Non-coding RNA in exosomes: Regulating bone metastasis of lung cancer and its clinical application prospect.

Lung cancer is a highly prevalent malignancy with poor prognosis and rapid progression. It most frequently metastasizes to the bone, where it can pose a severe threat to the patient's survival. Once metastasized, the disease is often incurable and can result in severe complications such as hypercalcemia, bone pain, fractures, spinal cord compression, and subsequent paralysis. Exosomes are bilayer vesicle nanoparticles secreted by most of the extracellular vesicles, which can be found in almost all organisms and play an essential role in intercellular communication. Through their ability to regulate related bone cells, exosomes carry bioactive molecules, including proteins, lipids, and non-coding RNAs (ncRNAs), that can be extremely important in bone remodeling. Studies have been conducted on the role play by proteins, lncRNA, and microRNA-all ncRNAs-carried by exosomes in the bone metastases of lung cancer. In this review, the latest progress of the regulatory mechanism of ncRNAs carried by exosomes in lung cancer bone metastasis has been reviewed. The clinical use of exosomes as a promising biomarker, drug transporter, and therapeutic target was highlighted to offer a novel diagnostic and treatment approach for patients with lung cancer bone metastases.

A retrospective study of ovarian tissue cryopreservation in female patients with hematological diseases for fertility preservation.

PURPOSES: To investigate the effect and safety of ovarian tissue cryopreservation (OTC) for fertility preservation in female patients with hematological diseases. METHODS: We designed a retrospective study. The clinical data of patients with hematological diseases undergoing OTC admitted to Peking University People's Hospital from April 2017 to January 2023 were analyzed and summarized. RESULTS: A total of 24 patients were included in the study, including 19 patients with malignant hematological diseases and 5 patients with non-malignant hematological diseases. The former included 14 patients with acute leukemia, 1 patient with chronic leukemia, and 4 patients with myelodysplastic syndrome, while the latter 5 patients were aplastic anemia (AA). 16 patients had received chemotherapy before OTC. The average age of 24 patients was 22.80 ± 6.81 years. The average anti-Mullerian hormone (AMH) was 1.97 ± 2.12 ng/mL, and the average follicle-stimulating hormone (FSH) was 7.01 ± 4.24 IU/L in examination before OTC. FSH was greater than 10.0 IU/L in 4 cases. The pre-OTC laboratory tests showed that the average white blood cell (WBC) count was (3.33 ± 1.35) × 109/L, the average hemoglobin was 91.42 ± 22.84 g/L, and the average platelet was (147.38 ± 114.46) × 109/L. After injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF), blood transfusion, and iron supplementation in pre-OTC treatment, the average WBC count was (4.91 ± 3.07) × 109/L, the average hemoglobin was 98.67 ± 15.43 g/L, and the average platelet was (156.38 ± 103.22) × 109/L. Of the 24 patients, 22 underwent laparoscopic bilateral partial oophorectomy and oophoroplasty, and 2 underwent laparoscopic unilateral oophorectomy. The average duration of OTC was 59.54 ± 17.58 min, and the average blood loss was 32.1 ± 41.6 mL. The maximum blood loss was 200 mL. There was no significant difference in WBC count and hemoglobin concentration after OTC compared to pre-OTC period. Only the platelet count after OTC surgery was significantly different from that before surgery ([134.54 ± 80.84 vs. 156.38 ± 103.22] × 109/L, p < 0.05). None of the 24 patients had serious complications after OTC. 2 patients had mild infection symptoms, but both recovered well. 23 patients underwent hematopoietic stem cell transplantation (HSCT) after OTC. The median and interquartile range from OTC to the pretreatment of HSCT was 33 (57) days, and the median and interquartile range from OTC to HSCT was 41 (57) days. Seven of them began pretreatment of HSCT within 20 days and began HSCT within 30 days after OTC. All patients were followed up. Of the 23 patients who underwent HSCT after surgery, 22 presented with amenorrhea and 1 with scanty menstrual episodes. Seven patients underwent hormone replacement therapy (HRT) after HSCT. A patient with AA underwent ovarian tissue transplantation (OTT) 3 years after HSCT and resumed regular menstruation 6 months after OTT. CONCLUSIONS: Ovarian tissue cryopreservation has a promising future in fertility protection in patients with hematological diseases. However, patients with hematological malignancies often have received gonadotoxic therapy before OTC, which may be accompanied by myelosuppression while patients with non-malignant hematological diseases often present with severe hemocytopenia. So perioperative complete blood count of patients should be paid attention to. There was no significant difference in the WBC count and hemoglobin concentration in patients with hematological diseases before and after OTC surgery, and the platelet count decreased slightly within the normal range. Infection is the most common post-OTC complication, and HSCT pretreatment can be accepted as early as the 10th day after OTC. OTC has no adverse effects on patients with hematological diseases and does not delay HSCT treatment. For young patients with hematological diseases, OTC is an effective method of fertility preservation.

Postmenopausal endometrial non-benign lesion risk classification through a clinical parameter-based machine learning model.

OBJECTIVE: This study aimed to develop and evaluate a machine learning model utilizing non-invasive clinical parameters for the classification of endometrial non-benign lesions, specifically atypical hyperplasia (AH) and endometrioid carcinoma (EC), in postmenopausal women. METHODS: Our study collected clinical parameters from a cohort of 999 patients with postmenopausal endometrial lesions and conducted preprocessing to identify 57 relevant characteristics from these irregular clinical data. To predict the presence of postmenopausal endometrial non-benign lesions, including atypical hyperplasia and endometrial cancer, we employed various models such as eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Back Propagation Neural Network (BPNN), as well as two ensemble models. Additionally, a test set was performed on an independent dataset consisting of 152 patients. The performance evaluation of all models was based on metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, and F1 score. RESULTS: The RF model demonstrated superior recognition capabilities for patients with non-benign lesions compared to other models. In the test set, it attained a sensitivity of 88.1% and an AUC of 0.93, surpassing all alternative models evaluated in this study. Furthermore, we have integrated this model into our hospital's Clinical Decision Support System (CDSS) and implemented it within the outpatient electronic medical record system to continuously validate and optimize its performance. CONCLUSIONS: We have trained a model and deployed a system with high discriminatory power that may provide a novel approach to identify patients at higher risk of postmenopausal endometrial non-benign lesions who may benefit from more tailored screening and clinical intervention.

Comparison of deep learning networks for fully automated head and neck tumor delineation on multi-centric PET/CT images.

OBJECTIVES: Deep learning-based auto-segmentation of head and neck cancer (HNC) tumors is expected to have better reproducibility than manual delineation. Positron emission tomography (PET) and computed tomography (CT) are commonly used in tumor segmentation. However, current methods still face challenges in handling whole-body scans where a manual selection of a bounding box may be required. Moreover, different institutions might still apply different guidelines for tumor delineation. This study aimed at exploring the auto-localization and segmentation of HNC tumors from entire PET/CT scans and investigating the transferability of trained baseline models to external real world cohorts. METHODS: We employed 2D Retina Unet to find HNC tumors from whole-body PET/CT and utilized a regular Unet to segment the union of the tumor and involved lymph nodes. In comparison, 2D/3D Retina Unets were also implemented to localize and segment the same target in an end-to-end manner. The segmentation performance was evaluated via Dice similarity coefficient (DSC) and Hausdorff distance 95th percentile (HD95). Delineated PET/CT scans from the HECKTOR challenge were used to train the baseline models by 5-fold cross-validation. Another 271 delineated PET/CTs from three different institutions (MAASTRO, CRO, BERLIN) were used for external testing. Finally, facility-specific transfer learning was applied to investigate the improvement of segmentation performance against baseline models. RESULTS: Encouraging localization results were observed, achieving a maximum omnidirectional tumor center difference lower than 6.8 cm for external testing. The three baseline models yielded similar averaged cross-validation (CV) results with a DSC in a range of 0.71-0.75, while the averaged CV HD95 was 8.6, 10.7 and 9.8 mm for the regular Unet, 2D and 3D Retina Unets, respectively. More than a 10% drop in DSC and a 40% increase in HD95 were observed if the baseline models were tested on the three external cohorts directly. After the facility-specific training, an improvement in external testing was observed for all models. The regular Unet had the best DSC (0.70) for the MAASTRO cohort, and the best HD95 (7.8 and 7.9 mm) in the MAASTRO and CRO cohorts. The 2D Retina Unet had the best DSC (0.76 and 0.67) for the CRO and BERLIN cohorts, and the best HD95 (12.4 mm) for the BERLIN cohort. CONCLUSION: The regular Unet outperformed the other two baseline models in CV and most external testing cohorts. Facility-specific transfer learning can potentially improve HNC segmentation performance for individual institutions, where the 2D Retina Unets could achieve comparable or even better results than the regular Unet.

The roles of tissue resident macrophages in health and cancer.

As integral components of the immune microenvironment, tissue resident macrophages (TRMs) represent a self-renewing and long-lived cell population that plays crucial roles in maintaining homeostasis, promoting tissue remodeling after damage, defending against inflammation and even orchestrating cancer progression. However, the exact functions and roles of TRMs in cancer are not yet well understood. TRMs exhibit either pro-tumorigenic or anti-tumorigenic effects by engaging in phagocytosis and secreting diverse cytokines, chemokines, and growth factors to modulate the adaptive immune system. The life-span, turnover kinetics and monocyte replenishment of TRMs vary among different organs, adding to the complexity and controversial findings in TRMs studies. Considering the complexity of tissue associated macrophage origin, macrophages targeting strategy of each ontogeny should be carefully evaluated. Consequently, acquiring a comprehensive understanding of TRMs' origin, function, homeostasis, characteristics, and their roles in cancer for each specific organ holds significant research value. In this review, we aim to provide an outline of homeostasis and characteristics of resident macrophages in the lung, liver, brain, skin and intestinal, as well as their roles in modulating primary and metastatic cancer, which may inform and serve the future design of targeted therapies.

Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.

LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy.

Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. In addition, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, whereas phosphorylation of proliferation regulators, for example, AKT, cyclin D1, and retinoblastoma protein, was decreased. Conversely, transcriptomic analysis showed LILRB3 activation by agonist antibodies may enhance leukemia survival through upregulation of cholesterol metabolism, which has been shown to promote leukemia cell survival. Moreover, LILRB3-targeted CAR T cells exhibited potent antitumor effects both in vitro and in vivo. Taken together, our results suggest that LILRB3 is a potentially potent target for multiple treatment modalities in AML. SIGNIFICANCE: LILRB3 regulates differentiation and proliferation in acute myeloid leukemia and can be targeted with monoclonal antibodies and CAR T cells to suppress leukemia growth.

Alterations of interhemispheric functional homotopic connectivity and corpus callosum microstructure in bulimia nervosa.

Background: Accumulating evidence indicates maladaptive neural information interactions between different brain regions underlie bulimia nervosa (BN). However, little is known about the alterations in interhemispheric communication of BN, which is facilitated by the corpus callosum (CC), the major commissural fiber connecting the two hemispheres. To shed light on the interhemispheric communications in BN, the present study aims to explore alterations of interhemispheric homotopic functional connectivity and the CC microstructure in BN. Methods: Based on magnetic resonance imaging (MRI) data collected from 42 BN patients and 38 healthy controls (HCs), the group differences of voxel-mirrored homotopic connectivity (VMHC) index and CC white matter microstructure were compared. Then brain regions with significant group differences in VMHC were selected as seeds for subsequent functional connectivity (FC) analysis. Seed-based fiber tracking and correlation analysis were used to analyze the relationship between VMHC and CC changes. And correlation analysis was used to reveal the correlation between abnormal imaging variables and the clinical features of BN. Results: Compared with HCs, the BN group showed decreased fractional anisotropy (FA) in middle part of CC (CCMid) and increased VMHC in bilateral orbitofrontal cortex (OFC) and middle temporal gyrus (MTG) [false discovery rate (FDR) correction with a corrected threshold of P<0.05]. Subsequent FC analyses indicated increased FC between left OFC and right OFC, bilateral MTG, left middle occipital gyrus and right precuneus (PCUN); between right OFC and left cerebellum crus II and right PCUN; and between left MTG and right inferior temporal gyrus, right cerebellum lobule VI and right medial superior frontal gyrus (FDR correction with a corrected threshold of P<0.05). The VMHC values of OFC and MTG showed no correlations with FA values of the CCMid and the white fibers between the bilateral OFC and MTG were not through the CCMid. In addition, several regions with abnormal FC had a potential correlation trend with abnormal eating behaviors in BN patients (P<0.05, uncorrected). Conclusions: Aberrant interhemispheric homotopic functional connectivity and CC microstructure were observed in BN, and they may be independent of each other. Regions with aberrant interhemispheric homotopic functional connectivity showed hyperconnectivity with regions related to reward processing, body shape perception, and self-reference.

Chemokines: Function and therapeutic potential in bone metastasis of lung cancer.

Lung cancer is a rapidly progressing disease with a poor prognosis. Bone metastasis is commonly found in 40.6% of advanced-stage patients. The mortality rate of lung cancer patients with bone metastasis can be significantly decreased by implementing novel diagnostic techniques, improved staging and classification systems, precise surgical interventions, and advanced treatment modalities. However, it is important to note that there is currently a lack of radical procedures available for these patients due to the development of drug resistance. Consequently, palliative care approaches are commonly employed in clinical practice. Therefore, new understandings of the process of bone metastasis of lung cancer are critical for developing better treatment strategies to improve patient's clinical cure rate and quality of life. Chemokines are cell-secreted small signaling proteins in cancer occurrence, proliferation, invasion, and metastasis. In this study, we review the development of bone metastasis in lung cancer and discuss the mechanisms of specific chemokine families (CC, CXC, CX3C, and XC) in regulating the biological activities of tumors and promoting bone metastasis. We also highlight some preclinical studies and clinical trials on chemokines for lung cancer and bone metastasis.

Development of convenient crystallization inhibition assays for structure-activity relationship studies in the discovery of crystallization inhibitors.

Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies. Herein, we report a convenient, medium-to-high throughput assay platform using, as an example, the screening and evaluation of inhibitors of L-cystine crystallization for the prevention of kidney stones in cystinuria. The assay involves preparing a supersaturated solution, followed by incubating small volumes (<1 mL) of the supersaturated solution with test inhibitors for 72 hours, and finally measuring L-cystine concentrations in the supernatants after centrifugation using either a colorimetric or fluorometric method. Compared to traditional techniques for studying crystallization inhibitors, this miniaturized multi-well assay format is simple to implement, cost-effective, and widely applicable in determining and distinguishing the activities of compounds that inhibit crystallization. This assay has been successfully employed to discover L-cystine diamides as highly potent inhibitors of L-cystine crystallization such as LH708 with an EC50 of 0.058 µM, 70-fold more potent than L-CDME (EC50 = 4.31 µM).

Design, synthesis and anti-osteosarcoma activity study of novel pyrido[2,3-d]pyrimidine derivatives by inhibiting DKK1-Wnt/ß-catenin pathway.

Osteosarcoma is a common primary malignant bone tumor in adolescents. Wnt/ß-catenin has been proved to play a pro-oncogenic role and was overactivated in osteosarcoma. Therefore, this pathway has become an interesting therapeutic target for osteosarcoma. Herein we report the design, synthesis and biological activities of a series of novel pyrido[2,3-d]pyrimidine derivatives based on our previous work. Among these, the representative compound 2-{[1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]amino}-N-[4-(trifluoromethoxy)phenyl]acetamide (7m) has exhibited good antiproliferative activity towards 143B and MG63 cells with good selectivity over non-cancerous HSF cells. In the assay of Ca2+ concentration, the compound 7m increased the intracellular Ca2+ concentration in 143B cells. In addition, the expression of DKK1 increased, and that of p-ß-catenin decreased by 7m treatment. Finally, the Hoechst 33,342 staining, Annexin-FITC/PI staining and mitochondrial fluorescence staining have clearly demonstrated that compound 7m induced apoptosis in 143B cells.

Tumor microenvironment responsive metal nanoparticles in cancer immunotherapy.

Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione (GSH) levels, among others. Recently, TME regulation approaches have attracted widespread attention in cancer immunotherapy. Nanoparticles as drug delivery systems have ability to modulate the hydrophilicity of drugs to affect drug uptake and efflux in tumor. Especially, the metal nanoparticles have been extensive applied for tumor immunotherapy due to their unique physical properties and elaborate design. However, the potential deficiencies of metal nanoparticles due to their low biodegradability, toxicity and treatment side effects restrict their clinical application. In this review, we briefly introduce the feature characteristics of the TME and the recent advances in tumor microenvironment responsive metal nanoparticles for tumor immunotherapy. In addition, nanoparticles could be combined with other treatments, such as chemotherapy, radiotherapy and photodynamic therapy also is presented. Finally, the challenges and outlook for improving the antitumor immunotherapy efficiency, side effect and potential risks of metal nanoparticles has been discussed.

Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson's disease.

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1ß, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8+ T-cell cluster C16 (CD57- naïve CD8+ T) and natural killer (NK) cell cluster C32 (CD57- CD28- NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8+ T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.

Targeting LncRNA LLNLR-299G3.1 with antisense oligonucleotide inhibits malignancy of esophageal squamous cell carcinoma cells in vitro and in vivo.

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanisms of lncRNAs in ESCC are still incompletely understood and therapeutic attempts for in vivo targeting cancer-associated lncRNA remain a challenge. By RNA-sequencing analysis, we identified that LLNLR-299G3.1 was a novel ESCC-associated lncRNA. LLNLR-299G3.1 was up-regulated in ESCC tissues and cells and promoted ESCC cell proliferation and invasion. Silencing of LLNLR-299G3.1 with ASO (antisense oligonucleotide) resulted in opposite effects. Mechanistically, LLNLR-299G3.1 bound to cancer-associated RNA binding proteins and regulated the expression of cancer-related genes, including OSM, TNFRSF4, HRH3, and SSTR3. ChIRP-seq (chromatin isolation by RNA purification and sequencing) revealed that these genes contained enriched chromatin binding sites for LLNLR-299G3.1. Rescue experiments confirmed that the effects of LLNLR-299G3.1 on ESCC cell proliferation were dependent on interaction with HRH3 and TNFRSF4. Therapeutically, intravenous delivery of placental chondroitin sulfate A binding peptide-coated nanoparticles containing antisense oligonucleotide (pICSA-BP-ANPs) strongly inhibited ESCC tumor growth and significantly improved animal survival in vivo. Overall, our results suggest that LLNLR-299G3.1 promotes ESCC malignancy through regulating gene-chromatin interactions and targeting ESCC by pICSA-BP-ANPs may be an effective strategy for the treatment of lncRNA-associated ESCC.

DDX3 suppresses hepatocellular carcinoma progression through modulating the secretion and composition of exosome.

Due to the lack of predictive biomarkers and the lack of conspicuous symptoms at the early stage, hepatocellular carcinoma (HCC) remains difficult to diagnose and treat effectively. During cancer development, exosomes secreted from tumor cells carry functional molecules to surrounding recipient cells, thereby participating in the regulation of cancer progression. DDX3, a DEAD-box RNA helicase, performs many important functions in several cellular processes and is therefore implicated as a tumor suppressor in HCC. However, whether DDX3 affects the secretion and cargo sorting of HCC exosomes remains obscure. In this study, our results revealed that reduced DDX3 expression in HCC cells promoted the release of exosomes and enhanced the expression of several exosome biogenesis-associated proteins, such as exosome markers (e.g., TSG101, Alix, and CD63) and Rab proteins (e.g., Rab5, Rab11, and Rab35). By double knockdown of the expression of DDX3 and these exosome biogenesis-related factors, we confirmed that DDX3 participated in the regulation of exosome secretion by modulating the expression of these cellular factors in HCC cells. In addition, exosomes derived from DDX3-knockdown HCC cells enhanced cancer stem cell properties, including self-renewal capability, migration, and drug resistance, in recipient HCC cells. Moreover, up-regulation of the exosome markers TSG101, Alix, and CD63 as well as down-regulation of tumor-suppressive miR-200b and miR-200c were observed in exosomes derived from DDX3-knockdown HCC cells, which may account for the enhanced hepatic cancer stemness of the recipient cells treated with DDX3-knockdown HCC cell-derived exosomes. Taken together, our findings provide a new molecular mechanism supporting the tumor-suppressor role of DDX3 in HCC, which may contribute to the development of new therapeutic strategies against HCC.

Application of iron oxide nanoparticles in the diagnosis and treatment of leukemia.

Leukemia is a malignancy initiated by uncontrolled proliferation of hematopoietic stem cell from the B and T lineages, resulting in destruction of hematopoietic system. The conventional leukemia treatments induce severe toxic and a long series of unwanted side-effects which are caused by lack of specificity of anti-leukemic drugs. Recently, nanotechnology have shown tremendous application and clinical impact with respect to diagnosis and treatment of leukemia. According to considerable researches in the context of finding new nanotechnological platform, iron oxide nanoparticles have been gained increasing attention for the leukemia patients use. In this review, a short introduction of leukemia is described followed by the evaluation of the current approaches of iron oxide nanoparticles applied in the leukemia detection and treatment. The enormous advantages of iron oxide nanoparticles for leukemia have been discussed, which consist of the detection of magnetic resonance imaging (MRI) as efficient contrast agents, magnetic biosensors and targeted delivery of anti-leukemia drugs by coating different targeting moieties. In addition, this paper will briefly describe the application of iron oxide nanoparticles in the combined treatment of leukemia. Finally, the shortcomings of the current applications of iron-based nanoparticles in leukemia diagnosis and treatment will be discussed in particular.

Bidirectional Mendelian randomization study of insulin-related traits and risk of ovarian cancer.

Background: It is well known that the occurrence and development of ovarian cancer are closely related to the patient's weight and various endocrine factors in the body. Aim: Mendelian randomization (MR) was used to analyze the bidirectional relationship between insulin related characteristics and ovarian cancer. Methods: The data on insulin related characteristics are from up to 5567 diabetes free patients from 10 studies, mainly including fasting insulin level, insulin secretion rate, peak insulin response, etc. For ovarian cancer, UK Biobank data just updated in 2021 was selected, of which the relevant gene data was from 199741 Europeans. Mendelian randomization method was selected, with inverse variance weighting (IVW) as the main estimation, while MR Pleiotropy, MR Egger, weighted median and other methods were used to detect the heterogeneity of data and whether there was multi validity affecting conclusions. Results: Among all insulin related indicators (fasting insulin level, insulin secretion rate, peak insulin response), the insulin secretion rate was selected to have a causal relationship with the occurrence of ovarian cancer (IVW, P < 0.05), that is, the risk of ovarian cancer increased with the decrease of insulin secretion rate. At the same time, we tested the heterogeneity and polymorphism of this indicator, and the results were non-existent, which ensured the accuracy of the analysis results. Reverse causal analysis showed that there was no causal effect between the two (P>0.05). Conclusion: The impairment of the insulin secretion rate has a causal effect on the risk of ovarian cancer, which was confirmed by Mendel randomization. This suggests that the human glucose metabolism cycle represented by insulin secretion plays an important role in the pathogenesis of ovarian cancer, which provides a new idea for preventing the release of ovarian cancer.

Synthesis of Bispecific Antibody Conjugates Using Functionalized Poly-ADP-ribose Polymers.

Poly-ADP-ribose (PAR) is a natural type of polymer derived from enzymatic reactions catalyzed by cellular poly(ADP-ribose) polymerases (PARPs). Given its notable solubility and biocompatibility, the PAR polymer may function as effective carriers for therapeutics in addition to modulating biomolecular interactions in cells. To explore its therapeutic potential, we herein developed a PAR polymer-based bispecific antibody targeting both human epidermal growth factor receptor 2 (HER2) and T-cell CD3 antigens. This was accomplished by conjugating anti-HER2 and anti-CD3 monoclonal antibodies to azido-functionalized PAR polymers through click chemistry. The generated PAR polymer-anti-HER2/anti-CD3 antibody conjugate could not only bind specifically to both HER2- and CD3-expressing target cells but also display potent cytotoxicity against HER2-positive breast cancer cells in the presence of non-activated human peripheral blood mononuclear cells (PBMCs). Functionalized PAR polymers provide a new strategy for synthesizing bispecific antibodies and may enable generation of PAR polymer-based conjugates with unique pharmacological activities for biomedical applications.

A Poly-ADP-Ribose Polymer-GCSF Conjugate.

Poly-ADP-ribose (PAR) is a naturally occurring form of polymers synthesized through enzymatic reactions catalyzed by poly(ADP-ribose) polymerases (PARPs). It is known for regulating various important cellular signaling pathways and processes. As a water soluble and biocompatible type of polymer, PAR may hold promise for safe and efficient delivery of therapeutics. To explore the therapeutic potential of PAR polymers, we herein generate PAR polymers conjugated with human granulocyte colony-stimulating factor (GCSF) protein by harnessing human PARP1-catalyzed auto-poly-ADP-ribosylation and a clickable analogue of nicotinamide adenine dinucleotide (NAD+). The resulting PAR polymer-based conjugate with multivalent GCSF ligands exhibits a potent cell proliferative activity. Notably, mice treated with a single dose of the PAR polymer-GCSF conjugate show sustained high levels of neutrophil in blood for 11 days, demonstrating excellent in vivo efficacy. Functionalized PAR polymers may provide new scaffolds for conjugating with therapeutic proteins or peptides toward improved pharmacological activities.

Current Molecular Combination Therapies Used for the Treatment of Breast Cancer.

Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used for many years, they are not always effective, and many patients relapse after initial treatment. Moreover, in some patients the response to therapy becomes weaker, or resistance to monotherapy develops over time. This is especially problematic for metastatic breast cancer or triple-negative breast cancer. Recently, combination therapies (in which two or more drugs are used to target two or more pathways) have emerged as promising new treatment options. Combination therapies are often more effective than monotherapies and demonstrate lower levels of toxicity during long-term treatment. In this review, we provide a comprehensive overview of current combination therapies, including molecular-targeted therapy, hormone therapy, immunotherapy, and chemotherapy. We also describe the molecular basis of breast cancer and the various treatment options for different breast cancer subtypes. While combination therapies are promising, we also discuss some of the challenges. Despite these challenges, the use of innovative combination therapy holds great promise compared with traditional monotherapies. In addition, the use of multidisciplinary technologies (such as nanotechnology and computer technology) has the potential to optimize combination therapies even further.