ABSTRACT
BACKGROUND: The chemokine receptor CXCR6 is critical for sustained tumor control mediated by CD8+ cytotoxic T cells (CTLs) in tumors. Previous studies have shown that ionizing radiation induces an inflamed immune contexture by upregulating CXCR6. However, the clinical significance of CXCR6 expression in triple-negative breast cancer (TNBC) and its correlation with radiotherapy remains unknown. This study aimed to clarify the prognostic value of CXCR6 and its role in the breast tumor microenvironment (TME). METHODS: The messenger RNA and protein expression of CXCR6 in human TNBC and their association with survival were analyzed. The role of CXCR6 in the immune context was investigated using a combination of single-cell RNA sequencing, bulk transcriptome sequencing data, and fluorescence-based multiplex immunohistochemistry (mIHC) techniques. RESULTS: Elevated CXCR6 expression correlated with better clinical outcomes and superior response to adjuvant radiotherapy and immunotherapy in TNBC. CXCR6 fostered an immunostimulatory microenvironment characterized by upregulated cytotoxic markers. We also found that CXCR6 plays a crucial role in regulating the differentiation of CD8+ T cells and the intercellular communication of immune cell subtypes, thus shaping the TME. CONCLUSIONS: This study highlights the emerging role of CXCR6 in shaping the TME and targeting CXCR6 may be a promising strategy for improving the effectiveness of radiotherapy and immunotherapy in TNBC.
Subject(s)
Receptors, CXCR6 , Triple Negative Breast Neoplasms , Tumor Microenvironment , Humans , Triple Negative Breast Neoplasms/radiotherapy , Triple Negative Breast Neoplasms/immunology , Female , Tumor Microenvironment/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Prognosis , Immunotherapy/methods , Radiotherapy, AdjuvantSubject(s)
Biological Evolution , Ear, Middle , Jaw , Tooth , Animals , Ear, Middle/anatomy & histology , Tooth/anatomy & histology , Jaw/anatomy & histology , MammalsABSTRACT
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.
ABSTRACT
OBJECTIVES: Pituitary abscess (PA) accounts for only 0.3-0.5% of sellar masses, and the lack of specific clinical symptoms makes diagnosing PA difficult without a surgical biopsy. In clinical practice, PA is often mistaken for cystic pituitary adenoma, craniopharyngioma, and Rathke's cyst. Thus, this study aims to investigate challenges in diagnosing PA and evaluate the importance of combining intraoperative surgery with postoperative antibiotic treatment. METHODS: We conducted a retrospective analysis of 19 patients diagnosed with PA through histopathology. All patients underwent transsphenoidal surgery (TSS) for pituitary adenomas after undergoing comprehensive preoperative evaluations, including routine tests, endocrine assay, and imaging examination. Furthermore, we compared different treatments for pituitary abscess (PA) to determine the most effective approach for achieving a favorable prognosis. RESULTS: The most prevalent symptom of PA was headache, especially in the frontal-temporal and vertex regions, ranging from mild to moderate severity. Hypopituitarism-related symptoms were also frequently observed, including hypaphrodisia, cold sensitivity, fatigue, weight loss, polyuria, and amenorrhea. Twelve patients exhibited abnormalities in endocrinology examinations. Diagnosing PA correctly is challenging. In our study, none of the patients were correctly diagnosed with PA prior to surgery, and many sellar lesions were misdiagnosed. The favorable prognosis was largely attributed to surgical intervention and active postoperative antibiotic therapy. CONCLUSIONS: Given the lack of clarity in preoperative diagnosis, typical intraoperative findings and effective antibiotics treatment are more indicative of the correct diagnosis than other tests. In terms of therapy, optimal surgical intervention and active postoperative antibiotic treatment contribute to resolving the challenges posed by PA.
Subject(s)
Pituitary Diseases , Humans , Female , Male , Middle Aged , Adult , Retrospective Studies , Pituitary Diseases/diagnosis , Pituitary Diseases/surgery , Pituitary Diseases/therapy , Aged , Pituitary Neoplasms/diagnosis , Pituitary Neoplasms/surgery , Pituitary Neoplasms/therapy , Pituitary Neoplasms/pathology , Brain Abscess/diagnosis , Brain Abscess/therapy , Abscess/diagnosis , Abscess/therapy , Anti-Bacterial Agents/therapeutic useABSTRACT
Influenced by heating, the concentration of atmospheric fine particulate matter (PM2.5) rises in autumn and winter in northern cities. In this study, Q-ACSM, AE33, and Xact 625 were used to carry out online monitoring of PM2.5 chemical components with high time resolution in Xi'an from October 25 to November 17, 2019, to analyze the characteristics of PM2.5 pollution during the transition period of the heating season. Additionally, we analyzed the sources of PM2.5 in combination with the positive matrix factorization model. The results showed that the average PM2.5 concentration during the observation period was (78.3 ± 38.5) µg·m-3, and the main chemical components were organic matter (OA), secondary inorganic ions (SIA), and dust, which accounted for 38.7%, 31.6%, and 21.2%, respectively. The average concentrations of sulfate, nitrate, and ammonium were (4.0 ± 3.1), (14.9 ± 13.7), and (5.8 ± 4.8) µg·m-3, and the average concentrations of the major metals potassium, calcium, and iron were (1.0 ± 0.4), (1.5 ± 1.1), and (1.4 ± 0.9) µg·m-3. Black carbon, chloride ions, and trace elements contributed relatively little to PM2.5 (5.7%, 1.3%, and 1.5%, respectively). In the pollution development and maintenance stage, the concentration of OA and SIA increased by 137.7% to 537.0%, whereas in the pollution dissipation stage, only the concentration of dust gradually increased. The source apportionment results showed that secondary sources, biomass burning, dust, vehicle emission, industrial emission, and coal combustion were the main sources of PM2.5 during the observation period, contributing 29.1%, 21.1%, 15.3%, 12.9%, 11.4%, and 10.2%, respectively. The contribution rate of secondary sources and biomass burning was higher in the pollution development and maintenance stage, and dust was higher in the pollution dissipation stage.
ABSTRACT
The dual jaw joint of Morganucodon1,2 consists of the dentary-squamosal joint laterally and the articular-quadrate one medially. The articular-quadrate joint and its associated post-dentary bones constitute the precursor of the mammalian middle ear. Fossils documenting the transition from such a precursor to the mammalian middle ear are poor, resulting in inconsistent interpretations of this hallmark apparatus in the earliest stage of mammaliaform evolution1-5. Here we report mandibular middle ears from two Jurassic mammaliaforms: a new morganucodontan-like species and a pseudotribosphenic shuotheriid species6. The morganucodontan-like species shows many previously unknown post-dentary bone morphologies1,2 and exhibits features that suggest a loss of load-bearing function in its articular-quadrate joint. The middle ear of the shuotheriid approaches the mammalian condition in that it has features that are suitable for an exclusively auditory function, although the post-dentary bones are still attached to the dentary. With size reduction of the jaw-joint bones, the quadrate shifts medially at different degrees in relation to the articular in the two mammaliaforms. These changes provide evidence of a gradual loss of load-bearing function in the articular-quadrate jaw joint-a prerequisite for the detachment of the post-dentary bones from the dentary7-12 and the eventual breakdown of the Meckel's cartilage13-15 during the evolution of mammaliaforms.
Subject(s)
Biological Evolution , Ear, Middle , Fossils , Jaw , Mammals , Temporomandibular Joint , Animals , Ear, Middle/anatomy & histology , Jaw/anatomy & histology , Mammals/anatomy & histology , Mammals/classification , Mandible/anatomy & histology , Temporomandibular Joint/anatomy & histologyABSTRACT
Shuotheriids are Jurassic mammaliaforms that possess pseudotribosphenic teeth in which a pseudotalonid is anterior to the trigonid in the lower molar, contrasting with the tribosphenic pattern of therian mammals (placentals, marsupials and kin) in which the talonid is posterior to the trigonid1-4. The origin of the pseudotribosphenic teeth remains unclear, obscuring our perception of shuotheriid affinities and the early evolution of mammaliaforms1,5-9. Here we report a new Jurassic shuotheriid represented by two skeletal specimens. Their complete pseudotribosphenic dentitions allow reidentification of dental structures using serial homology and the tooth occlusal relationship. Contrary to the conventional view1,2,6,10,11, our findings show that dental structures of shuotheriids can be homologized to those of docodontans and partly support homologous statements for some dental structures between docodontans and other mammaliaforms6,12. The phylogenetic analysis based on new evidence removes shuotheriids from the tribosphenic ausktribosphenids (including monotremes) and clusters them with docodontans to form a new clade, Docodontiformes, that is characterized by pseudotribosphenic features. In the phylogeny, docodontiforms and 'holotherians' (Kuehneotherium, monotremes and therians)13 evolve independently from a Morganucodon-like ancestor with triconodont molars by labio-lingual widening their posterior teeth for more efficient food processing. The pseudotribosphenic pattern passed a cusp semitriangulation stage9, whereas the tribosphenic pattern and its precursor went through a stage of cusp triangulation. The two different processes resulted in complex tooth structures and occlusal patterns that elucidate the earliest diversification of mammaliaforms.
Subject(s)
Biological Evolution , Fossils , Mammals , Tooth , Animals , Eutheria/anatomy & histology , Mammals/anatomy & histology , Mammals/classification , Mammals/physiology , Marsupialia/anatomy & histology , Molar/anatomy & histology , Molar/physiology , Phylogeny , Tooth/anatomy & histology , Tooth/physiology , MasticationABSTRACT
With the development of autonomous driving, there has been considerable attention on 3D object detection using LiDAR. Pillar-based LiDAR point cloud detection algorithms are extensively employed in the industry due to their simple structure and high real-time performance. Nevertheless, the pillar-based detection network suffers from significant loss of 3D coordinate information during the feature degradation and extraction process. In the paper, we introduce a novel framework with high performance, termed EFNet. The EFNet uses the Enhancing Pillar Feature Module (EPFM) to provide more accurate representations of features from two directions: pillar internal space and pillar external space. Additionally, the Head Up Module (HUM) is utilized in the detection head to integrate multi-scale information and enhance the network's information perception ability. The EFNet achieves impressive results on the nuScenes datasets, namely, 53.3% NDS and 42.4% mAP. Compared to the baseline PointPillars, EFNet improves 8% NDS and 11.9% mAP. The results demonstrate that the proposed framework can effectively improve the network's accuracy while ensuring deployability.
ABSTRACT
SUMMARY: We evaluated the role and mechanism of acteoside in the regulation of memory impairment induced by chronic unpredictable mild stress (CUMS). CUMS was used to induce depression in rats and the successful establishment of CUMS model were verified by forced swimming test and sucrose preference test. The Y-maze test and novel object recognition test assessed memory functions. The structural changes in the cortex and hippocampus were observed by hematoxylin and eosin (HE) staining. Immunofluorescence staining and western blotting determined the protein levels. Y-maze test and novel object recognition test showed that there was memory performance impairment in rats of CUMS group, which was improved by the acteoside treatment. HE staining showed that CUMS exposure damaged the structure in the cortex and hippocampus, while the acteoside treatment alleviated the structural changes. Compared with the control group, the levels of BNDF and CREB in the cortex and hippocampus of the CUMS group were significantly decreased. Acteoside significantly reversed the expressions of these proteins in CUMS rats. Meanwhile, compared with the control group, the levels of p-mTOR and p- P70S6K in the cortex and hippocampus of the CUMS group were significantly increased, and these changes were significantly reversed by acteoside. Nevertheless, the effect of acteoside on mTOR signaling was markedly blocked by rapamycin, a specific inhibitor of mTOR signaling. Acteoside can attenuate memory impairment and ameliorate neuronal damage and synaptic plasticity in depression rats probably via inhibiting the mTOR signaling pathway. Acteoside may serve as a novel reagent for the prevention of depression.
Evaluamos el papel y el mecanismo del acteoside en la regulación del deterioro de la memoria inducido por estrés leve crónico impredecible (ELCI). Se utilizó ELCI para inducir depresión en ratas y el establecimiento exitoso del modelo ELCI se verificó mediante una prueba de natación forzada y una prueba de preferencia de sacarosa. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos evaluaron las funciones de la memoria. Los cambios estructurales en la corteza y el hipocampo se observaron mediante tinción con hematoxilina y eosina (HE). La tinción por inmunofluorescencia y la transferencia Western determinaron los niveles de proteína. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos mostraron que había un deterioro del rendimiento de la memoria en ratas del grupo ELCI, que mejoró con el tratamiento con acteósidos. La tinción con HE mostró que la exposición a ELCI dañó la estructura de la corteza y el hipocampo, mientras que el tratamiento con actósidos alivió los cambios estructurales. En comparación con el grupo de control, los niveles de BNDF y CREB en la corteza y el hipocampo del grupo ELCI disminuyeron significativamente. Acteoside revirtió significativamente las expresiones de estas proteínas en ratas ELCI. Mientras tanto, en comparación con el grupo control, los niveles de p-mTOR y p-P70S6K en la corteza y el hipocampo del grupo ELCI aumentaron significativamente, y estos cambios fueron revertidos significativamente ELCI por el acteoside. Sin embargo, el efecto del acteoside sobre la señalización de mTOR fue notablemente bloqueado por la rapamicina, un inhibidor específico de la señalización de mTOR. El acteoside puede atenuar el deterioro de la memoria y mejorar el daño neuronal y la plasticidad sináptica en ratas con depresión, probablemente mediante la inhibición de la vía de señalización mTOR. Acteoside puede servir como un reactivo novedoso para la prevención de la depresión.
Subject(s)
Animals , Rats , Depression/drug therapy , Polyphenols/administration & dosage , Glucosides/administration & dosage , Memory Disorders/drug therapy , Stress, Psychological/complications , Blotting, Western , Fluorescent Antibody Technique , Rats, Sprague-Dawley , Maze Learning , Recognition, Psychology/drug effects , Disease Models, Animal , TOR Serine-Threonine Kinases/antagonists & inhibitors , Polyphenols/therapeutic use , Behavior Rating Scale , MTOR Inhibitors , Glucosides/therapeutic use , Neuronal Plasticity/drug effects , NeuronsABSTRACT
BACKGROUND: Fried foods are favored for their unique crispiness, golden color and flavor, but they also face great challenge because of their high oil content, high calories and the existence of compounds such as acrylamide and polycyclic aromatic hydrocarbons. Long-term consumption of fried foods may adversely affect health. Therefore, it is necessary to explore fried foods with lower oil contents and a high quality to meet the demand. RESULTS: A method of enzyme treatment was explored to investigate the effects of maltogenic amylase (MA), transglutaminase (TG) and bromelain (BRO) on the physicochemical properties of the batter and the quality of fried spring roll wrapper (FSRW). The results showed that the MA-, TG- or BRO-treated batters had a significant shear-thinning behavior, especially with an increase in viscosity upon increasing TG contents. FSRW enhanced its fracturability from 419.19 g (Control) to 616.50 g (MA-6 U g-1), 623.49 g (TG-0.75 U g-1) and 644.96 g (BRO-10 U g-1). Meanwhile, in comparison with BRO and MA, TG-0.5 U g-1 endowed batter with the highest density and thermal stability. MA-15 U g-1 and TG-0.5 U g-1 displayed FSRW with uniform and dense pores, and significantly reduced its oil content by 18.05% and 25.02%, respectively. Moreover, compared to MA and TG, BRO-50 U g-1 improved the flavor of FSRW. CONCLUSION: MA, TG or BRO played a key role in affecting the physicochemical properties of the batter and the quality of FSRW. TG-0.5 U g-1 remarkly reduced the oil content of FSRW with a great potential in practical application. © 2024 Society of Chemical Industry.
Subject(s)
Bromelains , Cooking , Transglutaminases , Transglutaminases/chemistry , Bromelains/chemistry , Viscosity , Fruit/chemistry , Glycoside Hydrolases/chemistry , Glycoside Hydrolases/metabolism , Flour/analysis , Taste , Food Handling/methodsABSTRACT
Dental caries is one of the most common diseases afflicting modern humans and occurs in both living and extinct non-human primates, as well as other mammalian species. Compared to other primates, less is known about the etiology or frequency of caries among the Strepsirrhini. Given the link between caries and diet, caries frequency may be informative about the dietary ecology of a given animal. Understanding rates of caries in wild populations is also critical to assessing dental health in captive populations. Here, we examine caries frequency in a sample of 36 extant strepsirrhine species (n = 316 individuals) using odontological collections of wild-, non-captive animals housed at the American Museum of Natural History by counting the number of specimens characterized by the disease. Additionally, in the context of studying caries lesions in strepsirrhines, case studies were also conducted to test if similar lesions were found in their fossil relatives. In particular, two fossil strepsirrhine species were analyzed: the earliest Late Eocene Karanisia clarki, and the subfossil lemur Megaladapis madagascariensis. Our results suggest that caries affects 13.92% of the extant individuals we examined. The frugivorous and folivorous taxa were characterized by the highest overall frequency of caries, whereas the insectivores, gummivores, and omnivores had much lower caries frequencies. Our results suggest that caries may be common among wild populations of strepsirrhines, and in fact is more prevalent than in many catarrhines and platyrrhines. These findings have important implications for understanding caries, diet, and health in living and fossil taxa.
Subject(s)
Dental Caries , Diet , Fossils , Strepsirhini , Animals , Dental Caries/epidemiologyABSTRACT
Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.
Subject(s)
Exosomes , Mesenchymal Stem Cells , MicroRNAs , Myocardial Infarction , Rats , Animals , Nicorandil/metabolism , TNF Receptor-Associated Factor 6/metabolism , Exosomes/metabolism , Myocardial Infarction/pathology , Mesenchymal Stem Cells/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Signal Transduction , Macrophages/metabolism , Interferon Regulatory Factors/metabolismABSTRACT
This study aims to investigate the relationship between the human papillomavirus (HPV) infection and the altered vaginal microecological environment of patients. Initially, HPV genotyping and microecological detection were performed in 1281 subjects in the Department of Obstetrics and Gynecology of The First Hospital of Qinhuangdao (Qinhuangdao, China). The relationship between the enzymes of vaginal microecology, that is, proline aminopeptidase and acetylglucosaminidase, and vaginal inflammatory diseases, as well as the prognosis of HPV infection, was analyzed. The experimental findings indicated a close relationship between the expression of positive prolyl aminopeptidase and trichomonas vaginitis, as well as bacterial vaginitis. In addition, the expression of acetylglucosaminidase is closely associated with trichomonas vaginitis and vulvovaginal candidiasis. Furthermore, the observations indicated that positive prolyl aminopeptidase and acetylglucosaminidase could increase the risk of various subtypes of HPV infection in patients. The receiver operating characteristic curve analysis presented that the expression of prolyl aminopeptidase and acetylglucosaminidase could offer exceptional diagnostic efficacy, indicating their association with persistent HPV infection. In summary, our results highlighted that the expression of positive prolyl aminopeptidase and acetylglucosaminidase in the vaginal microecology could be substantially correlated to the occurrence and the development of vaginal inflammatory diseases, as well as the outcome and the risk of persistent HPV infection.
Subject(s)
Papillomavirus Infections , Trichomonas Vaginitis , Female , Pregnancy , Humans , Papillomavirus Infections/epidemiology , Acetylglucosaminidase , Vagina/microbiology , Human Papillomavirus VirusesABSTRACT
Importance: The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear. Objective: To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases. Design, Setting, and Participants: This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023. Interventions: Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function. Results: A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points. Conclusions and Relevance: The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT04582968.
Subject(s)
Acrylamides , Aminoquinolines , Brain Neoplasms , Breast Neoplasms , Female , Humans , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Capecitabine/adverse effects , Receptor, ErbB-2/metabolismABSTRACT
BACKGROUND: Supraclavicular nodal (SCL) irradiation is commonly used for patients with high-risk breast cancer after breast surgery. The Radiation Therapy Oncology Group (RTOG) and European Society for Radiotherapy and Oncology (ESTRO) breast contouring atlases delineate the medial part of the SCL region, while excluding the posterolateral part. However, recent studies have found that a substantial proportion of SCL failures are located in the posterolateral SCL region, outside of the RTOG/ESTRO-defined SCL target volumes. Consequently, many radiation oncologists advocate for enlarging the SCL irradiation target volume to include both the medial and posterolateral SCL regions. Nevertheless, it remains uncertain whether adding the posterolateral SCL irradiation improves survival outcomes for high-risk breast cancer patients. METHODS: The SUCLANODE trial is an open-label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) and medial plus posterolateral SCL irradiation (entire SCL irradiation, E-SCLI group) in high-risk breast cancer patients who underwent breast conserving-surgery or mastectomy. Patients with pathological N2-3b disease following initial surgery, or clinical stage III or pathological N1-3b if receiving neoadjuvant systemic therapy, are eligible and randomly assigned (1:1) to M-SCLI group and E-SCLI group. Stratification is by chemotherapy sequence (neoadjuvant vs. adjuvant), T stage (T3-4 vs. T1-2), N stage (N1-2 vs. N3), and ER status (positive vs. negative). Other radiation volumes are identical in the two arms, including breast/chest wall, undissected axillary lymph node, and internal mammary node. Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended. Both hypofractionated and conventional fractionation schedules are permitted. The primary end point is invasive disease-free survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes. The target sample size is 1650 participants. DISCUSSION: The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05059379. Registered 28 September 2021, https://www. CLINICALTRIALS: gov/ct2/show/NCT05059379 .
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Mastectomy , Adjuvants, Immunologic , Lymph Nodes , Breast , Randomized Controlled Trials as Topic , Multicenter Studies as Topic , Clinical Trials, Phase III as TopicABSTRACT
After successfully diversifying during the Paleocene, the descendants of the first wave of mammals that survived the end-Cretaceous mass extinction waned throughout the Eocene. Competition with modern crown clades and intense climate fluctuations may have been part of the factors leading to the extinction of these archaic groups. Why these taxa went extinct has rarely been studied from the perspective of the nervous system. Here, we describe the first virtual endocasts for the archaic order Tillodontia. Three species from the middle Eocene of North America were analyzed: Trogosus hillsii, Trogosus grangeri, and Trogosus castoridens. We made morphological comparisons with the plaster endocast of another tillodont, Tillodon fodiens, as well as groups potentially related to Tillodontia: Pantodonta, Arctocyonidae, and Cimolesta. Trogosus shows very little inter-specific variation with the only potential difference being related to the fusion of the optic canal and sphenorbital fissure. Many ancestral features are displayed by Trogosus, including an exposed midbrain, small neocortex, orbitotemporal canal ventral to rhinal fissure, and a broad circular fissure. Potential characteristics that could unite Tillodontia with Pantodonta, and Arctocyonidae are the posterior position of cranial nerve V3 exit in relation to the cerebrum and the low degree of development of the subarcuate fossa. The presence of large olfactory bulbs and a relatively small neocortex are consistent with a terrestrial lifestyle. A relatively small neocortex may have put Trogosus at risk when competing with artiodactyls for potentially similar resources and avoiding predation from archaic carnivorans, both of which are known to have had larger relative brain and neocortex sizes in the Eocene. These factors may have possibly exacerbated the extinction of Tillodontia, which showed highly specialized morphologies despite the increase in climate fluctuations throughout the Eocene, before disappearing during the middle Eocene.
Subject(s)
Artiodactyla , Eutheria , Animals , Female , Pregnancy , Biological Evolution , Fossils , Placenta , Brain/anatomy & histology , Mammals/anatomy & histology , Artiodactyla/anatomy & histology , Phylogeny , Extinction, BiologicalABSTRACT
BACKGROUND@#Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.@*METHODS@#We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.@*RESULTS@#The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes.@*CONCLUSION@#The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 .@*TRIAL REGISTRATION@#No. NCT00454519 ( https://clinicaltrials.gov/ ).
Subject(s)
Humans , Prognosis , Genotype , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci , Colorectal Neoplasms , Tumor Microenvironment , Aminopeptidases/metabolism , Minor Histocompatibility Antigens/geneticsABSTRACT
Background Nano-alumina (nano-Al2O3) is a widely utilized nanomaterial. Its impacts on the environment and biological systems have garnered significant attention. Zebrafish serves as a common model organism in scientific research due to its high homology with the human genome and is extensively used in toxicity studies. Objective To investigate the developmental toxicity and neurotoxicity of nano-Al2O3 exposure in zebrafish and the corresponding mechanisms of action. Method Zebrafish embryos at 6 h post-fertilization (hpf) were randomly assigned to a control group and five dose groups exposed to nano-Al2O3 at concentrations of 200, 400, 600, 800, and 1000 μg·mL−1, respectively. Thirty embryos were included in each group, and the culture medium was replaced every 24 h until 144 hpf. The hatching rates at 48 and 72 hpf and the cumulative malformation rates up to 144 hpf were calculated. At 144 hpf, a zebrafish behavior analyzer was used to record the movement trajectories of the zebrafish, and the total distance traveled and average speed were analyzed for each group. At 144 hpf, the development of dopaminergic neurons in transgenic zebrafish expressing vmat2: GFP, brain vessels in those expressing vegf: GFP, and central nervous system neurons in those expressing elavl3: EGFP were observed under a fluorescence microscope, and statistical analysis was conducted using Image Pro Plus. Real-time quantitative PCR was employed to detect the expression levels of neuron development-related genes (syn2α, gap43, dat), Lewy body formation-related gene (α-syn), and autophagy-related genes (pink1, parkin) at 144 hpf. Results Compared to the control group, the nano-Al2O3 exposed groups exhibited reduced hatching rates at 48 hpf and increased cumulative malformation rates (P<0.05), with phenomena such as delayed development, absence of the swim bladder, and body curvature. The autonomous behavioral tests revealed that the nano-Al2O3 exposed zebrafish showed a decrease in the total distance swum (P<0.001) and a significant reduction in average speed compared to the control group. The fluorescence observations indicated that the length of dopaminergic neurons in vmat2: GFP transgenic zebrafish was reduced in the nano-Al2O3 exposed groups (P<0.001). Additionally, vegf: GFP transgenic zebrafish exhibited a significant absence of brain vessels, while elavl3: EGFP transgenic zebrafish showed a weakened fluorescence intensity of central nervous system neurons (P<0.001) and a decreased length of these neurons (P<0.01). The real-time quantitative PCR analysis revealed that compared to the control group, the gene expression levels of α-syn, syn2α, dat, and gap43 were upregulated in the zebrafish exposed to nano-Al2O3 (except for the 400 μg·mL−1 exposure group) (P<0.01), while the expression levels of parkin were downregulated in the 600 and 800 μg·mL−1 nano-Al2O3 exposed groups, and the expression levels of pink1 were downregulated in all exposure groups except for the 200 μg·mL−1 group (P<0.05). Conclusion Exposure to nano-Al2O3 exhibits developmental toxicity in zebrafish larvae and induces Parkinsonism-like symptoms in zebrafish. The preliminary speculation of the mechanism suggests that it may be related to nano-Al2O3-induced mitochondrial autophagy impairment.
ABSTRACT
A 65-year-old woman presented to our hospital with 5 days of chest tightness, dyspnoea, and lower abdominal distension. Echocardiography revealed a mass in the right atrium. An emergency operation was carried out to prevent tumour shedding. The patient was discharged on the 4th day of tumour resection, without any complications At the 18 months follow-up, she suffered from kidney and lung tumours. She refused any treatment and passed away. scRNA-seq was applied to analyse the nature of the tumour. The cellular components of benign tumours include chondrocytes, smooth muscle cells, fibroblasts, mesenchymal stromal cells, and osteoblasts. Additionally, the cyclic guanosine monophosphate (cGMP-PKG) signalling pathway, transcriptional misregulation in cancer, and the p53 signalling pathway may be related to the growth of this tumour. scRNA-seq is a good approach to analyse growth patterns of cardiac tumours and helpful for distinguishing the nature of the tumour.
Subject(s)
Heart Neoplasms , Female , Humans , Aged , Heart Neoplasms/diagnostic imaging , Heart Neoplasms/genetics , Sequence Analysis, RNAABSTRACT
BACKGROUND: Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). METHODS: This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. RESULTS: In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. CONCLUSIONS: This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios.