GSH-responsive bithiophene Aza-BODIPY@HMON nanoplatform for achieving triple-synergistic photoimmunotherapy.

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON's large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON's rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.

ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics.

Immunogenic cell death (ICD) represents a modality of apoptosis distinguished by the emanation of an array of damage-related molecular signals. This mechanism introduces a novel concept in the field of contemporary tumor immunotherapy. The inception of reactive oxygen species (ROS) within tumor cells stands as the essential prerequisite and foundation for ICD induction. The formulation of highly efficacious photodynamic therapy (PDT) nanomedicines for the successful induction of ICD is an area of significant scientific inquiry. In this work, we devised a ROS-responsive and triple-synergistic mitochondria-targeted polymer micelle (CAT/CPT-TPP/PEG-Ce6, CTC) that operates with multistage amplification of ROS to achieve the potent induction of ICD. Utilizing an "all-in-one" strategy, we direct both the PDT and chemotherapeutic units to the mitochondria. Concurrently, a multistage cyclical amplification that caused by triple synergy strategy stimulates continuous, stable, and adequate ROS generation (domino effect) within the mitochondria of cells. Conclusively, influenced by ROS, tumor cell-induced ICD is effectively activated, remodeling immunogenicity, and enhancing the therapeutic impact of PDT when synergized with chemotherapy. Empirical evidence from in vitro study substantiates that CTC micelles can efficiently provoke ICD, catalyzing CRT translocation, the liberation of HMGB1 and ATP. Furthermore, animal trials corroborate that polymer micelles, following tail vein injection, can induce ICD, accumulate effectively within tumor tissues, and markedly inhibit tumor growth subsequent to laser irradiation. Finally, transcriptome analysis was carried out to evaluate the changes in tumor genome induced by CTC micelles. This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.

Clinical outcomes of fresh and frozen embryos transfer after in vitro fertilization in spouses of patients with severely low sperm count and motility. / å› é å¶é‡åº¦å°‘å¼±ç²¾å­ç—‡ä¸å­•æ‚£è€ ä½“å¤–å—ç²¾åŽç§»æ¤æ–°é²œèƒšèƒŽä¸Žå†·å†»èƒšèƒŽçš„ä¸´åºŠç»“å±€æ¯”è¾ƒ.

OBJECTIVES: To compare the pregnancy and neonatal outcomes of in vitro fertilization-embryo transfer (IVF-ET) with fresh or frozen embryos for male patients with severely low sperm count and motility. METHODS: A total of 2300 male patients with severely low sperm count and motility underwent IVT-ET in the Reproduction Medicine Center, Sir Run Run Shaw Hospital from April 2018 to April 2022. After applying the propensity score matching (PSM), 473 fresh embryo transferred cycles and 473 frozen embryo transferred cycles were selected in the study, and the pregnancy and neonatal outcomes were compared between two groups. RESULTS: There were no significant differences in pregnancy outcomes and neonatal outcomes between fresh and frozen embryo groups (all P>0.05). In the stratification analysis, the number of retrieved oocytes in the fresh good-quality embryo transfer group was significantly increased compared with the fresh poor-quality embryo group (P<0.05), but the very early pregnancy loss rates were similar between the two groups, while the rate in fresh good-quality embryo transfer group was significantly higher than that in the frozen good-quality embryo transfer group (P<0.05). Among different age groups of women, the number of retrieved oocytes and the level of estrogen in the fresh embryo transfer group was significantly higher in the 20 to <30 years old group than that in the 30 to <35 years old group (both P<0.05), but the clinical pregnancy rate was lower in the 20 to <30 years old group than that in the 30 to <35 years old group (P>0.05). Additionally, the very early pregnancy loss was significantly increased in the fresh embryo group compared with the frozen embryo group in the 20 to <30 years age group (P<0.05). CONCLUSIONS: There is no significant difference in pregnancy and neonatal outcomes between fresh embryo transfer and frozen embryo transfer for male patients with severely low sperm count and motility undergoing IVF-ET. Due to shorter transfer time, less embryo freezing damage and reduced costs, fresh embryo transfer can be considered a first choice. However, it is not necessary to pursue fresh embryo transfer if maternal oestrogen levels are too high and there is a tendency of overstimulation.

Artemisinin and its derivatives modulate glucose homeostasis and gut microbiota remodeling in a nutritional context.

Glucose metabolic disorders, prevalent in numerous metabolic diseases, have become a pressing global public health concern. Artemisinin (ART) and its derivatives, including artesunate (ARTs) and artemether (ARTe), have shown potential as metabolic regulators. However, the specific effects of ART and its derivatives on glucose metabolism under varying nutritional conditions and the associated molecular mechanisms remain largely unexplored. In this study, we examined the impact of ART, ARTs, and ARTe on glucose homeostasis using a mouse model subjected to different dietary regimens. Our findings revealed that ART, ARTs, and ARTe increased blood glucose levels in mice on a normal-chow diet (ND) while mitigating glucose imbalances in high-fat diet (HFD) mice. Notably, treatment with ART, ARTs, and ARTe had contrasting effects on in vivo insulin signaling, impairing it in ND mice and enhancing it in HFD mice. Moreover, the composition of gut microbiota underwent significant alterations following administration of ART and its derivatives. In ND mice, these treatments reduced the populations of bacteria beneficial for improving glucose homeostasis, including Parasutterella, Alloprevotella, Bifidobacterium, Ileibacterium, and Alistipes. In HFD mice, there was an increase in the abundance of beneficial bacteria (Alistipes, Akkermanisia) and a decrease in bacteria known to negatively impact glucose metabolism (Coprobacillus, Helicobacter, Mucispirillum, Enterorhabdus). Altogether, ART, ARTs, and ARTe exhibited distinct effects on the regulation of glucose metabolism, depending on the nutritional context, and these effects were closely associated with modifications in gut microbiota composition.

The timing for embryo transfer after antibiotic therapy for chronic endometritis.

OBJECTIVE: To explore the optimal timing of embryo transfer after the first round treatment of chronic endometritis (CE) in vitro. MATERIALS AND METHODS: A total of 184 patients were recruited from a retrospective analysis of a large university-affiliated reproduction center in 2021. Some people chose to undergo embryo transfer in the same menstrual cycle with the first round of antibiotic treatment (Group 1, n = 29). Others received embryo transfer in the next cycle after the first round of treatment (Group 2, n = 69) or even one cycle later (Group 3，n = 96). RESULTS: Patients in Group 1 got significantly lower biochemical pregnancy rate and clinical pregnancy rate and live birth rate than Group 2 (p < 0.05) and also Group 3 (p < 0.05). Then after comparing the influence factors, we found embryo transfer in the next cycle after antibiotic treatment had a higher clinical pregnancy rate than group 1 (OR = 3.2 p < 0.05) and group 3(OR = 2.5, p < 0.05). The live birth rate in group 2 was higher than group 1(OR = 3.5, p < 0.05). CONCLUSION: These findings illustrate that embryo transfer in the next menstrual cycle is the optimal time. Embryo transfer in the same menstrual cycle with the first round of treatment reduces the pregnancy rate.

Immunogenicity evaluation of primary polio vaccination schedule with inactivated poliovirus vaccines and bivalent oral poliovirus vaccine.

BACKGROUND: To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV, wIPV). METHODS: A cross-sectional investigation was conducted at four sites in Chongqing, China, healthy infants aged 60-89 days were conveniently recruited and divided into four groups according to their received primary polio vaccination schedules (2sIPV + bOPV, 2wIPV + bOPV, 3sIPV, and 3wIPV). The sero-protection and neutralizing antibody titers against poliovirus serotypes (type 1, 2, and 3) were compared after the last dose. RESULTS: There were 408 infants completed the protocol. The observed seropositivity was more than 96% against poliovirus types 1, 2, and 3 in all groups. IPV-only groups induced higher antibody titers(GMT) against poliovirus type 2 (Median:192, QR: 96-384, P<0.05) than the "2IPV + bOPV" group. While the "2IPV + bOPV" group induced significantly higher antibody titers against poliovirus type 1 (Median:2048, QR: 768-2048, P<0.05)and type 3 (Median:2048, QR: 512-2048, P<0.05) than the IPV-only group. CONCLUSIONS: Our findings have proved that the two doses of IPV with one dose of bOPV is currently the best polio routine immunization schedule in China.

Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Identification and validation of serum metabolite biomarkers for endometrial cancer diagnosis.

Endometrial cancer (EC) stands as the most prevalent gynecological tumor in women worldwide. Notably, differentiation diagnosis of abnormity detected by ultrasound findings (e.g., thickened endometrium or mass in the uterine cavity) is essential and remains challenging in clinical practice. Herein, we identified a metabolic biomarker panel for differentiation diagnosis of EC using machine learning of high-performance serum metabolic fingerprints (SMFs) and validated the biological function. We first recorded the high-performance SMFs of 191 EC and 204 Non-EC subjects via particle-enhanced laser desorption/ionization mass spectrometry (PELDI-MS). Then, we achieved an area-under-the-curve (AUC) of 0.957-0.968 for EC diagnosis through machine learning of high-performance SMFs, outperforming the clinical biomarker of cancer antigen 125 (CA-125, AUC of 0.610-0.684, p < 0.05). Finally, we identified a metabolic biomarker panel of glutamine, glucose, and cholesterol linoleate with an AUC of 0.901-0.902 and validated the biological function in vitro. Therefore, our work would facilitate the development of novel diagnostic biomarkers for EC in clinics.

Neoadjuvant chemotherapy-induced remodeling of human hormonal receptor-positive breast cancer revealed by single-cell RNA sequencing.

Hormone receptor-positive breast cancer (HR+ BC) is known to be relatively insensitive to chemotherapy, and since chemotherapy has remained the major neoadjuvant therapy for HR+ BC, the undetermined mechanism of chemoresistance and how chemotherapy reshapes the immune microenvironment need to be explored by high-throughput technology. By using single-cell RNA sequencing and multiplexed immunofluorescence staining analysis of HR+ BC samples (paired pre- and post-neoadjuvant chemotherapy (NAC)), the levels of previously unrecognized immune cell subsets, including CD8+ T cells with pronounced expression of T-cell development (LMNA) and cytotoxicity (FGFBP2) markers, CD4+ T cells characterized by proliferation marker (ATP1B3) expression and macrophages characterized by CD52 expression, were found to be increased post-NAC, which were predictive of chemosensitivity and their antitumor function was also validated with in vitro experiments. In terms of immune checkpoint expression of CD8+ T cells, we found their changes were inconsistent post-NAC, that LAG3, VSIR were decreased, and PDCD1, HAVCR2, CTLA4, KLRC1 and BTLA were increased. In addition, we have identified novel genomic and transcriptional patterns of chemoresistant cancer cells, both innate and acquired, and have confirmed their prognostic value with TCGA cohorts. By shedding light on the ecosystem of HR+ BC reshaped by chemotherapy, our results uncover valuable candidates for predicting chemosensitivity and overcoming chemoresistance in HR+ BC.

Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells.

Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

Rac2 mediate foam cell formation and associated immune responses in THP-1 to promote the process of atherosclerotic plaques.

Macrophages play an important role in the pathogenesis of atherosclerosis (AS) by mediating oxidative stress, inflammation and lipid metabolism, which can lead to the formation of vascular plaque. The Rac family isoforms of small molecules GTPase are active by binding to GTPase, but are inactivated by binding to GDP, and play a role in the switch of cell information conduction. This experiment adopts shRNA interference THP-1 cells respectively each subtype expression and inhibiting Rac1, Rac2, Rac3 activity, each subtype of Rac family on lipid metabolism, inflammatory reaction and oxidative stress. THP-1 cells were stimulated with Ox-LDL to establish AS cell models including lipid loading, adhesion, migration and chemotaxis. Oil Red O staining, cell immunofluorescence, scratching test, transwell, Western blot and other experiments were performed. To observe the different effects of three subtypes of Rac family on multiple links in the foaming process of THP-1 cells. ApoE-/- mice on a high-fat diet were used as animal models to examine the effects of Rac subtypes in vivo. The results showed that the activation of immune cells induced by ox-LDL was inhibited when Rac1, Rac2 and Rac3 in THP-1 were decreased, respectively. Thus, Rac1 and Rac3 act in combination with ox-LDL and are associated with cellular oxidative stress and inflammation. This study provides new means and ideas for finding potential intervention targets that have important regulatory effects on atherosclerosis, and provides a new direction for the development of clinical drugs.

Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis.

BACKGROUND: Chronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer. METHODS: Breast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry. RESULTS: Breast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases. CONCLUSIONS: Chronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

MnO2 nanoparticles decorated with Ag/Au nanotags for label-based SERS determination of cellular glutathione.

A novel stimulus-responsive surface-enhanced Raman scattering (SERS) nanoprobe has been developed for sensitive glutathione (GSH) detection based on manganese dioxide (MnO2) core and silver/gold nanoparticles (Ag/Au NPs). The MnO2 core is not only capable to act as a scaffold to amplify the SERS signal via producing "hot spots", but also can be degraded in the presence of the target and thus greatly enhance the nanoprobe sensitivity for sensing of GSH. This approach enables a wide linear range from 1 to 100 µM with a 2.95 µM (3σ/m) detection limit. Moreover, the developed SERS nanoprobe represents great possibility in both sensitive detection of intracellular GSH and even can monitor the change of intracellular GSH level when the stimulant occurs. This sensing system not merely offers a novel strategy for sensitive sensing of GSH, but also provides a new avenue for other biomolecules detection.

Identification of new aptamer BC-3 targeting RPS7 from rapid screening for bladder carcinoma.

Aptamers, short single DNA or RNA oligonucleotides, have shown immense application potential as molecular probes for the early diagnosis and therapy of cancer. However, conventional cell-SELEX technologies for aptamer discovery are time-consuming and laborious. Here we discovered a new aptamer BC-3 by using an improved rapid X-Aptamer selection process for human bladder carcinoma, for which there is no specific molecular probe yet. We show that BC-3 exhibited excellent affinity in bladder cancer cells but not normal cells. We demonstrate that BC-3 displayed high selectivity for tumor cells over their normal counterparts in vitro, in mice, and in patient tumor tissue specimens. Further endocytosis pathway analysis revealed that BC-3 internalized into bladder cancer cells via clathrin-mediated endocytosis. Importantly, we identified ribosomal protein S7 (RPS7) as the binding target of BC-3 via an integrated methodology (mass spectrometry, colocalization assay, and immunoblotting). Together, we report that a novel aptamer BC-3 is discovered for bladder cancer and its properties in the disease are unearthed. Our findings will facilitate the discovery of novel diagnostic and therapeutic strategies for bladder cancer.

A Non-G-Quadruplex DNA Aptamer Targeting NCL for Diagnosis and Therapy in Bladder Cancer.

Bladder cancer (BC) is a highly aggressive malignant tumor affecting the urinary system, characterized by metastasis and a poor prognosis that often leads to limited therapeutic success. This study aims to develop a novel DNA aptamer for the diagnosis and treatment of BC using a tissue-based systematic evolution of ligands by an exponential enrichment (SELEX) process. By using SELEX, this work successfully generates a new aptamer named TB-5, which demonstrates a remarkable and specific affinity for nucleolin (NCL) in BC tissues and displays marked biocompatibility both in vitro and in vivo. Additionally, this work shows that NCL is a reliable tissue-specific biomarker in BC. Moreover, according to circular dichroism spectroscopy, TB-5 forms a non-G-quadruplex structure, distinguishing it from the current NCL-targeting aptamer AS1411, and exhibits a distinct binding region on NCL compared to AS1411. Notably, this study further reveals that TB-5 activates NCL function by promoting autophagy and suppressing the migration and invasion of BC cells, which occurs by disrupting mRNA transcription processes. These findings highlight the critical role of NCL in the pathological examination of BC and warrant more comprehensive investigations on anti-NCL aptamers in BC imaging and treatment.

Targeting tumor endothelial cells with methyltransferase inhibitors: Mechanisms of action and the potential of combination therapy.

Tumor endothelial cells (TECs) reside in the inner lining of blood vessels and represent a promising target for targeted cancer therapy. DNA methylation is a chemical process that involves the transfer of a methyl group to a specific base in the DNA strand, catalyzed by a DNA methyltransferase (DNMT). DNMT inhibitors (DNMTis) can inhibit the activity of DNMTs, thereby preventing the transfer of methyl groups from s-adenosyl methionine (SAM) to cytosine. Currently, the most viable therapy for TECs is the development of DNMTis to release cancer suppressor genes from their repressed state. In this review, we first outline the characteristics of TECs and describe the development of tumor blood vessels and TECs. Abnormal DNA methylation is closely linked to tumor initiation, progression, and cell carcinogenesis, as evidenced by numerous studies. Therefore, we summarize the role of DNA methylation and DNA methyltransferase and the therapeutic potential of four types of DNMTi in targeting TECs. Finally, we discuss the accomplishments, challenges, and opportunities associated with combination therapy with DNMTis for TECs.

ChillsDB: A Gold Standard for Aesthetic Chills Stimuli.

We introduce ChillsDB the first validated database of audiovisual stimuli eliciting aesthetic chills (goosebumps, psychogenic shivers) in a US population. To discover chills stimuli "in the wild", we devised a bottom-up, ecologically-valid method consisting in searching for mentions of the emotion' somatic markers in user comments throughout social media platforms (YouTube and Reddit). We successfully captured 204 chills-eliciting videos of three categories: music, film, and speech. We then tested the top 50 videos in the database on 600+ participants and validated a gold standard of 10 stimuli with a 0.9 probability of generating chills. All ChillsDB tools and data are fully available on GitHub for researchers to be able to contribute and perform further analysis.

Cocrystallization of 5-fluorouracil with gallic acid: A novel 5-fluorouracil cocrystal displaying synergistic anti-tumor activity both in oral and intraperitoneal injection administration.

Gallic acid (GA) is a naturally occurring polyphenolic compound exhibiting anti-tumor activity. To clarify the capability of GA in optimizing the in vitro/in vivo properties of the first line anti-tumor drug 5-fluorouracil (5-FU) and achieve synergistically enhanced anti-tumor activity, a novel cocrystal hydrate of 5-FU-GA-H2O was successfully screened and characterized based on various spectroscopic and experimental analysis including Fourier transform infrared spectroscopy (FT-IR), Raman spectra (Raman), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric (TG) and scanning electric microscope (SEM) techniques. The results suggested the existence of hydrogen bonding interactions between C=O group of 5-FU and O-H group of GA. Although the dissolution rate and solubility of 5-FU-GA-H2O cocrystal were slowed and lowered compared with that of 5-FU, respectively, the membrane permeability was enhanced for cocrystal compared with that of intact 5-FU and physical mixture (PM) of 5-FU and GA. For the cocrystal, the cumulative amount per unit area of permeated 5-FU in the first 10 h was 2.56 and 9.97 times of that of pure 5-FU and PM, respectively, in the case that transmembrane behavior of 5-FU depended on the type of solution from which the powder was dissolved. Meanwhile, improvement on oral bioavailability by co-crystallization was observed; AUC0-t of cocrystal was 2.78-fold higher than that of 5-FU. Furthermore, the cocrystal displayed a superior cytotoxic activity on 4T1 mouse breast cancer cells compared with pure 5-FU and even the PM. It was confirmed that the cocrystal solution induced higher autophagic flux than those of 5-FU and PM in 4T1 cell, suggesting that autophagy rather than apoptosis mainly mediated cell death. The obvious difference of tumor inhibition activity between PM and cocrystal in intraperitoneal injection administration indicated that some of the interactions formed in the solid cocrystal could retain in solution in some way. Benefiting from synergistic cytotoxicity, drug efficacy in vivo was enhanced through injection administration of solution from which cocrystal was dissolved.