Case report: A case with atypical presentation oftesticular choriocarcinoma.

Testicular choriocarcinoma is a relatively rare malignancy with a highly aggressive nature. Timely diagnosis and treatment can help prolong the survival of patients and even cure them. This case reports a 29-year-old male who presented to the clinic for a month with epigastric pain. On examination, a massive mass of approximately 9*10 cm could be palpated in the upper abdomen. When asked about his previous history, the patient only described a history of a right inguinal hernia that had been repaired 12 years earlier. The admission diagnosis was considered the retroperitoneal tumor, which was found to have metastasized to the liver and lungs after the completion of relevant tests. We then performed a CT-guided lune puncture biopsy on day 8 of admission. The biopsy pathology suggested metastatic cancer was considered. As the symptoms of tumor compression gradually worsened, we performed surgical treatment (retroperitoneal tumor resection + partial duodenal resection + enteroanastomosis) on day 13 of admission. The postoperative pathology was choriocarcinoma. We subsequently conducted a detailed inquiry with the patient's family about his medical history and found a history of inguinal testicle. Through testicular ultrasound examination, it was preliminarily determined to be testicular choriocarcinoma (not yet pathologically confirmed). We wanted to start salvage chemotherapy as soon as possible after surgery. However, the patient's postoperative condition was poor, with rapid progression of hepatopulmonary metastases and gradually increased thyrotoxicosis, and we started salvage chemotherapy (EP regimen: etoposide and cisplatin) on postoperative day 12. However, the patient was forced to stop due to a severe chemotherapy reaction and died of respiratory and cardiac arrest in the hospital. For male patients with retroperitoneal mass, the possibility of germ-cell neoplasm should first be excluded. By inquiring in detail about a history of cryptorchidism and in the initial days of hospitalization, testicular exploration, ultrasounds, and serum tumor markers (AFP, ß-HCG) tests can be conducted to rule out the possibility of germ-cell neoplasm, thereby preventing misdiagnosis and treatment delays. If the clinical diagnosis is metastatic germ-cell tumor with severe symptoms of metastatic disease, surgery should never be used as the initial treatment.

A feasible way to explore real blood vessels thermal responses to laser irradiation by combing optical clearing and the reflectance spectra measurements: animal experiment study.

Laser therapy has been widely used to treat port-wine stains (PWS) and other cutaneous vascular lesions via selective photothermolysis. Animal models are a valuable tool for investigating thermal responses beneath the skin. However, in previous animal experiments, such as the dorsal skin chamber model, one side of the skin was removed, resulting in the loss of mechanical support for the target blood vessel. In this study, the optical clearing technique was applied to the dorsal skin, allowing direct observation of real thermal responses within the tissue without removing the covering skin. The target blood vessels were irradiated with a pulsed 1064 nm Nd: YAG laser. The corresponding thermal responses were recorded using a CCD camera. Additionally, variations in skin reflectance spectra were measured before and after laser irradiation. Due to the optical clearing and reflectance spectra measurement, vessel responses such as contraction, reperfusion, and full occlusion were correlated with specific variation patterns in reflectance spectral signals.

New polycyclic polyprenylated acylphloroglucinols with antidepressant activities from Hypericum perforatum L.

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1-6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo2(OCOCH3)4] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1-6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 µM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST) of mice, which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerted an antidepressant effect through the hypothalamic-pituitary-adrenal (HPA) axis.

Causal association between skin cancer and immune cells: mendelian randomization (MR) study.

BACKGROUND: Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. METHODS: This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. RESULTS: We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. CONCLUSION: This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Cu(II)-based complex loaded with drug paclitaxel hydrogels against thyroid cancer and optimizing novel derivatives.

This study introduces a novel approach for synthesizing a Cu(II)-based coordination polymer (CP), {[Cu(L)(4,4´-OBA)]·H2O}n (1), using a mixed ligand method. The CP was successfully prepared by reacting Cu(NO3)2·3H2O with the ligand 3,6-bis(benzimidazol-1-yl)pyridazine in the presence of 4,4´-H2OBA, demonstrating an innovative synthesis strategy. Furthermore, a novel hydrogel composed of hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) with a porous structure was developed for drug delivery purposes. This hydrogel facilitates the encapsulation of CP1, and enables the loading of paclitaxel onto the composite to form HA/CMCS-CP1@paclitaxel. In vitro cell experiments demonstrated the promising modulation of thyroid cancer biomarker genes S100A6 and ARID1A by HA/CMCS-CP1@paclitaxel. Finally, reinforcement learning simulations were employed to optimize novel metal-organic frameworks, underscoring the innovative contributions of this study.

Fascin-1 Promotes Cell Metastasis through Epithelial-Mesenchymal Transition in Canine Mammary Tumor Cell Lines.

Canine mammary tumors (CMTs) are the most common type of tumor in female dogs. In this study, we obtained a metastatic key protein, Fascin-1, by comparing the proteomics data of in situ tumor and metastatic cell lines from the same individual. However, the role of Fascin-1 in the CMT cell line is still unclear. Firstly, proteomics was used to analyze the differential expression of Fascin-1 between the CMT cell lines CHMm and CHMp. Then, the overexpression (CHMm-OE and CHMp-OE) and knockdown (CHMm-KD and CHMp-KD) cell lines were established by lentivirus transduction. Finally, the differentially expressed proteins (DEPs) in CHMm and CHMm-OE cells were identified through proteomics. The results showed that the CHMm cells isolated from CMT abdominal metastases exhibited minimal expression of Fascin-1. The migration, adhesion, and invasion ability of CHMm-OE and CHMp-OE cells increased, while the migration, adhesion, and invasion ability of CHMm-KD and CHMp-KD cells decreased. The overexpression of Fascin-1 can upregulate the Tetraspanin 4 (TSPAN4) protein in CHMm cells and increase the number of migrations. In conclusion, re-expressed Fascin-1 could promote cell EMT and increase lamellipodia formation, resulting in the enhancement of CHMm cell migration, adhesion, and invasion in vitro. This may be beneficial to improve female dogs' prognosis of CMT.

Optimising operating theatre (OT) efficiency while maintaining the standardised patient care in adolescent idiopathic scoliosis (AIS) surgery with the dedicated spine team approach: a specialised spine unit experience.

PURPOSE: To report the efficiency of OT utilisation and perioperative outcomes with a dedicated spine team approach in AIS patients who underwent posterior spinal fusion (PSF) surgeries in a consecutive case operation list. METHODS: Three AIS patients operated in a day (8:00 AM-8:00 PM) by a dedicated spine team were recruited between 2021 and 2022. The dedicated team comprised of three senior spine consultants who operated using a dual attending surgeon strategy, an anaesthetic consultant, dedicated surgical scrub nurses, anaesthesiology nurses, radiographers, and neuromonitoring technicians. Patients were categorised according to the sequence of operation list of the day (Case 1, Case 2, and Case 3). OT efficiency was represented by OT time in five stages (preoperative time, operative time, postoperative time, total OT time, and turnover time). OT time and perioperative outcomes were compared. RESULTS: 102 cases were analysed. On average, Case 1 began at 8:38 AM whereas Case 3 ended by 5:54 PM. OT efficiency was consistent throughout the day of operation with comparable OT time in all five stages between groups (p > 0.05). The mean turnover time was 15.1 ± 13.5 min and the mean operative time was 123.0 ± 28.1 min. Intraoperative arterial blood gas (ABG) parameters were maintained in an optimal range. The complication rate was 2.0% (N = 2/102). CONCLUSION: Consistent OT efficiency was demonstrated with a dedicated spine team approach. Despite performing three AIS cases in a consecutive case operation list, patients' safety was not compromised as perioperative outcomes between groups were comparable.

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Stromal B Lymphocytes Affecting Prognosis in Triple-Negative Breast Cancer by Opal/TSA Multiplexed Immunofluorescence.

Objective: Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer. Methods: We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people's Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan-Meier method and further analyzed with multivariate analysis. Results: Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes. Conclusion: The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.

Dietary supplementation of osthole and icariin improves the production performance of laying hens by promoting follicular development.

Osthole (Ost) and icariin (Ica) are extracted from traditional Chinese medicine Cnidium monnieri and Epimedii Folium, respectively, and both exhibit estrogen-like biological activity. This study aimed to determine the efficacy and safety of combining Ost with Ica on the production performance of laying hens and to explore their possible mechanisms. The production performance, egg quality, residues of Ost and Ica in eggs, serum reproductive hormone levels, expression of ovarian reproductive hormone receptor, proliferation of granulosa cells in small yellow follicles (SYF), and progesterone secretion in large yellow follicles (LYF) related genes and proteins expression were detected. The results showed that adding 2 mg/kg Ost + 2 mg/kg Ica to the feed increased the laying rate, average egg weight, Haugh unit, and protein height of laying hens. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and progesterone (P4) levels increased, and the expression of ovarian estrogen receptor (ER), follicle-stimulating hormone receptor (FSHR), and progesterone receptor (PGR) mRNA was up-regulated. Additionally, the mRNA and protein levels of steroidogenesis acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) increased in LYF. Furthermore, mRNA and protein levels of proliferating cell nuclear antigen (PCNA), cyclin E1, and cyclin A2 were up-regulated in SYF. The residues of Ost and Ica in egg samples were not detected by high-performance liquid chromatography (HPLC). In conclusion, dietary supplementation of Ost and Ica increased granulosa cells proliferation in SYF and increased P4 secretion in granulosa cells of LYF, ultimately improving the production performance of laying hens.

Bulk anda single-cell transcriptome profiling reveals the molecular characteristics of T cell-mediated tumor killing in pancreatic cancer.

Background: Despite the potential of immune checkpoint blockade (ICB) as a promising treatment for Pancreatic adenocarcinoma (PAAD), there is still a need to identify specific subgroups of PAAD patients who may benefit more from ICB. T cell-mediated tumor killing (TTK) is the primary concept behind ICB. We explored subtypes according to genes correlated with the sensitivity to TKK and unraveled their underlying associations for PAAD immunotherapies. Methods: Genes that control the responsiveness of T cell-induced tumor destruction (GSTTK) were examined in PAAD, focusing on their varying expression levels and association with survival results. Moreover, samples with PAAD were separated into two subsets using unsupervised clustering based on GSTTK. Variability was evident in the tumor immune microenvironment, genetic mutation, and response to immunotherapy among different groups. In the end, we developed TRGscore, an innovative scoring system, and investigated its clinical and predictive significance in determining sensitivity to immunotherapy. Results: Patients with PAAD were categorized into 2 clusters based on the expression of 52 GSTTKs, which showed varying levels and prognostic relevance, revealing unique TTK patterns. Survival outcome, immune cell infiltration, immunotherapy responses, and functional enrichment are also distinguished among the two clusters. Moreover, we found the CATSPER1 gene promotes the progression of PAAD through experiments. In addition, the TRGscore effectively predicted the responses to chemotherapeutics or immunotherapy in patients with PAAD and overall survival. Conclusions: TTK exerted a vital influence on the tumor immune environment in PAAD. A greater understanding of TIME characteristics was gained through the evaluation of the variations in TTK modes across different tumor types. It highlights variations in the performance of T cells in PAAD and provides direction for improved treatment approaches.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Indolent T-Cell/Natural Killer-Cell Lymphomas/Lymphoproliferative Disorders of the Gastrointestinal Tract-What Have We Learned in the Last Decade?

Primary gastrointestinal (GI) T-cell and natural killer (NK)-cell lymphomas/lymphoproliferative disorders (LPD) are uncommon, and they are usually aggressive in nature. However, T-cell and NK-cell lymphoma/LPD of the GI tract with indolent clinical course has been reported over the past 2 decades. Indolent T-cell LPD was formally proposed a decade ago in 2013 and 4 years later recognized as a provisional entity by the revised fourth edition of WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues in 2017. Indolent T-cell LPD of the GI tract has been changed to indolent T-cell lymphoma of the GI tract as a distinct entity by the fifth edition of WHO Classification of Haematolymphoid Tumours, but the International Consensus Classification of mature lymphoid neoplasms prefers indolent clonal T-cell LPD of the GI tract instead. In the past decade, indolent lymphoma/LPD of the GI tract has been expanded to NK cells, and as such, indolent NK-cell LPD of the GI tract was recognized as an entity by both the fifth edition of WHO Classification of Haematolymphoid Tumours and the International Consensus Classification. The underlying genetic/molecular mechanisms of both indolent T-cell lymphoma/LPD of the GI tract and indolent NK-cell LPD of the GI tract have been recently discovered. In this review, we describe the history; salient clinical, cytohistomorphologic, and immunohistochemical features; and genetic/genomic landscape of both entities. In addition, we also summarize the mimics and differential diagnosis. Finally, we propose future directions with regard to the pathogenesis and clinical management.

Characterization of m6A methylation modifications in gastric cancer.

Widely recognized as an essential epitranscriptomic modification, RNA N6-methyladenosine (m6A) is involved in both physiological and pathological processes. Here, we want to investigate m6A modification's potential roles in gastric cancer. Gastric cancer samples were selected from TCGA-STAD and GEO (GSE84426, GSE84433) datasets. Based on 18 regulators of m6A, m6A modification patterns were thoroughly evaluated in gastric cancer samples. Principal component analysis algorithms were used to construct the m6Ascore, using which, m6A modification features in tumor somatic mutations and immune checkpoint blockade therapy were analyzed. 34 gastric cancer samples were collected to verify the effectiveness of the m6Ascore. Here, we determined three different m6A modification patterns. m6Acluster-C modification pattern presented immune activation-associated enrichment pathways and have significant survival advantages. Then, in gastric cancer, m6Ascore could act as an independent prognostic biomarker. A significant survival benefit was exhibited in patients with high m6Ascore. Moreover, the modification signature of m6A uncovered in this study would help to predict immune checkpoint blockade therapy's responses. In conclusion, our discoveries all pointed to the fact that modification patterns of m6A were linked to the TME. Moreover, evaluation of individual tumor's m6A modification pattern will help to guide immunotherapy strategies that shows more therapeutic effects.

Analysis of duration of different stages of surgery in posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) patients: comparison between severe versus non-severe AIS.

PURPOSE: Prolonged surgical duration in severe adolescent idiopathic scoliosis (AIS) patients is associated with increased blood loss and perioperative complications. The aim of this study was to compare the duration of each stage of posterior spinal fusion (PSF) in severe AIS (Cobb angle ≥ 90°) with non-severe AIS patients. This analysis will identify the most time-consuming stage of PSF and help surgeons formulate strategies to shorten operative time. METHODS: Retrospective study whereby 90 AIS patients (Lenke type 2, 3, 4, and 6) who underwent PSF from 2019 to 2023 were recruited. Twenty-five severe AIS patients were categorized in Gp1 and 65 non-severe AIS patients in Gp2. Propensity score matching (PSM) with one-to-one with nearest neighbor matching (match tolerance 0.05) was performed. Outcomes measured via operation duration of each stage of surgery, blood loss, number of screws, fusion levels and screw density. RESULTS: Twenty-five patients from each group were matched. Total operative time was significantly higher in Gp1 (168.2 ± 30.8 vs. 133.3 ± 24.0 min, p < 0.001). The lengthiest stage was screw insertion which took 58.5 ± 13.4 min in Gp1 and 44.7 ± 13.7 min in Gp2 (p = 0.001). Screw insertion contributed 39.5% of the overall increased surgical duration in Gp1. Intraoperative blood loss (1022.2 ± 412.5 vs. 714.2 ± 206.7 mL, p = 0.002), number of screws (17.1 ± 1.5 vs. 15.5 ± 1.1, p < 0.001) and fusion level (13.1 ± 0.9 vs. 12.5 ± 1.0, p = 0.026) were significantly higher in Gp1. CONCLUSION: Screw insertion was the most time-consuming stage of PSF and was significantly longer in severe AIS. Adjunct technologies such as CT-guided navigation and robotic-assisted navigation should be considered to reduce screw insertion time in severe AIS.

A comparison between Boston brace and European braces in the treatment of adolescent idiopathic scoliosis (AIS) patients: a systematic review based on the standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment.

PURPOSE: To compare the Boston brace and European braces using a standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment as well as consensus recommendations for treatment outcome. METHODS: This was a systematic review that was carried out using MeSH terminology in our search protocol in PubMed, Cochrane Library, Scopus, Clinicaltrials.gov and Web of Science database between 1976 and 29th of Jan 2023. All studies that were included in this review had applied fully/partially the SRS inclusion criteria for brace wear. Outcome measures were divided into primary and secondary outcome measures. RESULTS: 3830 literatures were found in which 176 literatures were deemed relevant to the study once duplicates were removed and titles and abstracts were screened. Of these literatures, only 15 had fulfilled the eligibility criteria and were included in the study. 8 of the studies were Level IV studies, 5 were Level III studies and 2 studies were Level I studies (1 prospective randomised controlled trial (RCT) and 1 Quasi-RCT). The percentage of patients who avoided surgery for European braces ranged from 88 to 100%, whereas for Boston brace ranged from 70 to 94%. When treatment success was assessed based on the final Cobb angle > 45°, approximately 15% of patients treated with European braces had treatment failure. In contrast, 20-63% of patients treated with Boston brace had curves > 45° at skeletal maturity. The BrAIST study used a cut-off point of 50° to define failure of treatment and the rate of treatment failure was 28%. Curve correction was not achieved in most patients (24-51% of patients) who were treated with the Chêneau brace and its derivatives. However, none of the patients treated with Boston brace achieved curve correction. CONCLUSION: Boston brace and European braces were effective in the prevention of surgery. In addition, curve stabilisation was achieved in most studies. Limitation in current literature included lack of studies providing high level of evidence and lack of standardisation in terms of compliance to brace as well as multidisciplinary management of brace wear.

Deep Learning Radiomics Nomogram Based on Multiphase Computed Tomography for Predicting Axillary Lymph Node Metastasis in Breast Cancer.

PURPOSE: This study aims to develop and validate a deep learning radiomics nomogram (DLRN) for prediction of axillary lymph node metastasis (ALNM) in breast cancer patients. MATERIALS AND METHODS: We retrospectively enrolled 196 patients with non-specific invasive breast cancer confirmed by pathology, radiomics and deep learning features were extracted from unenhanced and biphasic (arterial and venous phase) contrast-enhanced CT, and the non-linear support vector machine was used to construct the radiomics signature and the deep learning signature, respectively. Next, a DLRN was developed with independent predictors and evaluated the performance of models in terms of discrimination and clinical utility. RESULTS: Multivariate logistic regression analysis showed that the radiomics signature, deep learning signature, and clinical n stage were independent predictors. The DLRN accurately predicted ALNM and yielded an area under the receiver operator characteristic curve of 0.893 (95% confidence interval, 0.814-0.972) in the validation set, with good calibration. Decision curve analysis confirmed that the DLRN had higher clinical utility than other predictors. CONCLUSIONS: The DLRN had good predictive value for ALNM in breast cancer patients and provide valuable information for individual treatment.

Screening and Characterization of Allosteric Small Molecules Targeting Bruton's Tyrosine Kinase.

Bruton's Tyrosine Kinase (BTK) is a nonreceptor tyrosine kinase that belongs to the TEC family. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA) leading to an arrest in B-cell development. BTK is also a drug target for B-cell lymphomas that rely on an intact B-cell receptor signaling cascade for survival. All FDA approved drugs for BTK target the ATP binding site of the catalytic kinase domain, leading to potential adverse events due to off-target inhibition. In addition, acquired resistance mutations occur in a subset of patients, rendering available BTK inhibitors ineffective. Therefore, allosteric sites on BTK should be explored for drug development to target BTK more specifically and in combination with active site inhibitors. Virtual screening against nonactive site pockets and in vitro experiments resulted in a series of small molecules that bind to BTK outside of the active site. We characterized these compounds using biochemical and biophysical techniques and narrowed our focus to compound "C2". C2 activates full-length BTK and smaller multidomain BTK fragments but not the isolated kinase domain, consistent with an allosteric mode of action. Kinetic experiments reveal a C2-mediated decrease in Km and an increase in kcat leading to an overall increase in the catalytic efficiency of BTK. C2 is also capable of activating the BTK XLA mutants. These proof-of-principle data reveal that BTK can be targeted allosterically with small molecules, providing an alternative to active site BTK inhibitors.

Vasculogenic mimicry-associated novel gene signature predicted prognosis and response to immunotherapy in lung adenocarcinoma.

BACKGROUNDS: It was highlighted by recent studies on the biological significance of vasculogenic mimicry (VM) in tumorigenicity and progression. However, it is unclear whether VM also plays a potential role in immune regulation and tumor microenvironment (TME) formation. METHODS: To identify patterns of VM alterations and VM-associated genetic features in non-small cell lung adenocarcinoma, we have screened 309 VM regulators and performed consensus molecular typing by the NMF algorithm. The ssGSEA and CIBORSORT algorithms were employed to measure the relative infiltration of distinct immune cell subpopulations. Individual tumors with immune responses were evaluated for alteration patterns of VM with typing-based differential genes. RESULTS: In 490 LUAD samples, two distinctive VM alteration patterns connected to different clinical outcomes and biochemical pathways were established. TME characterization showed that the observed VM patterns were primarily saturated with cell proliferation and metabolic pathways and higher in immune cell infiltration of the C1 type. Vasculogenic mimicry-related genes (VMRG) risk scores were constructed to divide patients with lung adenocarcinoma into subgroups with high and low scores. Patients with lower scores had better immunological scores and longer survival times. Upon further investigation, higher scores were positively correlated with higher tumor mutation burden (TMB), M1-type macrophages and immune checkpoint molecules. Nevertheless, in two other immunotherapy cohorts, individuals with lower scores had enhanced immune responses and long-lasting therapeutic benefits. Finally, we monitored the ANLN gene from the VMRG model, which was highly expressed in lung adenocarcinoma tissues and negatively correlated with prognosis; it was also highly expressed in lung adenocarcinoma cell lines, and knockdown of ANLN elicited low expression of VEGFA, MMP2 and MMP9. CONCLUSION: This study highlights that VM modifications are significantly associated with the diversity and complexity of TME, revealing new features of the immune microenvironment in lung adenocarcinoma and providing a new strategy for immunotherapy. Screening ANLN as a critical target for vasculogenic mimicry in lung adenocarcinoma provides a novel perspective for the targeted treatment of lung adenocarcinoma.