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Life Science Alliance Aug 2024Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for...
Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.
Topics: Animals; Actins; Mice; Humans; Female; Cell Line, Tumor; Neoplasm Metastasis; Breast Neoplasms; Lung Neoplasms; Microfilament Proteins; Cell Movement; Actin Cytoskeleton; Cell Proliferation; Cell Adhesion; Protein Binding
PubMed: 38760173
DOI: 10.26508/lsa.202302307 -
BMJ Open May 2024The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate... (Observational Study)
Observational Study
PURPOSE
The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate trajectories for microbiome maturation and bone development and to identify the influence of dietary factors in the process.
PARTICIPANTS
The recruitment started in September 2021 and was completed in February 2023. A total of 1380 subjects were recruited, 690 at birth (group 1) and 690 at 6 months of age (group 2). Groups 1 and 2 will be followed up for 12 months and 36 months, respectively.
FINDINGS TO DATE
The age of the mothers was 31.1±3.7 (mean±SD), and the birth weight of infants was 3.3±0.5 kg with an incidence of caesarean section 50.4%. Food diary information of the first 100 subjects showed that 64 food items were introduced by 6 months. A pilot microbiome analysis revealed that at the species level, bacterial communities were composed of mostly and , which were consistent with that of previous reports. Feasibility assessments of breast milk vitamin D and human milk oligosaccharides were validated through certified reference measurements. The early data assessment showed a high reliability of the data generated from this study.
FUTURE PLANS
Data collection will be completed in August 2025. Four stage-statistical analyses will be performed as the cohort reaches certain age thresholds before the final report. Analysis of BAMBOO data will be used to develop age-appropriate trajectories for microbiome maturation and bone development for children aged 0-3 years and investigate the contribution of dietary factors in the process.
TRIAL REGISTRATION NUMBER
ChiCTR2100049972.
Topics: Humans; China; Infant; Female; Prospective Studies; Infant, Newborn; Male; Bone Development; Milk, Human; Gastrointestinal Microbiome; Adult; Child, Preschool; Vitamin D; Diet; Cohort Studies
PubMed: 38760054
DOI: 10.1136/bmjopen-2023-075417 -
BMJ Open May 2024The administration of immune checkpoint inhibitors (ICIs) may lead to renal adverse events, notably including renal dysfunction. To early predict the probability of...
Development and validation of a nomogram for predicting the occurrence of renal dysfunction after treatment of immune checkpoint inhibitor: a retrospective case-control study.
PURPOSE
The administration of immune checkpoint inhibitors (ICIs) may lead to renal adverse events, notably including renal dysfunction. To early predict the probability of renal dysfunction after ICIs therapy, a retrospective case-control study was conducted.
METHODS
Clinical information on ICIs-treated patients was collected. Multivariable logistic regression was applied to identify risk factors for renal dysfunction after ICIs treatment. Moreover, a nomogram model was developed and validated internally.
RESULTS
A total of 442 patients were included, among which 35 (7.9%) experienced renal dysfunction after ICIs treatment. Lower baseline estimated glomerular filtration rate (eGFR) (OR 0.941; 95% CI 0.917 to 0.966; p<0.001), concurrent exposure of platinum(OR 4.014; 95% CI 1.557 to 10.346; p=0.004), comorbidities of hypertension (OR 3.478; 95% CI 1.600 to 7.562; p=0.002) and infection (OR 5.402; 95% CI 1.544 to 18.904; p=0.008) were found to be independent associated with renal dysfunction after ICIs treatment. To develop a predictive nomogram for the occurrence of renal dysfunction after ICIs treatment, the included cases were divided into training and validation groups in a ratio of 7:3 randomly. The above four independent risk factors were included in the model. The area under the receiver operating characteristic curves of the predictiive model were 0.822 (0.723-0.922) and 0.815 (0.699-0.930) in the training and validation groups, respectively.
CONCLUSIONS
Lower baseline eGFR, platinum exposure, comorbidities of hypertension and infection were predictors of renal dysfunction in ICIs-treated patients with cancer. A nomogram was developed to predict the probability of renal dysfunction after ICIs treatment, which might be operable and valuable in clinical practice.
Topics: Humans; Nomograms; Male; Female; Retrospective Studies; Immune Checkpoint Inhibitors; Middle Aged; Case-Control Studies; Aged; Glomerular Filtration Rate; Risk Factors; Logistic Models; Neoplasms; Renal Insufficiency; Kidney Diseases
PubMed: 38760047
DOI: 10.1136/bmjopen-2023-082484 -
Cell Reports. Medicine May 2024Patients with human epidermal receptor 2 (HER2)-positive breast cancer are experiencing a consistent shift toward better survival across the years, thanks to tremendous... (Review)
Review
Patients with human epidermal receptor 2 (HER2)-positive breast cancer are experiencing a consistent shift toward better survival across the years, thanks to tremendous advancements in treatment strategies. The consistent improvements of outcomes set a high bar for new drug development and the need to explore new ways to overcome resistance mechanisms. Emerging treatments in HER2-positive breast cancer aim to tackle the disease by acting on different targets, including not only HER2 (both at the extra- and intracellular level), but also HER3, PD-(L)1, CTLA4, NKG2A, AKT, PI3K, and, in triple-positive tumors, the estrogen receptors and the cyclin-dependent kinases 4/6. This review describes the evolving treatment landscape of HER2-positive breast cancer, from the current approved therapies to the future perspectives, with a focus on the new agents which are likely to get approved in the next future.
PubMed: 38759648
DOI: 10.1016/j.xcrm.2024.101575 -
PLoS Medicine May 2024Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble...
BACKGROUND
Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer.
METHODS AND FINDINGS
This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial.
CONCLUSIONS
MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials.
TRIAL REGISTRATION
clinicaltrials.gov, identifier NCT04431674.
PubMed: 38758967
DOI: 10.1371/journal.pmed.1004408 -
Medicine May 2024This randomized controlled trial aimed to evaluate the efficacy of preoperative inhaled budesonide combined with intravenous dexamethasone on postoperative sore throat... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of preoperative inhaled budesonide combined with intravenous dexamethasone on postoperative sore throat in patients who underwent thyroidectomy: A randomized controlled trial.
BACKGROUND
This randomized controlled trial aimed to evaluate the efficacy of preoperative inhaled budesonide combined with intravenous dexamethasone on postoperative sore throat (POST) after general anesthesia in patients who underwent thyroidectomy.
METHODS
Patients who underwent elective thyroidectomy were randomly divided into the intravenous dexamethasone group (group A) and budesonide inhalation combined with intravenous dexamethasone group (group B). All patients underwent general anesthesia. The incidence and severity of POST, hoarseness, and cough at 1, 6, 12, and 24 hours after surgery were evaluated and compared between the 2 groups.
RESULTS
There were 48 and 49 patients in groups A and B, respectively. The incidence of POST was significantly lower at 6, 12, and 24 hours in group B than that in group A (P < .05). In addition, group B had a significantly lower incidence of coughing at 24 hours (P = .047). Compared with group A, the severity of POST was significantly lower at 6 (P = .027), 12 (P = .004), and 24 (P = .005) hours at rest, and at 6 (P = .002), 12 (P = .038), and 24 (P = .015) hours during swallowing in group B. The incidence and severity of hoarseness were comparable at each time-point between the 2 groups (P > .05).
CONCLUSION
Preoperative inhaled budesonide combined with intravenous dexamethasone reduced the incidence and severity of POST at 6, 12, and 24 hours after extubation compared with intravenous dexamethasone alone in patients who underwent thyroidectomy. Additionally, this combination decreased the incidence of postoperative coughing at 24 hours.
Topics: Humans; Male; Female; Dexamethasone; Budesonide; Thyroidectomy; Pharyngitis; Middle Aged; Administration, Inhalation; Postoperative Complications; Adult; Preoperative Care; Administration, Intravenous; Drug Therapy, Combination; Hoarseness; Anesthesia, General; Glucocorticoids; Treatment Outcome
PubMed: 38758857
DOI: 10.1097/MD.0000000000038235 -
PloS One 2024Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we...
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.
Topics: Humans; Plasminogen Activator Inhibitor 1; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Proto-Oncogene Proteins c-met; Crizotinib; Lung Neoplasms; Cell Line, Tumor; Protein Kinase Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38758826
DOI: 10.1371/journal.pone.0300644 -
PloS One 2024The workload of breast cancer pathological diagnosis is very heavy. The purpose of this study is to establish a nomogram model based on pathological images to predict...
BACKGROUND
The workload of breast cancer pathological diagnosis is very heavy. The purpose of this study is to establish a nomogram model based on pathological images to predict the benign and malignant nature of breast diseases and to validate its predictive performance.
METHODS
In retrospect, a total of 2,723 H&E-stained pathological images were collected from 1,474 patients at Qingdao Central Hospital between 2019 and 2022. The dataset consisted of 509 benign tumor images (adenosis and fibroadenoma) and 2,214 malignant tumor images (infiltrating ductal carcinoma). The images were divided into a training set (1,907) and a validation set (816). Python3.7 was used to extract the values of the R channel, G channel, B channel, and one-dimensional information entropy from all images. Multivariable logistic regression was used to select variables and establish the breast tissue pathological image prediction model.
RESULTS
The R channel value, B channel value, and one-dimensional information entropy of the images were identified as independent predictive factors for the classification of benign and malignant pathological images (P < 0.05). The area under the curve (AUC) of the nomogram model in the training set was 0.889 (95% CI: 0.869, 0.909), and the AUC in the validation set was 0.838 (95% CI: 0.7980.877). The calibration curve results showed that the calibration curve of this nomogram model was close to the ideal curve. The decision curve results indicated that the predictive model curve had a high value for auxiliary diagnosis.
CONCLUSION
The nomogram model for the prediction of benign and malignant breast diseases based on pathological images demonstrates good predictive performance. This model can assist in the diagnosis of breast tissue pathological images.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Adult; Nomograms; Fibroadenoma; Retrospective Studies; Breast; Aged
PubMed: 38758814
DOI: 10.1371/journal.pone.0294923 -
PloS One 2024The diagnosis of breast cancer through MicroWave Imaging (MWI) technology has been extensively researched over the past few decades. However, continuous improvements to...
The diagnosis of breast cancer through MicroWave Imaging (MWI) technology has been extensively researched over the past few decades. However, continuous improvements to systems are needed to achieve clinical viability. To this end, the numerical models employed in simulation studies need to be diversified, anatomically accurate, and also representative of the cases in clinical settings. Hence, we have created the first open-access repository of 3D anatomically accurate numerical models of the breast, derived from 3.0T Magnetic Resonance Images (MRI) of benign breast disease and breast cancer patients. The models include normal breast tissues (fat, fibroglandular, skin, and muscle tissues), and benign and cancerous breast tumors. The repository contains easily reconfigurable models which can be tumor-free or contain single or multiple tumors, allowing complex and realistic test scenarios needed for feasibility and performance assessment of MWI devices prior to experimental and clinical testing. It also includes an executable file which enables researchers to generate models incorporating the dielectric properties of breast tissues at a chosen frequency ranging from 3 to 10 GHz, thereby ensuring compatibility with a wide spectrum of research requirements and stages of development for any breast MWI prototype system. Currently, our dataset comprises MRI scans of 55 patients, but new exams will be continuously added.
Topics: Humans; Magnetic Resonance Imaging; Breast Neoplasms; Female; Breast; Microwave Imaging; Microwaves
PubMed: 38758760
DOI: 10.1371/journal.pone.0302974 -
Cell Reports May 2024The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer...
The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer progression. In this study, we examine the stress response landscape in four carcinomas-breast, pancreas, ovary, and prostate-across five pathways: heat shock, oxidative stress, hypoxia, DNA damage, and unfolded protein stress. Using a combination of experimental and computational methods, we create an atlas of stress responses across various types of carcinomas. We find that stress responses vary within the TME and are especially active near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer-associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering ways to intersect survival pathways within the tumor, and advance cancer therapy.
PubMed: 38758650
DOI: 10.1016/j.celrep.2024.114236