Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.

Lineage Replacement and Genetic Changes of Four HR-HPV Types during the Period of Vaccine Coverage: A Six-Year Retrospective Study in Eastern China.

OBJECTIVE: This study aimed to provide clinical evidence for lineage replacement and genetic changes of High-Risk Human Papillomavirus (HR-HPV) during the period of vaccine coverage and characterize those changes in eastern China. METHODS: This study consisted of two stages. A total of 90,583 patients visiting the Obstetrics and Gynecology Hospital of Fudan University from March 2018 to March 2022 were included in the HPV typing analysis. Another 1076 patients who tested positive for HPV31, 33, 52, or 58 from November 2020 to August 2023 were further included for HPV sequencing. Vaccination records, especially vaccine types and the third dose administration time, medical history, and cervical cytology samples were collected. Viral DNA sequencing was then conducted, followed by phylogenetic analysis and sequence alignment. RESULTS: The overall proportion of HPV31 and 58 infections increased by 1.23% and 0.51%, respectively, while infection by HPV33 and 52 decreased by 0.42% and 1.43%, respectively, within the four-year vaccination coverage period. The proportion of HPV31 C lineage infections showed a 22.17% increase in the vaccinated group, while that of the HPV58 A2 sublineage showed a 12.96% increase. T267A and T274N in the F-G loop of HPV31 L1 protein, L150F in the D-E loop, and T375N in the H-I loop of HPV58 L1 protein were identified as high-frequency escape-related mutations. CONCLUSIONS: Differences in epidemic lineage changes and dominant mutation accumulation may result in a proportional difference in trends of HPV infection. New epidemic lineages and high-frequency escape-related mutations should be noted during the vaccine coverage period, and regional epidemic variants should be considered during the development of next-generation vaccines.

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.

Deep learning-based predictive model for pathological complete response to neoadjuvant chemotherapy in breast cancer from biopsy pathological images: a multicenter study.

Introduction: Early predictive pathological complete response (pCR) is beneficial for optimizing neoadjuvant chemotherapy (NAC) strategies for breast cancer. The hematoxylin and eosin (HE)-stained slices of biopsy tissues contain a large amount of information on tumor epithelial cells and stromal. The fusion of pathological image features and clinicopathological features is expected to build a model to predict pCR of NAC in breast cancer. Methods: We retrospectively collected a total of 440 breast cancer patients from three hospitals who underwent NAC. HE-stained slices of biopsy tissues were scanned to form whole-slide images (WSIs), and pathological images of representative regions of interest (ROI) of each WSI were selected at different magnifications. Based on several different deep learning models, we propose a novel feature extraction method on pathological images with different magnifications. Further, fused with clinicopathological features, a multimodal breast cancer NAC pCR prediction model based on a support vector machine (SVM) classifier was developed and validated with two additional validation cohorts (VCs). Results: Through experimental validation of several different deep learning models, we found that the breast cancer pCR prediction model based on the SVM classifier, which uses the VGG16 model for feature extraction of pathological images at ×20 magnification, has the best prediction efficacy. The area under the curve (AUC) of deep learning pathological model (DPM) were 0.79, 0.73, and 0.71 for TC, VC1, and VC2, respectively, all of which exceeded 0.70. The AUCs of clinical model (CM), a clinical prediction model established by using clinicopathological features, were 0.79 for TC, 0.73 for VC1, and 0.71 for VC2, respectively. The multimodal deep learning clinicopathological model (DPCM) established by fusing pathological images and clinicopathological features improved the AUC of TC from 0.79 to 0.84. The AUC of VC2 improved from 0.71 to 0.78. Conclusion: Our study reveals that pathological images of HE-stained slices of pre-NAC biopsy tissues can be used to build a pCR prediction model. Combining pathological images and clinicopathological features can further enhance the predictive efficacy of the model.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

Targeting PUF60 prevents tumor progression by retarding mRNA decay of oxidative phosphorylation in ovarian cancer.

PURPOSE: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies, and its etiology and pathogenesis are currently unclear. Recent studies have found that PUF60 overexpressed in various cancers. However, the exact function of PUF60 in global RNA processing and its role in OC has been unclear. METHODS: The expression of PUF60 and its relationship with clinical characteristics were analyzed by multiple database analysis and immunohistochemistry. Phenotypic effects of PUF60 on ovarian cancer cell proliferation and metastasis were examined by in vitro cell proliferation assay, migration assay, and in vivo xenograft models and lung metastasis models. RNA immunoprecipitation, seahorse analyses, RNA stability assay were used to study the effect of PUF60 on the stability of oxidative phosphorylation (OXPHOS)-related genes in OC. RESULTS: We report PUF60 is highly expressed in OC with frequent amplification of up to 33.9% and its upregulation predicts a poor prognosis. PUF60 promotes the proliferation and migration of OC cells both in vitro and in vivo. Mechanistically, we demonstrated that silencing of PUF60 enhanced the stability of mRNA transcripts involved in OXPHOS and decreased the formation of processing bodies (P-bodies), ultimately elevating the OXPHOS level. CONCLUSION: Our study unveils a novel function of PUF60 in OC energy metabolism. Thus, PUF60 may serve as a novel target for the treatment of patients with OC.

Prevalence of respiratory viruses among hospitalized children with lower respiratory tract infections during the COVID-19 pandemic in Wuhan, China.

OBJECTIVES: We aimed to investigate the continuous changes in respiratory virus epidemics in hospitalized children with lower respiratory tract infections (LRTIs) persisting from January 2019 to December 2022 in Wuhan, China. METHODS: We retrospectively enrolled children with LRTIs admitted to the Wuhan Children's Hospital. Specimens were nasopharyngeal aspirates which had been collected and detected the following microorganisms with direct immunofluorescence: influenza virus types A and B, respiratory syncytial virus, parainfluenza virus types 1-3, and adenovirus. We also analyzed demographic data and laboratory test results. RESULTS: A total of 22,660 patients were enrolled. The total virus detection rate in 2019, 2021, and 2022 significantly declined gradually (36.96% vs 29.47% vs 22.62%, P value < 0.001). All the detected viruses did not follow previously observed seasonal patterns during the COVID-19 pandemic. Children hospitalized for LRTIs were older during the COVID-19 pandemic in contrast to the pre-period, particularly notable in cases attributed to respiratory syncytial virus and parainfluenza virus type 3 infections. CONCLUSIONS: This work adds to our knowledge of the epidemiology characteristics of respiratory viruses spanning the COVID-19 pandemic among children with LRTIs. The circulation of respiratory viruses changed consistently, and active LRTI surveillance in children remains critical for defining the healthcare burden of respiratory viruses.

Removal of an impacted apricot pit from a scarring duodenal stenosis using endoscopic retrograde cholangiopancreatography (ERCP) stone extraction technique.

A 66-year-old man presented with repeated vomiting for 5 days. Initial gastroscopy showed gastric retention while computed tomography (CT) revealed a 1.8*1.1 cm, oval-shaped, high-density object in the duodenum. Considering his past medical history of a surgical repair for duodenal ulcer perforation 20 years ago, a diagnosis of foreign body (FB) impaction causing gastric outlet obstruction was established. After gastric lavage, a second gastroscopy was performed. A brownish round FB impacted upon scarring stenoses at the junction of the 1st and 2nd part of duodenum was visualized after advancement of the scope with effort through a deformed pylorus. Attempts to capture the FB using a polypectomy snare failed because the snare loop could not be advanced across the stenotic impaction site to allow adequate opening. A grasper was also ineffective due to the smooth surface of the FB. Then the ERCP stone extraction technique was applied. Directed by the adjustable tip of a sphincterotome which was introduced through the same gastroscope, a guidewire passed with little resistance over the impaction site for an adequate length. Subsequently, an extraction balloon was advanced through the guidewire with slight inflation to avoid injury to the stenotic duodenal wall and fully inflated in the distal lumen. Gradual balloon deflation and withdrawal applied simultaneously achieved successful removal of the BF, which was identified as an apricot pit. The patient resumed his diet of soft food immediately after the procedure without complaint of any discomfort.

Multifactor artificial intelligence model assists axillary lymph node surgery in breast cancer after neoadjuvant chemotherapy: multicenter retrospective cohort study.

BACKGROUND: The high false negative rate (FNR) associated with sentinel lymph node biopsy often leads to unnecessary axillary lymph node dissection following neoadjuvant chemotherapy (NAC) in breast cancer. The authors aimed to develop a multifactor artificial intelligence (AI) model to aid in axillary lymph node surgery. MATERIALS AND METHODS: A total of 1038 patients were enrolled, comprising 234 patients in the primary cohort, 723 patients in three external validation cohorts, and 81 patients in the prospective cohort. For predicting axillary lymph node response to NAC, robust longitudinal radiomics features were extracted from pre-NAC and post-NAC magnetic resonance images. The U test, the least absolute shrinkage and selection operator, and the spearman analysis were used to select the most significant features. A machine learning stacking model was constructed to detect ALN metastasis after NAC. By integrating the significant predictors, we developed a multifactor AI-assisted surgery pipeline and compared its performance and false negative rate with that of sentinel lymph node biopsy alone. RESULTS: The machine learning stacking model achieved excellent performance in detecting ALN metastasis, with an area under the curve (AUC) of 0.958 in the primary cohort, 0.881 in the external validation cohorts, and 0.882 in the prospective cohort. Furthermore, the introduction of AI-assisted surgery reduced the FNRs from 14.88 (18/121) to 4.13% (5/121) in the primary cohort, from 16.55 (49/296) to 4.05% (12/296) in the external validation cohorts, and from 13.64 (3/22) to 4.55% (1/22) in the prospective cohort. Notably, when more than two SLNs were removed, the FNRs further decreased to 2.78% (2/72) in the primary cohort, 2.38% (4/168) in the external validation cohorts, and 0% (0/15) in the prospective cohort. CONCLUSION: Our study highlights the potential of AI-assisted surgery as a valuable tool for evaluating ALN response to NAC, leading to a reduction in unnecessary axillary lymph node dissection procedures.

The first nano-cocrystal formulation of marine drug cytarabine with uracil based on cocrystal nanonization strategy for long-acting injection exhibiting enhanced antitumor activity.

To emphasize the superiority of uracil (UR) in ameliorating biopharmaceutical characteristics of marine antitumor medicine cytarabine (ARA), thus gaining some innovative opinions for the exploitation of nanococrystal formulation, a cocrystal nanonization strategy is proposed by integrating cocrystallization and nanosize preparation techniques. For one thing, based on UR's unique structural features and natures together with advantages of preferential uptake by tumor cells, cocrystallizing ARA with UR is expected to improve the in vitro/vivo performances. For another, the nanonization procedure is oriented towards maintaining the long-term effective drug level. Along this route, a cocrystal of ARA with UR, viz., ARA-UR, is successfully synthesized and then transformed into nano-cocrystal. The cocrystal structure is precisely confirmed by various methods, demonstrating that a 1:1 ARA and UR in the crystal forms cytosine-UR hydrogen-bonding interactions, thus constructing supramolecular frameworks by strong π-π stacking interplays; while the nano-cocrystal is block-shaped particles of 562.70 nm with zeta potential -33.40 mV. The properties of cocrystal ARA-UR and its nano-cocrystal in vitro/vivo are comparatively explored by theoretical calculations and experimental analyses, revealing that permeability of both is significantly increased than ARA per se. Notably, the meliorative natures of both the cocrystal and nano-cocrystal in vitro bring excellent antitumor activity, but the latter has greater strengths over the former. More notably, the nano-cocrystal can sustain effective concentration for a relatively longer time, causing lengthened retention time and better absorption in vivo. The contribution offers a fire-new dosage form of ARA for long-lasting delivery, thus filling the vacancy in nanococrystal studies about marine drugs.

Exosome-Mediated lncRNA LINC01140 Attenuates Breast Cancer Progression by Regulating the Wnt/ß-Catenin Pathway.

Exosome-delivered long non-coding RNAs have a role in the cancer control. It is unknown how exosomal LINC01140 contributes to the breast cancer (BC) growth. The purpose of this investigation is to identify exosomal LINC01140's function in the development of breast cancer. Using quantitative reverse transcripion polymerase chain reaction, the expression of LINC01140 was measured. To investigate how LINC01140 overexpression impacts BC cell proliferation, CCK-8 as well as colony formation assays (CFA) were employed. The expression of apoptosis-related proteins (Bax and Bcl-2) and Wnt/ß-catenin signal pathway-related proteins (Wnt, C-myc, ß-catenin, and p-GSK-3ß) was assessed through Western blotting. Exosomes from BC cells were verified by western blotting to measure CD63 and CD9 levels. To examine how exosomal LINC01140 affects Wnt/ß-catenin signaling pathway and xenograft tumor in nude mice, BC cell exosomes that were overexpressing LINC01140 were obtained and co-cultured with BC cells. In BC, it was discovered that LINC01140 had poor expression. BC cell proliferation was inhibited by overexpressing LINC01140, and the levels of the proteins Bcl-2, ß-catenin, C-myc, and Wnt were lowered while Bax and p-GSK-3 were increased. In addition, exosomal LINC01140 hindered the activation of the Wnt/ß-catenin signaling pathway, leading to a decrease in the growth of breast cancer cells in vivo. The presence of exosomal LINC01140 impedes the initiation of Wnt/ß-catenin and reduces the cancerous characteristics of BC cells.

Effects of uniportal thoracoscopic pulmonary segmentectomy and lobectomy on patients with early-stage non-small-cell lung cancer and risk factors of postoperative complications.

OBJECTIVE: To determine the effects of uniportal thoracoscopic pulmonary segmentectomy and lobectomy on patients with early-stage non-small-cell lung cancer (ES-NSCLC) and risk factors of postoperative complications. METHODS: The clinical data of 97 patients with early lung cancer treated in Mingguang People's Hospital between October 2019 and December 2021 were retrospectively analyzed. A total of 45 patients who underwent pulmonary segmentectomy were assigned to the observation group. The remaining 52 patients who underwent lobectomy were assigned to the control group. The perioperative indexes of the two groups were compared, including operation time, intraoperative blood loss, intraoperative lymph node dissection, postoperative indwelling time of drainage tube and postoperative drainage volume. The treatment cost and hospitalization time of the two groups were compared. The changes of inflammatory indexes including C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, and tumour necrosis factor (TNF)-α before and after treatment were compared between the two groups. The changes of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were compared between the two groups. The incidence of postoperative complications in the two groups was counted. Logistic regression was conducted for analyzing the risk factors of postoperative complications. RESULTS: The two groups were similar in operation time, intraoperative blood loss, and number of intraoperative lymph node dissected (all P>0.05). The observation group experienced a significantly shorter postoperative indwelling time of drainage tube and less postoperative drainage volume than the control group after surgery (P<0.05). The observation group presented significantly lower CRP, IL-1ß, IL-6, and TNF-α levels than the control group (P<0.001). The observation group presented significantly higher FEV1 and FVC levels than the control group at 3 months after operation (P<0.001). The treatment cost of the two groups was not greatly different (P>0.05), but the observation group experienced a significantly shorter hospitalization time than the control group (P<0.001). The two groups were similar in the incidence of complications (P>0.05). According to multivariate logistics regression analysis, age, operation time, and number of lymph nodes dissected were independent risk factors for postoperative complications (P<0.05). CONCLUSION: To sum up, for patients with early LC, pulmonary segmentectomy is significantly more effective than lobectomy in terms of pulmonary function and inflammatory response, and age, operation time and number of lymph node dissected during operation are independent risk factors affecting postoperative complications.

Tumor-selective Blockade of CD47 Signaling with CD47 Antibody for Enhanced Anti-tumor Activity in Malignant Meningioma.

BACKGROUND: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a "don't eat me" signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood. METHODS: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo. RESULTS: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68+ macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro. In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot. CONCLUSION: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma.

Genomic and transcriptomic insights into the precision treatment of pulmonary enteric adenocarcinoma.

BACKGROUND: Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung adenocarcinoma. More investigations about precision therapy in PEAC were required to improve the prognosis. METHODS: Twenty-four patients with PEAC were enrolled in this study. Tumor tissue samples were available from 17 patients for both DNA and RNA based next-generation sequencing, PD-L1 IHC staining and PCR-based microsatellite instability (MSI) analysis. RESULTS: TP53 (70.6%) and KRAS (47.1%) were the most frequently mutated genes in PEAC. For KRAS mutations, the prevalence of G12D (37.5%) and G12V (37.5%) was higher than G12A (12.5%) and G12C (12.5%). Actionable mutations in receptor tyrosine kinase (including one EGFR and two ALK mutations), PI3K/mTOR, RAS/RAF/MEK, homologous recombination repair (HRR) and cell cycle signaling pathways were identified in 94.1% of patients with PEAC. While PD-L1 expression was observed in 17.6% (3/17) patients, no MSI-H patients were identified. Transcriptomic data showed that two patients with positive PD-L1 expression had relatively high immune infiltration. In addition, prolonged survival was obtained with the treatment of osimertinib, ensartinib, and immunotherapy combined with chemotherapy in two EGFR-mutated, one ALK-rearranged, and one PD-L1 expressed patients, respectively. CONCLUSION: PEAC is a disease of genetic heterogeneity. The administration of EGFR and ALK inhibitors was effective in patients with PEAC. PD-L1 expression and KRAS mutation type may be used as predictive biomarkers for immunotherapy in PEAC. This study provided both theoretical basis and clinical evidence for PEAC.

Longitudinal MRI-based fusion novel model predicts pathological complete response in breast cancer treated with neoadjuvant chemotherapy: a multicenter, retrospective study.

Background: Accurate identification of pCR to neoadjuvant chemotherapy (NAC) is essential for determining appropriate surgery strategy and guiding resection extent in breast cancer. However, a non-invasive tool to predict pCR accurately is lacking. Our study aims to develop ensemble learning models using longitudinal multiparametric MRI to predict pCR in breast cancer. Methods: From July 2015 to December 2021, we collected pre-NAC and post-NAC multiparametric MRI sequences per patient. We then extracted 14,676 radiomics and 4096 deep learning features and calculated additional delta-value features. In the primary cohort (n = 409), the inter-class correlation coefficient test, U-test, Boruta and the least absolute shrinkage and selection operator regression were used to select the most significant features for each subtype of breast cancer. Five machine learning classifiers were then developed to predict pCR accurately for each subtype. The ensemble learning strategy was used to integrate the single-modality models. The diagnostic performances of models were evaluated in the three external cohorts (n = 343, 170 and 340, respectively). Findings: A total of 1262 patients with breast cancer from four centers were enrolled in this study, and pCR rates were 10.6% (52/491), 54.3% (323/595) and 37.5% (66/176) in HR+/HER2-, HER2+ and TNBC subtype, respectively. Finally, 20, 15 and 13 features were selected to construct the machine learning models in HR+/HER2-, HER2+ and TNBC subtypes, respectively. The multi-Layer Perception (MLP) yields the best diagnostic performances in all subtypes. For the three subtypes, the stacking model integrating pre-, post- and delta-models yielded the highest AUCs of 0.959, 0.974 and 0.958 in the primary cohort, and AUCs of 0.882-0.908, 0.896-0.929 and 0.837-0.901 in the external validation cohorts, respectively. The stacking model had accuracies of 85.0%-88.9%, sensitivities of 80.0%-86.3%, and specificities of 87.4%-91.5% in the external validation cohorts. Interpretation: Our study established a novel tool to predict the responses of breast cancer to NAC and achieve excellent performance. The models could help to determine post-NAC surgery strategy for breast cancer. Funding: This study is supported by grants from the National Natural Science Foundation of China (82171898, 82103093), the Deng Feng project of high-level hospital construction (DFJHBF202109), the Guangdong Basic and Applied Basic Research Foundation (grant number, 2020A1515010346, 2022A1515012277), the Science and Technology Planning Project of Guangzhou City (202002030236), the Beijing Medical Award Foundation (YXJL-2020-0941-0758), and the Beijing Science and Technology Innovation Medical Development Foundation (KC2022-ZZ-0091-5). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.

Nickel-Catalyzed Amidation of Aryl Alkynyl Acids with Tetraalkylthiuram Disulfides: A Facile Synthesis of Aryl Alkynyl Amides.

Nickel-catalyzed amidation of aryl alkynyl acids using tetraalkylthiuram disulfides as the amine source is described, affording a series of aryl alkynyl amides in good to excellent yields under mild conditions. This general methodology provides an alternative pathway for the synthesis of useful aryl alkynyl amides in an operationally simple manner, which shows its practical synthetic value in organic synthesis. The mechanism of this transformation was explored through control experiments and DFT calculations.

GLUT10 is a novel immune regulator involved in lung cancer immune cell infiltration and predicts worse survival when transcriptionally downregulated.

Background: Glucose transporter 10 (GLUT10) is encoded by the SLC2A10 gene. Our recent investigations have shown that GLUT10 is not only involved in glucose metabolism but also involved in the body's immune response to cancer cells. However, the role of GLUT10 in tumor prognosis and in tumor immunity has not been reported. Methods: We knocked down SLC2A10 and performed transcriptome sequencing to analyse the biological function of GLUT10 and found that GLUT10 may be involved in immune signaling. Then, we studied the expression level of SLC2A10 in cancers by the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We also evaluated the prognostic potential of SLC2A10 in different cancers using the Kaplan‒Meier plotter database and PrognoScan online software. The correlations between SLC2A10 expression and immune infiltrates were analysed by TIMER. In addition, correlations between SLC2A10 expression and gene marker sets of immune infiltrates were analysed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). Immunofluorescence staining of cyclooxygenase-2 (COX-2) and GLUT10 in lung cancer tissue and adjacent tissue was performed to confirm our findings from the database research. Results: Knocking down SLC2A10 widely activated immune and inflammatory signaling. SLC2A10 was abnormally expressed in several tumors. The expression level of SLC2A10 was closely correlated with cancer prognosis. Low SLC2A10 expression was related to poorer prognosis and increased malignancy of lung cancer. Lung cancer patients with low expression of SLC2A10 have a much shorter median survival time than patients with high expression of SLC2A10. SLC2A10 expression is closely related to the infiltration of different types of immune cells, particularly macrophages. Both database research and lung cancer sample research revealed that GLUT10 might modulate immune cell infiltration via the COX-2 pathway. Conclusions: By transcriptome experiments, database studies, and human sample studies, we found that GLUT10 is a new immune signaling molecule involved in tumor immunity, especially in the immune cell infiltration of lung adenocarcinoma (LUAD). GLUT10 may modulate the immune cell infiltration of LUAD via the COX-2 pathway.

Risk Factors for Poor Prognosis in Acute Coronary Syndrome Admitted in the Emergency Department: A Retrospective Cohort Study.

BACKGROUND: In the present study, we aimed to identify risk factors of poor prognosis for patients with acute coronary syndrome in the emergency department. METHODS: The study included 2667 patients, who were admitted to the Emergency Department of Chest Pain Center, Fujian Provincial Hospital, due to chest pain from January 1, 2017 to March 31, 2020. Logistic regression was used to identify factors of poor prognosis for patients with ACS in the ED. Receiver operating characteristic (ROC) curve was plotted to assess the performance of the multivariate logistic regression model. Subgroup analysis was used to analyze the difference of SBP in ACS patients with different characteristics. RESULTS: The final analysis included 2667 patients, of whom 2,057 patients (77.8%) had poor prognosis. STEMI (compared with UA) (OR=20.139; 95% CI:12.448-32.581; P < 0.001), NSTEMI (compared with UA) (OR=7.430; 95% CI:5.159-10.700; P < 0.001), respiratory rate ≥20 bpm (compared with <20 bpm) (OR=1.334; 95% CI: 1.060-1.679; P = 0.014), and use of antiplatelets (OR=1.557; 95% CI:1.181-2.053; P = 0.002) was associated with increased likelihood of poor prognosis for ACS patients in ED. SBP ≥140 mmHg (compared with<140mmHg) (OR=0.574; 95% CI: 0.477-0.690; P < 0.001) was associated with decreased likelihood of poor prognosis for ACS patients in the ED. The area under curve (AUC) of the predictive efficacy of logistic regression model was 0.825 (95% CI: 0.795-0.833, P < 0.001). CONCLUSION: This study found that STEMI, NSTEMI, respiratory rate ≥20 bpm, and use of antiplatelets were associated with increased likelihood of poor prognosis for ACS patients in the ED. It also found that SBP≥140 was associated with decreased likelihood of poor prognosis. Our study may be useful for doctors to make clinical decisions for ACS patients.

Astragalus polysaccharides combined with simvastatin as an immunostimulant enhances the immune adjuvanticity of oil-in-water emulsion and immune responses in mice.

Oil-in-water emulsion-based adjuvants have demonstrated acceptable safety in many disease indications, while their adjuvant activities for vaccines still need to be improved. Recently, the strategy of combining adjuvants with multiple types of immunostimulants has been shown to enhance immune responses. In this study, astragalus polysaccharides were combined with simvastatin as an immunostimulant to construct a compound O/W emulsion adjuvant. The formulations were optimized according to the OVA-specific antibody responses induced in mice. For this reason, high (5 mg/mL), medium (2.5 mg/mL), and low (1.25 mg/mL) concentrations of astragalus polysaccharides and high (10 mg/mL), medium (1 mg/mL), and low (0.1 mg/mL) concentrations of simvastatin were selected. The final optimal formulation of the immunostimulant was a high concentration of astragalus polysaccharides combined with a medium concentration of simvastatin. The optimal compound O/W emulsion adjuvant could induce effective humoral and cellular immune responses that were stronger and more stable than those induced by aluminum adjuvant and Freund's adjuvant. The OVA/HAPS-MSim-OE induced dramatically strong and persistent IgG expressions and Th1-polarized immune responses. What's more, the highest CD4+/CD8+lymphocyte ratios were observed in OVA/HAPS-MSim-OE group. In addition, compound O/W emulsion adjuvant groups significantly promoted the secretion of IFN-γ and IL-6, which also indicated that the compound O/W emulsion adjuvants could induce both enhanced Th1 and Th2-mediated immune responses but prefer the Th1-mediated ones. This study would contribute to an interesting and promising direction in the development of emulsion-based adjuvants.

Impact of Homologous Recombination Deficiency on Outcomes in Patients With Triple-Negative Breast Cancer Treated With Carboplatin-Based Neoadjuvant Chemotherapy: Secondary Analysis of the NeoCART Randomized Clinical Trial.

PURPOSE: Pathologic complete response (pCR) rates of patients with triple-negative breast cancer who were administered docetaxel plus carboplatin were significantly higher than those of patients administered epirubicin/cyclophosphamide followed by docetaxel in the neoadjuvant NeoCART trial. Here, we performed a preplanned secondary analysis of the homologous recombination deficiency (HRD) score as a predictor of the pCR in patients with triple-negative breast cancer from the NeoCART cohort. METHODS: Pretherapeutic tumor tissues were assessed retrospectively by DNA extraction and sequencing. BRCA1/2 mutations were evaluated in both somatic and germline forms. HRD scores were calculated from genome-wide allele-specific copy number results and comprised telomeric allelic imbalance, loss of heterozygosity, and large-scale state transitions. High HRD scores were defined as ≥ 38, and HRD was defined as either a high HRD score or a deleterious BRCA1/2 mutation. RESULTS: HRD testing was completed for 43 (79.6%) of 54 NeoCART cohort patients. Thirty of 43 (69.8%) tumors had high HRD scores, and eight patients had BRCA-mutated tumors. No significant association between BRCA1/2 mutation status and pCR was observed either in the general population or in the two treatment arms. Docetaxel plus carboplatin group patients who achieved pCR had higher HRD scores than non-pCR patients, and this difference approached significance (61.69 ± 24.26 v 39.44 ± 22.83, P = .061). No significant correlations between HRD scores and pCR (61.29 ± 24.02 v 53.21 ± 24.31, P = .480) or residual cancer burden 0/1 (62.50 ± 22.50 v 51.85 ± 24.74, P = .324) were observed in the epirubicin/cyclophosphamide followed by docetaxel group. CONCLUSION: HRD is a potential predictive biomarker for clinical benefit from neoadjuvant carboplatin-based chemotherapy and provides a possibility for screening the optimum chemotherapy backbone to combine with immunotherapy.