NT5DC2 knockdown suppresses progression, glycolysis, and neuropathic pain in triple-negative breast cancer by blocking the EGFR pathway.

Triple-negative breast cancer (TNBC) is an exceptionally aggressive breast cancer subtype associated with neuropathic pain. This study explores the effects of 5'-nucleotidase domain-containing protein 2 (NT5DC2) on the progression of TNBC and neuropathic pain. Microarray analysis was conducted to identify differentially expressed genes in TNBC and the pathways involved. Gain- and loss-of-function assays of NT5DC2 were performed in TNBC cells, followed by detection of the extracellular acidification rate, adenosine triphosphate (ATP) levels, lactic acid production, glucose uptake, proliferation, migration, and invasion in TNBC cells. Macrophages were co-cultured with TNBC cells to examine the release of polarization-related factors and cytokines. A xenograft tumor model was established for in vivo validation. In addition, a mouse model of neuropathic pain was established through subepineural injection of TNBC cells, followed by measurement of the sciatic functional index and behavioral analysis to assess neuropathic pain. NT5DC2 was upregulated in TNBC and was positively correlated with epidermal growth factor receptor (EGFR). NT5DC2 interacted with EGFR to promote downstream signal transduction in TNBC cells. NT5DC2 knockdown diminished proliferation, migration, invasion, the extracellular acidification rate, ATP levels, lactic acid production, and glucose uptake in TNBC cells. Co-culture with NT5DC2-knockdown TNBC cells alleviated the M2 polarization of macrophages. Furthermore, NT5DC2 knockdown reduced tumor growth and neuropathic pain in mice. Importantly, activation of the EGFR pathway counteracted the effects of NT5DC2 knockdown. NT5DC2 knockdown protected against TNBC progression and neuropathic pain by inactivating the EGFR pathway.

Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing.

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

Construction of Hyaluronic Acid-Covered Hierarchically Porous MIL-nanoMOF for Loading and Controlled Release of Doxorubicin.

The porous nano-sized metal-organic framework (nanoMOF) and its proper surface modification could greatly promote the drug loading capability and introduce biocompatibility, biodegradability, and targeting functions into nano-drug delivery systems. Herein, the HACD@ADA-PA/MIL-101_NH2 (Fe)-P nanoparticle was successfully fabricated through supramolecular and coordination interactions from three building blocks, including hierarchically porous MIL-101_NH2 (Fe)-P nanoMOF, phosphite-modified adamantane (ADA-PA), and ß-cyclodextrin (ß-CD)-modified hyaluronic acid (HACD). The obtained HACD@ADA-PA/MIL-101_NH2 (Fe)-P nanoparticle was nano-sized and highly stable in physiological fluids. The porous structure of HACD@ADA-PA/MIL-101_NH2 (Fe)-P nanoparticle could effectively load the commercial chemotherapeutic drug doxorubicin (DOX) with an encapsulation rate of 41.20 % and a loading rate of 48.84 %. The obtained drug-loaded HACD@ADA-PA/MIL-101_NH2 (Fe)-P@DOX nanoparticle was pH-sensitive and relatively stable at neutral condition (pH 7.2) but could release DOX in a controlled way in subacid solution at pH 5.7. The simulated in vitro DOX release experiment signified that the HACD@ADA-PA/MIL-101_NH2 (Fe)-P@DOX nanoparticle could realize the controlled release of DOX in tumor issues.

Correlating somatic copy number alteration in aqueous humour cfDNA with chemotherapy history, eye salvage and pathological features in retinoblastoma.

BackgroundThis study determined to probe the potential association between somatic copy number alteration (SCNA) in retinoblastoma (RB) aqueous humour (AH) and pathological high-risk factors, clinical features and previous chemotherapy history. METHODS: Single-centre retrospective cohort study from including 58 AH samples collected from 58 patients diagnosed. Among them, 41 samples were collected after enucleation and 17 samples were collected before intravitreal chemotherapy. SCNAs were accessed by conducting shallow whole-genome sequencing in cell-free (cf) DNA of AH. HRs and ORs were applied to measure risk factors. RESULTS: Canonical RB SCNAs including 1q gain (87%), 2p gain (50%), 6p gain (76%), 16q loss (69%) were frequently detected. Non-classical RB SCNAs in AH including 17q gain (53%), 19q loss (43%), 7q gain (35%) were also commonly observed. 19q loss was significantly more common in patients with cT3c or worse stage than others (p=0.034). 2p gain(p=0.001) and 7q gain(p=0.001) were both more common in patients with primary enucleation than those with previous chemotherapy. Interestingly, both 2p gain (HR=1.933, p=0.027) and 7q gain (HR=2.394, p=0.005) might predict enucleation. Correlation analysis with pathological features among enucleated eyes showed that 19q loss can predict a higher risk for both massive choroid invasion (OR=4.909, p=0.038) and postlaminar optic nerve invasion (OR=4.250, p=0.043). DISCUSSION: Sequencing of AH cfDNA in RB can provide sufficient in vivo information. 19q loss was a potential signature of advanced cases clinically and pathologically.Repeated sampling from eyes receiving sequential chemotherapy should be conducted to evaluate fluctuation of SCNA in future study.

A Novel Nanozyme to Enhance Radiotherapy Effects by Lactic Acid Scavenging, ROS Generation, and Hypoxia Mitigation.

Uveal melanoma (UM) is a leading intraocular malignancy with a high 5-year mortality rate, and radiotherapy is the primary approach for UM treatment. However, the elevated lactic acid, deficiency in ROS, and hypoxic tumor microenvironment have severely reduced the radiotherapy outcomes. Hence, this study devised a novel CoMnFe-layered double oxides (LDO) nanosheet with multienzyme activities for UM radiotherapy enhancement. On one hand, LDO nanozyme can catalyze hydrogen peroxide (H2O2) in the tumor microenvironment into oxygen and reactive oxygen species (ROS), significantly boosting ROS production during radiotherapy. Simultaneously, LDO efficiently scavenged lactic acid, thereby impeding the DNA and protein repair in tumor cells to synergistically enhance the effect of radiotherapy. Moreover, density functional theory (DFT) calculations decoded the transformation pathway from lactic to pyruvic acid, elucidating a previously unexplored facet of nanozyme activity. The introduction of this innovative nanomaterial paves the way for a novel, targeted, and highly effective therapeutic approach, offering new avenues for the management of UM and other cancer types.

Correlation Analysis of Apparent Diffusion Coefficient Histogram Parameters and Clinicopathologic Features for Prognosis Prediction in Uveal Melanoma.

Purpose: To investigate the correlation between apparent diffusion coefficient (ADC) histograms and high-risk clinicopathologic features related to uveal melanoma (UM) prognosis. Methods: This retrospective study included 53 patients with UM who underwent diffusion-weighted imaging (DWI) between August 2015 and March 2024. Axial DWI was performed with a single-shot spin-echo echo-planar imaging sequence. ADC histogram parameters of ADCmean, ADC50%, interquartile range (IQR), skewness, kurtosis, and entropy were obtained from DWI. The relationships between histogram parameters and high-risk clinicopathological characteristics including tumor size, preoperative retinal detachment, histological subtypes, Ki-67 index, and chromosome status, were analyzed by Spearman correlation analysis, Mann-Whitney U test, or Kruskal-Wallis test. Results: A total of 53 patients (mean ± SD age, 55 ± 15 years; 22 men) were evaluated. The largest basal diameter (LBD) was correlated with kurtosis (r = 0.311, P = 0.024). Tumor prominence (TP) was correlated with entropy (r = 0.581, P < 0.001) and kurtosis (r = 0.273, P = 0.048). Additionally, significant correlations were identified between the Ki-67 index and ADCmean (r = -0.444, P = 0.005), ADC50% (r = -0.487, P = 0.002), and skewness (r = 0.394, P = 0.014). Finally, entropy was correlated with monosomy 3 (r = 0.541, P = 0.017). Conclusions: The ADC histograms provided valuable insights into high-risk clinicopathologic features of UM and hold promise in the early prediction of UM prognosis.

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy.

Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from  laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.

Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.

Adenomas of the ciliary body epithelium: clinics, histopathology and management.

AIMS: Adenomas of the ciliary body epithelium, including adenoma of the pigmented ciliary body epithelium (APCE) and adenoma of the non-pigmented ciliary body epithelium (ANPCE), are extremely rare, and most knowledge about them comes from sporadic case reports. The purpose of this study was to provide a comprehensive understanding of adenomas of the ciliary body epithelium and to identify the similarities and differences between APCE and ANPCE. METHODS: This study was a retrospective case series comprising data from 41 patients obtained from retrieved publications and five cases diagnosed at the Shanghai Ninth People's Hospital. The clinicopathological features, treatment and prognosis of APCE and ANPCE were compared using the non-parametric rank sum test, t-test and the χ2 test. RESULTS: The clinical and histopathological features and treatment were analogous between APCE (n=23) and ANPCE (n=23). The overall visual prognosis associated with the two tumours was good, with 63% of the patients having stable or improved vision after treatment. Enucleation was the primary cause of eventual vision loss (three in APCE vs two in ANPCE, p=0.001). Notably, iris invasion was commonly observed in patients with APCE (six in APCE vs zero in ANPCE, p=0.014), and iris invasion was associated with decreased vision eventually (p=0.003). Tumour size was irrelevant to the vision outcome (p=0.65). Metastasis or recurrence did not occur in any of the patients. CONCLUSION: In most cases, the clinicopathological features of ANPCE and APCE were similar. Iris invasion was commonly observed in patients with APCE, which was associated with poor visual prognosis.

The impact of wind energy on plant biomass production in China.

Global wind power expansion raises concerns about its potential impact on plant biomass production (PBP). Using a high-dimensional fixed effects model, this study reveals significant PBP reduction due to wind farm construction based on 2404 wind farms, 108,361 wind turbines, and 7,904,352 PBP observations during 2000-2022 in China. Within a 1-10 km buffer, the normalized differential vegetation and enhanced vegetation indices decrease from 0.0097 to 0.0045 and 0.0075 to 0.0028, respectively. Similarly, absorbed photosynthetically active radiation and gross primary productivity decline from 0.0094 to 0.0034% and 0.0003-0.0002 g*C/m2 within a 1-7 km buffer. Adverse effects last over three years, magnified in summer and autumn, and are more pronounced at lower altitudes and in plains. Forest carbon sinks decrease by 12,034 tons within a 0-20 km radius, causing an average economic loss of $1.81 million per wind farm. Our findings underscore the balanced mitigation strategies for renewable energy transition when transiting from fossil fuels.

Suicide Gene Delivery System Mediated by Ultrasound-Targeted Microbubble Destruction: A Promising Strategy for Cancer Therapy.

The treatment of malignant tumors has always been one of the challenges that have plagued researchers and clinicians. The ideal status in cancer treatment is to eliminate tumor cells while avoiding damage to normal tissues. Different approaches have been investigated to achieve such a goal, and suicide gene therapy has emerged as a novel mode of cancer treatment. This approach involves the delivery of genes encoding enzymes that activate non-toxic prodrugs into cytotoxic metabolites that cause the death of transfected cancer cells. Despite promising results obtained both in vitro and in vivo, this innovative approach has long been stalled in the clinic due to the lack of a suitable delivery system to introduce the suicide gene into cancer cells. Ultrasound-targeted microbubble destruction (UTMD) represents a valuable non-viral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents by increasing vascular and cell membrane permeability, especially in the presence of microbubbles. In this scenario, the true potential of suicide genes can be translated into clinically valuable treatments for patients. This review provides background information on suicide gene therapy and UTMD technology, summarizes the current state of knowledge about UTMD-mediated suicide gene delivery in cancer treatment, and presents an outlook on its future development.

Novel insights into RB1 mutation.

Since the discovery of the retinoblastoma susceptibility gene (RB1) decades ago, RB1 has been regarded as a prototype tumor suppressor gene providing a paradigm for tumor genetic research. Constant research has updated the understanding of RB1-related pathways and their impact on tumor and nontumor diseases. Mutation of RB1 gene has been observed in multiple types of malignant tumors including prostate cancer, lung cancer, breast cancer, and almost every familial and sporadic case of retinoblastoma. Even if well-known and long-investigated, the application potential of RB1 mutation has not been fully tapped. In this review, we focus on the mechanism underlying RB1 mutation during oncogenesis. Therapeutically, we have further discussed potential clinical strategies by targeting RB1-mutated cancers. The unsolved problems and prospects of RB1 mutation are also discussed.

Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn's disease.

Introduction: Researchers have investigated the potential role of intestinal permeability in Crohn's disease pathogenesis. Intestinal permeability is usually mediated by cytoskeleton and intercellular junctions. The myosin light chain kinase (MLCK) is an enzyme that activates the myosin light chain to exert its function related to cytoskeleton contraction and tight junction regulation. The correlation between MLCK and Crohn's disease pathogenesis has been consistently proven. Areas covered: This study aims to expand the understanding of the regulation and function of MLCK in Crohn's disease. An extensive literature search in the MEDLINE database (via PubMed) has been performed up to Oct. 2020. The roles of MLCK in tight junction activation, intestinal permeability enhancement, and cell signal regulation are comprehensively discussed. Expert opinion: Targeting the MLCK-related pathways such as TNF-α in CD treatment has been put into clinical use. More accurate targeting such as MLCK and TNFR2 has been proposed to reduce side effects. MLCK may also have the potential to become biomarkers in fields like CD activity. With the application of cutting age research methods and tools, the MLCK research could be accelerated.

Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach.

As an anticancer agent, irinotecan (CPT-11) has been widely applied in clinical, especially in the treatment of colorectal cancer. However, its clinical use has long been limited by the side effects and potential tissue toxicity. To discriminate the target toxic tissues and dissect the specific response of target tissues after CPT-11 administration in rats, untargeted metabolomic study was conducted. First, differential metabolites between CPT-11 treated group and control group in each tissue were screened out. Then, based on fold changes of these differential metabolites, principal component analysis and hierarchical cluster analysis were performed to visualize the degree and specificity of the influences of CPT-11 on the metabolic profiles of nine tissues. Using this step-wise method, ileum, jejunum, and liver were finally recognized as target toxic tissues. Furthermore, tissue specific responses of liver, ileum, and jejunum to CPT-11 were dissected and specific differential metabolites were screened out. Perturbations in Krebs cycle, amino acid, purine and bile acid metabolism were observed in target toxic tissues. In conclusion, our study put forward a new approach to dissect target toxic tissues and tissue specific responses of CPT-11 using metabolomics.