve infective endocarditis at a single heart center.
OBJECTIVE
To resolve an exceptional clustering of Cutibacterium avidum prosthetic valve infective endocarditis at a single heart center.
METHODS
During a period of 21 months, three patients experienced C. avidum bacteraemia 24-128 days after aortic valve replacement. Operative procedures and electronic prescriptions of antimicrobials were surveyed, and bacterial isolates were genome sequenced.
RESULTS
The prosthetic valves were inserted by separate surgical teams. In one case, echocardiographic confirmation of infective endocarditis was not achieved until four months after the first positive blood culture, but the causative agents were irrefutably documented in all cases by culture, or amplification of bacterial DNA, from removed prosthetic material. Whole genome sequencing clustered isolates to a distinctive subgroup of the species, but did not suggest inter-patient transmission of isolates.
CONCLUSIONS
Despite vigorous sampling of blood and tissue, detection of C. avidum was not unconditional, neither by culture nor PCR. The causative agent is likely underreported and should be meticulously searched for in culture-negative prosthetic valve endocarditis.
PubMed: 38762047
DOI: 10.1016/j.ijid.2024.107099