Combined detection of serum IL-6 and CEA contributes to the diagnosis of lung adenocarcinoma in situ.

Background: Effective discrimination of lung adenocarcinoma (LUAD) in situ (AIS) from benign pulmonary nodules (BPN) is critical for the early diagnosis of AIS. Our pilot study in a small cohort of 90 serum samples has shown that serum interleukin 6 (IL-6) detection can distinguish AIS from BPN and health controls (HC). In this study, we intend to comprehensively define the diagnostic value of individual and combined detection of serum IL-6 related to the traditional tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) for AIS. Methods: The diagnostic performance of serum IL-6 along with CEA and CYFRA21-1 were evaluated in a large cohort of 300 serum samples by a chemiluminescence immunoassay and an electrochemiluminescence immunoassay. A training set comprised of 65 AIS, 65 BPN, and 65 HC samples was used to develop the predictive model for AIS. Data obtained from an independent validation set was applied to evaluate and validate the predictive model. Results: In the training set, the levels of serum IL-6 and CEA in the AIS group were significantly higher than those in the BPN/HC group (P < 0.05). There was no significant difference in serum CYFRA21-1 levels between the AIS group and the BPN/HC group (P> 0.05). Serum IL-6 and CEA levels for AIS patients showed an area under the curve (AUC) of 0.622 with 23.1% sensitivity at 90.7% specificity, and an AUC of 0.672 with 24.6% sensitivity at 97.6% specificity, respectively. The combination of serum IL-6 and CEA presented an AUC of 0.739, with 60.0% sensitivity at 95.4% specificity. The combination of serum IL-6 and CEA showed an AUC of 0.767 for AIS patients, with 57.1% sensitivity at 91.4% specificity in the validation set. Conclusions: IL-6 shows potential as a prospective serum biomarker for the diagnosis of AIS, and the combination of serum IL-6 with CEA may contribute to increased accuracy in AIS diagnosis. However, it is worth noting that further research is still necessary to validate and optimize the diagnostic efficacy of these biomarkers and to address potential sensitivity limitations.

Diagnosis of benign and malignant nodules with a radiomics model integrating features from nodules and mammary regions on DCE-MRI.

Objectives: To establish a radiomics model for distinguishing between the benign and malignant mammary gland nodules via combining the features from nodule and mammary regions on DCE-MRI. Methods: In this retrospective study, a total of 103 cases with mammary gland nodules (malignant/benign = 80/23) underwent DCE-MRI, and was confirmed by biopsy pathology. Features were extracted from both nodule region and mammary region on DCE-MRI. Three SVM classifiers were built for diagnosis of benign and malignant nodules as follows: the model with the features only from nodule region (N model), with the features only from mammary region (M model) and the model combining the features from nodule region and mammary region (NM model). The performance of models was evaluated with the area under the curve of receiver operating characteristic (AUC). Results: One radiomic features is selected from nodule region and 3 radiomic features is selected from mammary region. Compared with N or M model, NM model exhibited the best performance with an AUC of 0.756. Conclusions: Compared with the model only using the features from nodule or mammary region, the radiomics-based model combining the features from nodule and mammary region outperformed in the diagnosis of benign and malignant nodules.

Emerging therapeutic strategies for metastatic uveal melanoma: Targeting driver mutations.

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo-YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.

Association of estrogen receptor and progesterone receptor genetic polymorphisms with recurrent pregnancy loss: A systematic review and meta-analysis.

OBJECTIVE: Estrogen and progesterone play key roles in the maintenance of pregnancy, and their function is mediated via estrogen receptor 1 (ESR1)/estrogen receptor 2 (ESR2) and progesterone receptor (PGR), respectively. It has been suggested the genetic variations in ESR1, ESR2, and PGR may contribute to recurrent pregnancy loss (RPL); however, the available evidence remains controversial. This meta-analysis aimed to explore the relation of various polymorphisms in ESR1, ESR2, and PGR genes to the risk of RPL. METHODS: A systematic literature search was conducted using PubMed and Scopus up to August 2023 to obtain relevant studies. The odds ratios (ORs) with 95% confidence intervals (95% CIs) were computed and pooled with the use of random-effects models to test the associations. RESULTS: A total of 31 studies with 12 different polymorphisms, including 5 polymorphisms for ESR1, 3 polymorphisms for ESR2, and 4 polymorphisms for PGR, were analyzed in this meta-analysis. Overall, no significant relationship was found between various polymorphisms of ESR1 and ESR2 with RPL in any of the genetic analysis models. PGR rs590688 (C > G) polymorphism was significantly related to the elevated risk of RPL under the dominant (OR = 1.67; 95 %CI: 1.15-2.44), allelic (OR = 1.55; 95 %CI: 1.13-2.12), and GC vs. CC (OR = 1.55; 95 %CI: 1.07-2.23) models. No significant association was identified for other variants of PGR gene. CONCLUSION: Unlike estrogen receptors, variations in PGR rs590688 (C > G) may be linked to the increased risk of RPL. More studies are required to confirm this finding.

DeepmdQCT: A multitask network with domain invariant features and comprehensive attention mechanism for quantitative computer tomography diagnosis of osteoporosis.

In the medical field, the application of machine learning technology in the automatic diagnosis and monitoring of osteoporosis often faces challenges related to domain adaptation in drug therapy research. The existing neural networks used for the diagnosis of osteoporosis may experience a decrease in model performance when applied to new data domains due to changes in radiation dose and equipment. To address this issue, in this study, we propose a new method for multi domain diagnostic and quantitative computed tomography (QCT) images, called DeepmdQCT. This method adopts a domain invariant feature strategy and integrates a comprehensive attention mechanism to guide the fusion of global and local features, effectively improving the diagnostic performance of multi domain CT images. We conducted experimental evaluations on a self-created OQCT dataset, and the results showed that for dose domain images, the average accuracy reached 91%, while for device domain images, the accuracy reached 90.5%. our method successfully estimated bone density values, with a fit of 0.95 to the gold standard. Our method not only achieved high accuracy in CT images in the dose and equipment fields, but also successfully estimated key bone density values, which is crucial for evaluating the effectiveness of osteoporosis drug treatment. In addition, we validated the effectiveness of our architecture in feature extraction using three publicly available datasets. We also encourage the application of the DeepmdQCT method to a wider range of medical image analysis fields to improve the performance of multi-domain images.

Real-Time Spatiotemporal Measurement of Extracellular Signaling Molecules Using an Aptamer Switch-Conjugated Hydrogel Matrix.

Cells rely on secreted signaling molecules to coordinate essential biological functions including development, metabolism, and immunity. Unfortunately, such signaling processes remain difficult to measure with sufficient chemical specificity and temporal resolution. To address this need, an aptamer-conjugated hydrogel matrix that enables continuous fluorescent measurement of specific secreted analytes - in two dimensions, in real-time is developed. As a proof of concept, real-time imaging of inter-cellular cyclic adenosine 3',5'-monophosphate (cAMP) signals in Dictyostelium discoideum amoeba cells is performed. A set of aptamer switches that generate a rapid and reversible change in fluorescence in response to cAMP signals is engineered. By combining multiple switches with different dynamic ranges, measure cAMP concentrations spanning three orders of magnitude in a single experiment can be measured. These sensors are embedded within a biocompatible hydrogel on which cells are cultured and their cAMP secretions can be imaged using fluorescent microscopy. Using this aptamer-hydrogel material system, the first direct measurements of oscillatory cAMP signaling that correlate closely with previous indirect measurements are achieved. Using different aptamer switches, this approach can be generalized for measuring other secreted molecules to directly visualize diverse extracellular signaling processes and the biological effects that they trigger in recipient cells.

Cancer chemoprevention with PV-1, a novel Prunella vulgaris-containing herbal mixture that remodels the tumor immune microenvironment in mice.

The herb Prunella vulgaris has shown significant immune-stimulatory and anti-inflammatory effects in mouse models. Here, the effects of a novel Prunella vulgaris-containing herbal mixture, PV-1, were examined in several mouse models for cancer, including chemically induced models of lung and oral cancers as well as syngraft models for lung cancer and melanoma. PV-1, consisting of extracts from Prunella vulgaris, Polygonum bistorta, Sonchus brachyotus and Dictamnus dasycarpus, exhibited no toxicity in a dose escalation study in A/J mice. PV-1 significantly inhibited mouse lung tumor development induced by the lung carcinogens vinyl carbamate and benzo[a]pyrene. PV-1 also hindered the induction of oral squamous cell carcinomas in C57BL/6 mice caused by 4-nitroquinoline-1-oxide. Flow cytometry analysis showed that PV-1 increased the numbers of CD8+ tumor-infiltrating lymphocytes (TILs) and increased the production of granzyme B, TNF-α, and IFN-γ by CD8+ TILs. PV-1 also suppressed granulocytic myeloid-derived suppressor cell numbers (g-MDSCs) and improved the anti-cancer activity of anti-PD-1 immunotherapy. These results indicate that PV-1 remodels the tumor immune microenvironment by selectively inhibiting g-MDSCs and increasing CD8+ TILs within tumors, resulting in decreased immune suppression and enhanced cancer chemopreventive efficacy.

Rapid visualization of PD-L1 expression level in glioblastoma immune microenvironment via machine learning cascade-based Raman histopathology.

INTRODUCTION: Combination immunotherapy holds promise for improving survival in responsive glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1) expression in immune microenvironment (IME) is the most important predictive biomarker for immunotherapy. Due to the heterogeneous distribution of PD-L1, post-operative histopathology fails to accurately capture its expression in residual tumors, making intra-operative diagnosis crucial for GBM treatment strategies. However, the current methods for evaluating the expression of PD-L1 are still time-consuming. OBJECTIVE: To overcome the PD-L1 heterogeneity and enable rapid, accurate, and label-free imaging of PD-L1 expression level in GBM IME at the tissue level. METHODS: We proposed a novel intra-operative diagnostic method, Machine Learning Cascade (MLC)-based Raman histopathology, which uses a coordinate localization system (CLS), hierarchical clustering analysis (HCA), support vector machine (SVM), and similarity analysis (SA). This method enables visualization of PD-L1 expression in glioma cells, CD8+ T cells, macrophages, and normal cells in addition to the tumor/normal boundary. The study quantified PD-L1 expression levels using the tumor proportion, combined positive, and cellular composition scores (TPS, CPS, and CCS, respectively) based on Raman data. Furthermore, the association between Raman spectral features and biomolecules was examined biochemically. RESULTS: The entire process from signal collection to visualization could be completed within 30 min. In an orthotopic glioma mouse model, the MLC-based Raman histopathology demonstrated a high average accuracy (0.990) for identifying different cells and exhibited strong concordance with multiplex immunofluorescence (84.31 %) and traditional pathologists' scoring (R2 ≥ 0.9). Moreover, the peak intensities at 837 and 874 cm-1 showed a positive linear correlation with PD-L1 expression level. CONCLUSIONS: This study introduced a new and extendable diagnostic method to achieve rapid and accurate visualization of PD-L1 expression in GBM IMB at the tissular level, leading to great potential in GBM intraoperative diagnosis for guiding surgery and post-operative immunotherapy.

How do aeration mode and influent carbon/nitrogen ratio affect pollutant removal, gas emission, functional genes and bacterial community in subsurface wastewater infiltration systems?

This study investigated the influences of aeration mode and influent carbon/nitrogen ratio on matrix oxygen concentration, pollutant removal, greenhouse gas emission, functional gene abundances and bacterial community in subsurface wastewater infiltration systems (SWISs). Intermittent or continuous aeration enhanced oxygen supply at 0.6 m depth in the matrix, which improved organics removal, nitrogen removal, the abundances of bacterial 16S rRNA, amoA, nxrA, narG, napA, nirK, nirS, norB, nosZ genes, bacterial community Alpha diversity, the relative abundances of Actinobacteria at 0.6 m depth, the relative abundances of Chloroflexi, Gemmatimonadetes, Bacteroidetes and Firmicutes at 0.9 and 1.2 m depth and reduced CH4 and N2O conversion efficiencies, the abundance of mcrA gene with carbon/nitrogen ratio of 12 and 16 compared with non-aeration. Increased carbon/nitrogen ratio resulted in higher TN removal efficiencies and lower CH4 and N2O conversion efficiencies in aeration SWISs than those in non-aeration SWIS. Intermittent aeration SWIS obtained high removal efficiencies of 83.2, 85.4 and 90.8% for TN, NH4+ -N and COD and low conversion efficiency of 0.21 and 0.65% for N2O and CH4 with optimal carbon/nitrogen ratio of 12. However, high TN (82.6%), NH4+ -N (84.9%) and COD (92.2%) removal efficiencies and low CH4 (0.67%) and N2O (0.23%) conversion efficiencies were achieved in continuous aeration SWIS with carbon/nitrogen ratio of 16.

ATRX is a predictive marker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ breast cancer through the regulation of the AR, GLI3 and GATA2 transcriptional network.

Drug resistance in breast cancer (BC) is a clinical challenge. Exploring the mechanism and identifying a precise predictive biomarker for the drug resistance in BC is critical. Three first-line drug (paclitaxel, doxorubicin and tamoxifen) resistance datasets in BC from GEO were merged to obtain 1,461 differentially expressed genes for weighted correlation network analysis, resulting in identifying ATRX as the hub gene. ATRX is a chromatin remodelling protein, therefore, ATRX-associated transcription factors were explored, thereby identifying the network of AR, GLI3 and GATA2. GO and KEGG analyses revealed immunity, transcriptional regulation and endocrinotherapy/chemotherapy resistance were enriched. Moreover, CIBERSORT revealed immunity regulation was inhibited in the resistance group. ssGSEA showed a significantly lower immune status in the ATRX-Low group compared to the ATRX-High group. Furthermore, the peaks of H3K9me3 ChIP-seq on the four genes were higher in normal tissues than in BC tissues. Notably, the frequency of ATRX mutation was higher than BRCA in BC. Moreover, depressed ATRX revealed worse overall survival and disease-free survival in the human epidermal growth factor receptor 2 (HER2)-/hormone receptor (HR)+ BC. Additionally, depressed ATRX predicted poor results for patients who underwent endocrinotherapy or chemotherapy in the HER2-/HR+ BC subgroup. A nomogram based on ATRX, TILs and ER exhibited a significantly accurate survival prediction ability. Importantly, overexpression of ATRX significantly inhibited the IC50 of the three first-line drugs on MCF-7 cell. Thus, ATRX is an efficient predictive biomarker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ BC and acts by suppressing the AR, GLI3 and GATA2 transcriptional network.

A General Survey of Pharynlaryngeal Diseases and Voice Disorders Among Basic Education Teachers in Tianjin.

OBJECTIVE: In this study, we created a city-wide database of pharynlaryngeal diseases and voice disorders among basic education teachers to analyze the incidence, distribution, and risk factors of pharynlaryngeal diseases and voice disorders. METHODS: A total of 47,823 teachers in primary and secondary schools and kindergartens of Tianjin were enrolled in this study and underwent questionnaires and throat examinations. In addition, the data were subjected to descriptive statistics, chi-square analysis, and univariate and multivariate logistic regression analyses. RESULTS: Pharynlaryngeal diseases and voice disorders had an overall prevalence of 69.42% among basic education teachers in Tianjin, wherein the prevalence of chronic pharyngitis, chronic hyperplastic laryngitis, and chronic simple laryngitis were the highest at 39.45%, 19.80%, and 15.59%, respectively. The results of multivariate logistic regression analysis suggest that pharynlaryngeal diseases and voice disorders were statistically correlated with gender (P < 0.001), years of teaching (P < 0.001), school district (P < 0.001), class size (P < 0.001), subjective assessment of teachers on vocal loudness (P < 0.001), neck and shoulder discomfort (P < 0.001), smoking (P < 0.001), psychological stress (P = 0.002), and frequent habitual throat clearing (P < 0.001). Furthermore, the risk factors for pharynlaryngeal diseases and voice disorders were age (P = 0.002), school district (P < 0.001), class size (P = 0.008), neck and shoulder discomfort (P = 0.038), smoking (P < 0.001), water intake habits during class (P = 0.023), and frequent habitual throat clearing (P = 0.001) for male teachers, and for female teachers, it was age (P < 0.001), school district (P < 0.001), daily teaching hours (P = 0.005), class size (P < 0.001), subjective assessment of teachers on vocal loudness (P < 0.001), neck and shoulder discomfort (P < 0.001), smoking (P = 0.033), psychological stress (P = 0.003), and frequent habitual throat clearing (P < 0.001). CONCLUSION: Due to the high prevalence of pharynlaryngeal diseases and voice disorders among basic education teachers, throat and voice health education-related activities should be conducted for teachers to intervene in the occurrence of pharynlaryngeal diseases and voice disorders at an early stage.

Chimeric Antigen Receptor T Cell Therapy for Acute Leukemia.

The worldwide use of CD19 chimeric antigen receptor (CAR)-T cells has increased the response rate in patients with refractory or relapsed B-cell acute lymphoblastic leukemia. Clinical practice has become much safer with the help of immunotherapy-related toxicity management guidelines, such as the ASTCT consensus grading system. Tocilizumab and steroids are the major interventions for controlling cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New drugs and interventions for uncontrolled CRS and ICANS, including JAK1/2 inhibitors, have also been investigated. The combination of ruxolitinib and steroids effectively controlled severe CRS without impeding CAR-T cell expansion. Patients with refractory CNS3 status and CNS masses were excluded from the clinical trials because of the high risk of severe ICANS. Intracranial injections of steroids and Ommaya capsule implantation were effective. For some heavily treated patients, the difficulties in CAR-T cell manufacturing and expansion may be resolved by combination with blinatumumab. Relapse is a major concern after CAR-T therapy, and combination interventions, such as allogeneic stem cell transplantation, dual-target CAR-T cell therapies, and sequential CD19/22 CAR-T infusion, have been investigated in many centers. For T-lineage-targeted CAR-T therapies, the CAR T-cell fratricide can be overcome using many techniques. The efficacy and safety of CD7+ CAR-T cell therapy have been widely reported in recent years. A high response rate can be achieved when the immune reconstitution is prolonged. Infections, particularly viral reactivations, should be carefully monitored, as relapses are another potential issue. Switching targets and eliminating residual CD7+ CAR-T cells in the blood are key points for patients who relapse after CD7+ CAR-T cell therapy. CAR-T cell therapies for AML have not been investigated in a large-scale cohort, except for CD19-positive AML with the AML1-ETO fusion gene.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Identification of novel lactate metabolism-related lncRNAs with prognostic value for bladder cancer.

Background: Bladder cancer (BCA) has high recurrence and metastasis rates, and current treatment options show limited efficacy and significant adverse effects. It is crucial to find diagnostic markers and therapeutic targets with clinical value. This study aimed to identify lactate metabolism-related lncRNAs (LM_lncRNAs) to establish a model for evaluating bladder cancer prognosis. Method: A risk model consisting of lactate metabolism-related lncRNAs was developed to forecast bladder cancer patient prognosis using The Cancer Genome Atlas (TCGA) database. Kaplan‒Meier survival analysis, receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA) were used to evaluate the reliability of risk grouping for predictive analysis of bladder cancer patients. The results were also validated in the validation set. Chemotherapeutic agents sensitive to lactate metabolism were assessed using the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: As an independent prognostic factor for patients, lactate metabolism-related lncRNAs can be used as a nomogram chart that predicts overall survival time (OS). There were significant differences in survival rates between the high-risk and low-risk groups based on the Kaplan‒Meier survival curve. decision curve analysis and receiver operating characteristic curve analysis confirmed its good predictive capacity. As a result, 22 chemotherapeutic agents were predicted to positively affect the high-risk group. Conclusion: An lactate metabolism-related lncRNA prediction model was proposed to predict the prognosis for patients with bladder cancer and chemotherapeutic drug sensitivity in high-risk groups, which provided a new idea for the prognostic evaluation of the clinical treatment of bladder cancer.

Striking efficacy of a vaccine targeting TOP2A for triple-negative breast cancer immunoprevention.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has a poor prognosis. TOP2A is a key enzyme in DNA replication and is a therapeutic target for breast and other cancers. TOP2A-specific Th1-promoting epitopes with optimal binding affinity to MHC II were identified using a combined scoring system. The multi-peptide TOP2A vaccine elicited a robust immunologic response in immunized mice, as demonstrated by the significant production of Th1 cytokines from immunized animals' splenocytes stimulated in vitro with TOP2A peptides. Anti-tumor efficacy of the TOP2A vaccine was demonstrated in a syngeneic TNBC mouse model, in which pre-graft preventive vaccination was associated with significantly decreased tumor growth as compared to adjuvant control. In a genetically engineered mouse (GEM) model of TNBC, vaccinated animals demonstrated a significant reduction in tumor incidence and average tumor volume compared to adjuvant control. Finally, we examined TCR sequences in CD4 tumor Infiltrating lymphocytes (TIL) from vaccinated mice and found that the TIL contained TCR sequences specific to the three vaccine peptides. These data indicate that our newly developed multi-peptide TOP2A vaccine is highly immunogenic, elicits TILs with vaccine specific TCRs, and is highly effective in preventing and intercepting TNBC development and progression in vivo.

An Intraoperative Sub-Anesthetic Dose of Esketamine on Postoperative Depressive Symptoms in Perimenopausal Women with Breast Cancer Undergoing Modified Radical Mastectomy: Protocol for a Randomized, Triple-Blinded, Controlled Trial.

Background: Depressive symptoms are common among perimenopausal women with breast cancer having modified radical mastectomy. Esketamine exerts antidepressant effects. This study aims to assess whether an intraoperative sub-anesthetic dose of esketamine prevents postoperative depressive symptoms in these patients. Methods: In this randomized, triple-blinded, placebo-controlled trial, we will enroll 130 perimenopausal women (aged 45-60 years) with breast cancer undergoing unilateral modified radical mastectomy. Patients will be randomly assigned with a 1:1 ratio to receive either esketamine (0.25 mg/kg i.v.) or normal saline after anesthesia induction and before skin incision. The primary outcome is the incidence of depressive symptoms at day 30 postoperatively, assessed using the Beck's Depression Inventory (BDI). Secondary outcomes include incidence of depressive symptoms and BDI scores at day 1, 3, and 180 postoperatively, anxiety symptoms and scores at day 1, 3, 30, and 180 postoperatively, pain intensity and quality of recovery at day 1 and 2 postoperatively, nausea and vomiting within 48 hours postoperatively, length of postoperative hospital stay, and cancer-specific outcomes. Data will be analyzed in the modified intention-to-treat population. Discussion: This is the first trial to evaluate the effects of a sub-anesthetic dose of esketamine on depressive symptoms in perimenopausal women after modified radical mastectomy. The results of this study will help to improve their mental health and recovery after breast cancer surgery. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2200064348).

Multidisciplinary recommendations for the management of CAR-T recipients in the post-COVID-19 pandemic era.

The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.

The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a poor prognosis. The growth of GBM cells depends on the core transcriptional apparatus, thus rendering RNA polymerase (RNA pol) complex as a candidate therapeutic target. The RNA pol II subunit B (POLR2B) gene encodes the second largest subunit of the RNA pol II (RPB2); however, its genomic status and function in GBM remain unclear. Certain GBM data sets in cBioPortal were used for investigating the genomic status and expression of POLR2B in GBM. The function of RPB2 was analyzed following knockdown of POLR2B expression by shRNA in GBM cells. The cell counting kit-8 assay and PI staining were used for cell proliferation and cell cycle analysis. A xenograft mouse model was established to analyze the function of RPB2 in vivo. RNA sequencing was performed to analyze the RPB2-regulated genes. GO and GSEA analyses were applied to investigate the RPB2-regulated gene function and associated pathways. In the present study, the genomic alteration and overexpression of the POLR2B gene was described in glioblastoma. The data indicated that knockdown of POLR2B expression suppressed tumor cell growth of glioblastoma in vitro and in vivo. The analysis further demonstrated the identification of the RPB2-regulated gene sets and highlighted the DNA damage-inducible transcript 4 gene as the downstream target of the POLR2B gene. The present study provides evidence indicating that RPB2 functions as a growth regulator in glioblastoma and could be used as a potential therapeutic target for the treatment of this disease.

Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention.

The development of chemopreventive strategies with the ability to prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. Delivery of microRNA (miRNA) by inhalation is a novel method for lung cancer prevention. In this study, we investigated the combined efficacy of aerosolized miR-138-5p and miR-200c miRNA mimics in lung cancer prevention. Combination of the two miRNAs inhibited Benzo(a)pyrene (B((a))P)-induced lung adenomas and N-nitroso-tris-chloroethylurea (NTCU)-induced lung squamous cell carcinomas with no detectable side effects. Using single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we found that both miRNAs inhibited programmed cell death ligand 1 (PD-L1) expression. Our flow cytometry results showed that aerosolized delivery of combined miRNAs increased CD4+ and CD8+ T cells and reduced the expression of programmed cell death protein 1 (PD-1) and T-regulatory cells. Our results demonstrated that the delivery of aerosolized microRNAs targeting PD-L1 can be highly effective in preventing lung cancer development and progression in mice.

Identification of different types of tumors based on photoacoustic spectral analysis: preclinical feasibility studies on skin tumors.

Significance: Collagen and lipid are important components of tumor microenvironments (TME) and participates in tumor development and invasion. It has been reported that collagen and lipid can be used as a hallmark to diagnosis and differentiate tumors. Aim: We aim to introduce photoacoustic spectral analysis (PASA) method that can provide both the content and structure distribution of endogenous chromophores in biological tissues to characterize the tumor-related features for identifying different types of tumors. Approach: Ex vivo human tissues with suspected squamous cell carcinoma (SCC), suspected basal cell carcinoma (BCC), and normal tissue were used in this study. The relative lipid and collagen contents in the TME were assessed based on the PASA parameters and compared with histology. Support vector machine (SVM), one of the simplest machine learning tools, was applied for automatic skin cancer type detection. Results: The PASA results showed that the lipid and collagen levels of the tumors were significantly lower than those of the normal tissue, and there was a statistical difference between SCC and BCC (p<0.05), consistent with the histopathological results. The SVM-based categorization achieved diagnostic accuracies of 91.7% (normal), 93.3% (SCC), and 91.7% (BCC). Conclusions: We verified the potential use of collagen and lipid in the TME as biomarkers of tumor diversity and achieved accurate tumor classification based on the collagen and lipid content using PASA. The proposed method provides a new way to diagnose tumors.