PKMYT1 Promotes Epithelial-Mesenchymal Transition Process in Triple-Negative Breast Cancer by Activating Notch Signaling.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

Transarterial chemoembolization with/without immune checkpoint inhibitors plus tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a single center, propensity score matching real-world study.

OBJECTIVES: To explore the efficacy and safety of Transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: 456 patients with HCC receiving either TACE in combination with ICIs and TKIs (combination group, n = 139) or TACE monotherapy (monotherapy group, n = 317) were included from Apr 2016 to Dec 2021 in this retrospective study. We employed propensity score matching (PSM), performed 1:2 optimal pair matching, to balance potential bias. RESULTS: The mean follow-up time is 24.7 months (95% CI 22.6-26.8) for matched patients as of March 2022. After matching, the combination group achieved longer OS and PFS (median OS:21.9 vs. 16.3 months, P = 0.022; median PFS: 8.3 vs. 5.1 months, P < 0.0001) than TACE monotherapy group. The combination group had better objective response rate (ORR) and disease control rate (DCR) (ORR: 52.5% vs. 32.8%, P < 0.001; DCR: 82.7% vs. 59.6%, P < 0.001). Subgroup analysis showed that patients who received "TKIs + ICIs" after the first TACE procedure (after TACE group) achieved longer OS than those before the first TACE procedure (before TACE group) (26.8 vs. 19.2 months, P = 0.011). Adverse events were consistent with previous studies of TACE-related trials. CONCLUSIONS: TACE plus TKIs and ICIs appeared to deliver longer PFS and OS in HCC patients than TACE monotherapy. "TKIs + ICIs" co-treatment within 3 months after the first TACE procedure might be a better medication strategy.

A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer.

Colorectal cancer (CRC) is a common malignancy involving multiple cellular components. The CRC tumor microenvironment (TME) has been characterized well at single-cell resolution. However, a spatial interaction map of the CRC TME is still elusive. Here, we integrate multiomics analyses and establish a spatial interaction map to improve the prognosis, prediction, and therapeutic development for CRC. We construct a CRC immune module (CCIM) that comprises FOLR2+ macrophages, exhausted CD8+ T cells, tolerant CD8+ T cells, exhausted CD4+ T cells, and regulatory T cells. Multiplex immunohistochemistry is performed to depict the CCIM. Based on this, we utilize advanced deep learning technology to establish a spatial interaction map and predict chemotherapy response. CCIM-Net is constructed, which demonstrates good predictive performance for chemotherapy response in both the training and testing cohorts. Lastly, targeting FOLR2+ macrophage therapeutics is used to disrupt the immunosuppressive CCIM and enhance the chemotherapy response in vivo.

New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges.

Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses.

Safety and feasibility of intra-arterial delivery of teniposide to high grade gliomas after blood-brain barrier disruption: a case series.

BACKGROUND: This case series describes the safety and efficacy of superselective intra-arterial (IA) cerebral infusion of teniposide for the treatment of patients with glioma, to provide new ideas and methods for the treatment of high grade gliomas. METHODS: 12 patients with glioma who were previously treated with standard therapy were treated with superselective IA cerebral infusion of teniposide. Patients received at least two cycles of treatment (one cycle: 150 mg/time, used for 1 day, repeated at 28 day intervals) after blood-brain barrier disruption. Patients received individualized treatment on the tumor location. The ophthalmic artery was bypassed during the super-selective arterial infusion. RESULTS: No significant differences in biochemical indexes and Karnofsky performance status (KPS) score were observed before and after treatment, and no evident adverse events occurred (P>0.05). In a recent response evaluation (August 2023), two (8%) patients presented with a complete response (16.7%), four had a partial response (33.3%), four had stable disease (33.3%), and two showed progressive disease (16.7%). The overall response rate and disease control rate were 50.0% and 83.3%, respectively. In addition, we described the detailed course of treatment in two patients. Case No 1 (recurrent tumor) and case No 2 (primary tumor) received six and three cycles of teniposide infusion, respectively. After treatment, the tumors of the patients were significantly reduced without evident adverse effects. CONCLUSION: This small series suggests that superselective IA cerebral infusion of teniposide may be a safe and effective therapy in the multimodal treatment of malignant glioma and warrants further study in larger prospective investigations.

The usefulness and utilization of Gold-finger retractor for endoscopic thyroid surgery.

Aims: In endoscopic surgery, the visual field is frequently obstructed by muscles, blood, and even smoke. To overcome this problem, we have developed a new detachable Gold-finger retractor for narrow-space surgery. Methods: Gold-finger retractor was used in 30 patients to facilitate surgical field exposure and smoke discharge, while in 27 patients, percutaneous silk thread suspension was employed for the same purpose. Both groups underwent endoscopic unilateral thyroidectomy and unilateral central lymph node dissection via oral vestibular microincision combined with the axillary-assisted approach. A comparative analysis was conducted to evaluate the efficacy of the Gold-finger retractor and silk thread suspension in relation to intraoperative exposure effect, surgical fluency, surgeon's comfort, operation time, postoperative complications, and length of hospital stay. This analysis was based on surgical video recordings and postoperative indicators. Results: With Gold-finger retractor support, surgeons were able to perform meticulous operations. Complication rates were similar between the two groups, and no serious complications occurred. The number of lymph nodes dissected in the Gold-finger group was significantly greater than that in the routine group (12.43 ± 6.18 and 5.7 ± 2.95, respectively). Further analysis of surgeons' comfort (visibility and convenience in peeling) revealed that the Gold-finger group was significantly better. Electrosurgery smoke was removed effectively with Gold-finger, and the operation time was significantly reduced. Conclusion: In thyroid surgery, Gold-fingers enhance visual field resolution, avoid muscle cutting, save time, and improve the surgical experience.

Biocompatible Snowman-like Dimer Nanoparticles for Improved Cellular Uptake in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive types of human cancers. Although paclitaxel (PTX) was proven to exert potent anti-tumor effects against ICC, the delivery of PTX is still challenging due to its hydrophobic property. Nanoparticle (NP)-based carriers have been proven to be effective drug delivery vehicles. Among their physicochemical properties, the shape of NPs plays a crucial role in their performance of cellular internalization and thus anti-tumor efficacy of loaded drugs. In this study, dumbbell-like and snowman-like dimer NPs, composed of a polylactic acid (PLA) bulb and a shellac bulb, were designed and prepared as drug nanocarriers to enhance the efficiency of cellular uptake and anti-tumor performance. PLA/shellac dimer NPs prepared through rapid solvent exchange and controlled co-precipitation are biocompatible and their shape could flexibly be tuned by adjusting the concentration ratio of shellac to PLA. Drug-loaded snowman-like PLA/shellac dimer NPs with a sharp shape exhibit the highest cellular uptake and best cell-killing ability against cancer cells in an in vitro ICC model over traditional spherical NPs and dumbbell-like dimer NPs, as proven with the measurements of flow cytometry, fluorescent confocal microscopy, and the CCK8 assay. The underlying mechanism may be attributed to the lower surface energy required for the smaller bulbs of snowman-like PLA/shellac dimer NPs to make the initial contact with the cell membrane, which facilitates the subsequent penetration through the cellular membrane. Therefore, these dimer NPs provide a versatile platform to tune the shape of NPs and develop innovative drug nanocarriers that hold great promise to enhance cellular uptake and therapeutic efficacy.

[One-stage repair of full-thickness skin defect at dorsal skin of middle phalanx fingers using artificial dermis combing with digital artery perforator fascial flaps].

OBJECTIVE: To explore clinical effects of the stageⅠrepair of full-thickness skin defect at dorsal skin of middle phalanx fingers using artificial dermis combing with digital artery perforator fascial flaps. METHODS: From January 2019 to May 2020, 21 patients(27 middle phalanx fingers)with full-thickness skin defect were repaired at stageⅠusing artificial dermis combing with digital artery perforator fascial flaps. All patients were emergency cases, and were accompanied by the exposure of bone tendon and the defects of periosteum and tendon membrane. Among patients, including 11 males and 10 females aged from 18 to 66 years old with an average age of (39.00±8.01) years old;9 index fingers, 10 middle fingers and 8 ring fingers;range of skin defect area ranged from (2.5 to 3.5) cm×(1.5 to 3.0) cm;range of exposed bone tendon area was (1.5 to 2.0) cm×(1.0 to 2.0) cm. The time from admission to hospital ranged from 1 to 6 h, operation time started from 3 to 8 h after injury. RESULTS: All patients were followed up from 6 to12 months with an average of (9.66±1.05) months. The wounds in 26 cases were completely healed at 4 to 6 weeks after operation. One finger has changed into wound infection with incompletely epithelialized dermis, and achieved wound healing at 8 weeks after dressing change. All fingers were plump with less scars. The healed wound surface was similar to the color and texture of the surrounding skin. These fingers have excellent wearability and flexibility. According to the upper limb function trial evaluation standard of Hand Surgery Society of Chinese Medical Association, the total score ranged from 72 to 100. 26 fingers got excellent result and 1 good. CONCLUSION: StageⅠrepair of full-thickness skin defect at dorsal skin of middle phalanx fingers using artificial dermis combing with digital artery perforator fascial flaps is easy to operate with less trauma. It has made satisfactory recovery of appearance and function of fingers. It could provide an effective surgical method for clinical treatment of full-thickness skin loss of fingers with tendon and bone exposure.

Zyxin promotes hepatocellular carcinoma progression via the activation of AKT/mTOR signaling pathway.

Hepatocellular carcinoma (HCC) is a common malignancy that is driven by multiple genes and pathways. The aim of this study was to investigate the role and specific mechanism of the actin-interacting protein zyxin (ZYX) in HCC. We found that the expression of ZYX was significantly higher in HCC tissues compared to that in normal liver tissues. In addition, overexpression of ZYX in hepatoma cell lines (PLC/PRF/5, HCCLM3) enhanced their proliferation, migration and invasion, whereas ZYX knockdown had the opposite effects (SK HEP-1, Huh-7). Furthermore, the change in the expression levels of ZYX also altered that of proteins related to cell cycle, migration and invasion. Similar results were obtained with xenograft models. The AKT/mTOR signaling pathway is one of the key mediators of cancer development. While ZYX overexpression upregulated the levels of phosphorylated AKT/mTOR proteins, its knockdown had the opposite effect. In addition, the AKT inhibitor MK2206 neutralized the pro-oncogenic effects of ZYX on the HCC cells, whereas the AKT activator SC79 restored the proliferation, migration and invasion of HCC cells with ZYX knockdown. Taken together, ZYX promotes the malignant progression of HCC by activating AKT/mTOR signaling pathway, and is a potential therapeutic target in HCC.

Transcriptomic analysis of spinal cord regeneration after injury in Cynops orientalis.

Cynops orientalis (C. orientalis) has a pronounced ability to regenerate its spinal cord after injury. Thus, exploring the molecular mechanism of this process could provide new approaches for promoting mammalian spinal cord regeneration. In this study, we established a model of spinal cord thoracic transection injury in C. orientalis, which is an endemic species in China. We performed RNA sequencing of the contused axolotl spinal cord at two early time points after spinal cord injury - during the very acute stage (4 days) and the subacute stage (7 days) - and identified differentially expressed genes; additionally, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, at each time point. Transcriptome sequencing showed that 13,059 genes were differentially expressed during C. orientalis spinal cord regeneration compared with uninjured animals, among which 4273 were continuously down-regulated and 1564 were continuously up-regulated. Down-regulated genes were most enriched in the Gene Ontology term "multicellular organismal process" and in the ribosome pathway at 10 days following spinal cord injury. We found that multiple genes associated with energy metabolism were down-regulated and multiple genes associated with the lysosome were up-regulated after spinal cord injury, indicating the importance of low metabolic activity during wound healing. Immune response-associated pathways were activated during the early acute phase (4 days), while the expression of extracellular matrix proteins such as glycosaminoglycan and collagen, as well as tight junction proteins, was lower at 10 days post-spinal cord injury than 4 days post-spinal cord injury. However, compared with 4 days post-injury, at 10 days post-injury neuroactive ligand-receptor interactions were no longer down-regulated, up-regulated differentially expressed genes were enriched in pathways associated with cancer and the cell cycle, and SHH, VIM, and Sox2 were prominently up-regulated. Immunofluorescence staining showed that glial fibrillary acidic protein was up-regulated in axolotl ependymoglial cells after injury, similar to what is observed in mammalian astrocytes after spinal cord injury, even though axolotls do not form a glial scar during regeneration. We suggest that low intracellular energy production could slow the rapid amplification of ependymoglial cells, thereby inhibiting reactive gliosis, at early stages after spinal cord injury. Extracellular matrix degradation slows cellular responses, represses the expression of neurogenic genes, and reactivates a transcriptional program similar to that of embryonic neuroepithelial cells. These ependymoglial cells act as neural stem cells: they migrate and proliferate to repair the lesion and then differentiate to replace lost glial cells and neurons. This provides the regenerative microenvironment that allows axon growth after injury.

The predictive role of soluble programmed death ligand 1 in digestive system cancers.

Introduction: The prognostic role of soluble programmed death ligand 1 (sPD-L1) in digestive system cancers (DSCs) remains inconclusive. This study aimed to explore the predictive value of sPD-L1 expression in DSCs. Methods: Comprehensive searches were run on the electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Library) to identify studies that assessed the prognostic role of sPD-L1 in DSCs. Review Manager software (version 5.3) was used for all analyses. Pooled data for survival outcomes were measured as hazard ratios (HRs), 95% confidence intervals (CIs), and odds ratios and their 95% CIs. Results: The search identified 18 studies involving 2,070 patients with DSCs. The meta-outcome revealed that a high level of sPD-L1 was related to poorer overall survival (HR, 3.06; 95% CI: 2.22-4.22, p<0.001) and disease-free survival (HR, 2.53; 95% CI: 1.67-3.83, p<0.001) in DSCs. Individually, the prognostic significance of high level of sPD-L1 expression was the highest in hepatic cell carcinoma (HR, 4.76; p<0.001) followed by gastric cancer (HR=3.55, p<0.001). Conclusion: sPD-L1 may be a prognostic factor in DSCs for overall survival and disease-free survival. Inflammatory cytokines, treatment approaches, and other factors may affect the expression of sPD-L1. Therefore, the prognostic value of sPD-L1 for recurrence and metastasis should be further investigated. sPD-L1 may also predict response to treatment. Well-designed prospective studies with standard assessment methods should be conducted to determine the prognostic value of sPD-L1 in DSCs.

NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and hypovascular tumor microenvironment. Nucleolar and spindle associated protein 1 (NUSAP1) is a microtubule-associated protein that is known to be involved in cancer biology. Our study aimed to investigate the role of NUSAP1 in glycolytic metabolism and metastasis in PDAC. Expression and prognostic value of NUSAP1 in PDAC and common gastrointestinal tumors was evaluated. The function of NUSAP1 in PDAC progression was clarified by single-cell RNA-seq and further experiments in vitro, xenograft mouse model, spontaneous PDAC mice model and human tissue microarray. The downstream genes and signaling pathways regulated by NUSAP1 were explored by RNA-Seq. And the regulation of NUSAP1 on Lactate dehydrogenase A (LDHA)-mediated glycolysis and its underlying mechanism was further clarified by CHIP-seq. NUSAP1 was an independent unfavorable predictor of PDAC prognosis that playing a critical role in metastasis of PDAC by regulating LDHA-mediated glycolysis. Mechanically, NUSAP1 could bind to c-Myc and HIF-1α that forming a transcription regulatory complex localized to LDHA promoter region and enhanced its expression. Intriguingly, lactate upregulated NUSAP1 expression by inhibiting NUSAP1 protein degradation through lysine lactylated (Kla) modification, thus forming a NUSAP1-LDHA-glycolysis-lactate feedforward loop. The NUSAP1-LDHA-glycolysis-lactate feedforward loop is one of the underlying mechanisms to explain the metastasis and glycolytic metabolic potential in PDAC, which also provides a novel insights to understand the Warburg effect in cancer. Targeting NUSAP1 would be an attractive paradigm for PDAC treatment.

Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel.

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.

Sodium Fluorescein-Guided Surgery for Resection of Brain Metastases from Lung Cancer: A Consecutive Case Series Study and Literature Review.

(1) Introduction and objective: Surgical resection plays an important role in the multidisciplinary treatment of lung cancer patients with brain metastases (BMs). Precisely distinguishing the tumor border intraoperatively to improve and maximize the extent of resection (EOR) without causing permanent neurological defects is crucial but still challenging. Therefore, we introduced our experience of utilizing sodium fluorescein (SF) in microneurosurgery of BMs from lung cancer. This study aims to evaluate whether the use of SF-guided surgery has a positive impact on postoperative outcomes. (2) Materials and methods: A retrospective study was performed to collect data on a consecutive case series of patients with BMs from lung cancer who underwent surgical resection from January 2020 to December 2021 at the Department of Neuro-Oncology, Chongqing University Cancer Hospital. A total of 52 patients were enrolled, of which 23 received SF-guided surgery and 29 did not. EOR was assessed pre- and postoperatively on T1 contrast-enhanced MRI. Clinical and epidemiological data as well as follow-up were gathered and analyzed. (3) Results: Compared with the non-SF-guided group, the SF-guided group revealed a significantly better EOR (87.0% vs. 62.1%) and a lower incidence of local recurrence (8.7% vs. 34.5%). Survival benefits were seen in patients with NSCLC, patients who were undergoing SF-guided surgery, and patients receiving postoperative systemic therapy. (4) Conclusions: SF-guiding under the YELLOW 560 nm filter is a safe and feasible tool for improving the EOR in patients with BMs from lung cancer, leading to better local recurrence control and prolonged survival.

Proteomic and single-cell landscape reveals novel pathogenic mechanisms of HBV-infected intrahepatic cholangiocarcinoma.

Despite the epidemiological association between intrahepatic cholangiocarcinoma (ICC) and hepatitis B virus (HBV) infection, little is known about the relevant oncogenic effects. A cohort of 32 HBV-infected ICC and 89 non-HBV-ICC patients were characterized using whole-exome sequencing, proteomic analysis, and single-cell RNA sequencing. Proteomic analysis revealed decreased cell-cell junction levels in HBV-ICC patients. The cell-cell junction level had an inverse relationship with the epithelial-mesenchymal transition (EMT) program in ICC patients. Analysis of the immune landscape found that more CD8 T cells and Th2 cells were present in HBV-ICC patients. Single-cell analysis indicated that transforming growth factor beta signaling-related EMT program changes increased in tumor cells of HBV-ICC patients. Moreover, ICAM1+ tumor-associated macrophages are correlated with a poor prognosis and contributed to the EMT in HBV-ICC patients. Our findings provide new insights into the behavior of HBV-infected ICC driven by various pathogenic mechanisms involving decreased cell junction levels and increased progression of the EMT program.

Fatty Acid Metabolism: A New Perspective in Breast Cancer Precision Therapy.

Breast cancer has a special tumor microenvironment compared to other solid tumors, which is usually surrounded by a large number of adipocytes that can produce and secrete fatty acids and adipokines. Adipocytes have a remodeling effect on breast cancer lipid metabolism, while fatty acids and lipid droplets can make breast cancer cells more aggressive. Lipid metabolism, especially the synthesis of fatty acids, is an important cellular process for membrane biosynthesis, energy storage, and signal molecule production. Therefore, blocking the lipid supply to cancer cells or changing the lipid composition has an important impact on the signal transmission and cell proliferation of cancer cells. Alterations in lipid availability can also affect cancer cell migration, induction of angiogenesis, metabolic symbiosis, evasion of immune surveillance, and cancer drug resistance. Fatty acid synthesis and metabolism have received extensive attention as potential targets for cancer therapy, and studies on modulating the tumor lipid microenvironment to improve the sensitivity of antitumor drugs have also been discussed; however, strategies to target these processes have not been translated into clinical practice.

Clinical and molecular profiling of EGFR-mutant lung adenocarcinomas transformation to small cell lung cancer during TKI treatment.

Introduction: Small cell lung cancer (SCLC) transformation serves as a significant mechanism of resistance to tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. To address this clinical challenge, we conducted a retrospective analysis at Zhejiang University School of Medicine, the First Affiliated Hospital, focusing on patients with EGFR sensitizing mutations. Methods: A total of 1012 cases were included in this retrospective analysis. The cohort primarily consisted of patients with EGFR sensitizing mutations. Biopsy-confirmed small cell transformation was observed in seven patients, accounting for 0.7% of the cases. All patients in this subset were initially diagnosed with stage IV adenocarcinoma (ADC), with four cases classified as poorly differentiated and three as moderately to poorly differentiated ADC. EGFR exon 19 deletions were identified in five of these cases. Next-generation sequencing (NGS) was performed on seven cases, revealing mutations in the tumor protein p53 (TP53) gene in four cases and loss of the retinoblastoma1 (RB1) gene in three cases. Results: The median duration from the initial diagnosis to small cell transformation was 35.9 months (interquartile range: 12.1-84 months). Following small cell transformation during EGFR inhibition, all patients received etoposide/platinum-based treatment, leading to a median progression-free survival (PFS) of 4.7 months (interquartile range: 2.7-10.1 months). Notably, most patients in this series had poorly differentiated adenocarcinomas at the outset. TP53 mutations and RB1 loss were common genetic alterations observed in patients with small cell transformation in this cohort. Discussion: The findings underscore the clinical significance of SCLC transformation as a resistance mechanism to EGFR TKIs in NSCLC with EGFR mutations. The observed genetic alterations, including TP53 mutations and RB1 loss, suggest potential associations with the transformation process and warrant further investigation. Understanding the genetic landscape and clinical outcomes in patients experiencing small cell transformation can contribute to improved strategies for managing resistance in EGFR-mutant NSCLC.

EMLI-ICC: an ensemble machine learning-based integration algorithm for metastasis prediction and risk stratification in intrahepatic cholangiocarcinoma.

Robust strategies to identify patients at high risk for tumor metastasis, such as those frequently observed in intrahepatic cholangiocarcinoma (ICC), remain limited. While gene/protein expression profiling holds great potential as an approach to cancer diagnosis and prognosis, previously developed protocols using multiple diagnostic signatures for expression-based metastasis prediction have not been widely applied successfully because batch effects and different data types greatly decreased the predictive performance of gene/protein expression profile-based signatures in interlaboratory and data type dependent validation. To address this problem and assist in more precise diagnosis, we performed a genome-wide integrative proteome and transcriptome analysis and developed an ensemble machine learning-based integration algorithm for metastasis prediction (EMLI-Metastasis) and risk stratification (EMLI-Prognosis) in ICC. Based on massive proteome (216) and transcriptome (244) data sets, 132 feature (biomarker) genes were selected and used to train the EMLI-Metastasis algorithm. To accurately detect the metastasis of ICC patients, we developed a weighted ensemble machine learning method based on k-Top Scoring Pairs (k-TSP) method. This approach generates a metastasis classifier for each bootstrap aggregating training data set. Ten binary expression rank-based classifiers were generated for detection of metastasis separately. To further improve the accuracy of the method, the 10 binary metastasis classifiers were combined by weighted voting based on the score from the prediction results of each classifier. The prediction accuracy of the EMLI-Metastasis algorithm achieved 97.1% and 85.0% in proteome and transcriptome datasets, respectively. Among the 132 feature genes, 21 gene-pair signatures were developed to establish a metastasis-related prognosis risk-stratification model in ICC (EMLI-Prognosis). Based on EMLI-Prognosis algorithm, patients in the high-risk group had significantly dismal overall survival relative to the low-risk group in the clinical cohort (P-value < 0.05). Taken together, the EMLI-ICC algorithm provides a powerful and robust means for accurate metastasis prediction and risk stratification across proteome and transcriptome data types that is superior to currently used clinicopathological features in patients with ICC. Our developed algorithm could have profound implications not just in improved clinical care in cancer metastasis risk prediction, but also more broadly in machine-learning-based multi-cohort diagnosis method development. To make the EMLI-ICC algorithm easily accessible for clinical application, we established a web-based server for metastasis risk prediction (http://ibi.zju.edu.cn/EMLI/).

Cancer cell membrane-wrapped nanoparticles for cancer immunotherapy: A review of current developments.

Background: As the forefront of nanomedicine, bionic nanotechnology has been widely used for drug delivery in order to obtain better efficacy but less toxicity for cancer treatments. With the rise of immunotherapy, the combination of nanotechnology and immunotherapy will play a greater potential of anti-tumor therapy. Due to its advantage of homologous targeting and antigen library from source cells, cancer cell membrane (CCM)-wrapped nanoparticles (CCNPs) has become an emerging topic in the field of immunotherapy. Key scientific concepts of review: CCNP strategies include targeting or modulating the tumor immune microenvironment and combination therapy with immune checkpoint inhibitors and cancer vaccines. This review summarizes the current developments in CCNPs for cancer immunotherapy and provides insight into the challenges of transferring this technology from the laboratory to the clinic as well as the potential future of this technology. Conclusion: This review described CCNPs have enormous potential in cancer immunotherapy, but there are still challenges in terms of translating their effects in vitro to the clinical setting. We believe that these challenges can be addressed in the future with a focus on individualized treatment with CCNPs as well as CCNPs combined with other effective treatments.

lncRNA NUTM2A-AS1 Targets the SRSF1/Trim37 Signaling Pathway to Promote the Proliferation and Invasion of Breast Cancer.

Method: Using the tumor database (TCGA) and analysis platform (GEPIA), NUTM2A-AS1 expression in breast cancer cases was compared with the normal cases. In addition, Kaplan-Meier curve of overall survival according to the various levels of NUTM2A-AS1 was assessed. Then, we constructed a knockdown plasmid of NUTM2A-AS1 and successfully reduced the expression function of NUTM2A-AS1 in BC cells. Results: We found NUTM2A-AS1 could promote the malignant phenotype of proliferation and invasion of BC. In terms of mechanism research, NUTM2A-AS1 was mainly located in the cytoplasm of BC cells, which indicated that NUTM2A-AS1 may achieve its function through transcriptional or posttranscriptional regulation pathways. While knocking down NUTM2A-AS1, we detected several major molecules of the trim family. The results showed that only trim37 mRNA was significantly affected, and protein detection also showed that knockdown NUTM2A-AS1 expression could reduce the expression of trim37. The results of RIP experiments suggested that NUTM2A-AS1 played a key role by combining with SRSF1 and affecting the interaction between SRSF1 and trim37 mRNA. The stability test of mRNA also confirmed that during the knockdown of NUTM2A-AS1, the mRNA stability of trim37 decreased significantly, but this downward trend could be reversed by overexpressed SRSF1. The above results suggested that NUTM2A-AS1 could maintain the stability and expression of trim37 through SRSF1 pathway. The results of rescue experiment showed the overexpression of trim37, while knocking down NUTM2A-AS1 could reverse the decrease of proliferation and invasiveness of BC cells induced by NUTM2A-AS1 knockdown. Conclusion: Therefore, trim37 is seen as a necessary target for NUTM2A-AS1 to exert the biological function of BC. Additionally, NUTM2A-AS1 is to regulate the malignant phenotype of BC through NUTM2A-AS1/trim37 pathway.