Metal-Phenolic Nanomaterial with Organelle-Level Precision Primes Antitumor Immunity via mtDNA-dependent cGAS-STING Activation.

New generation of nanomaterials with organelle-level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria-targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damages by the synergistic action of oxidative stress and furan-mediated DNA cross-linking. Moreover, the phenolic units on PF enable further self-assembly with Mn2+ via metal-phenolic coordination to form metal-phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS-STING pathway by Mn2+ and tumor-derived mtDNA in tumor-associated macrophages (TAMs), and subsequently repolarizing M2-like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS-STING-dependent immunity at the organelle level for potent antitumor efficacy.

Improving MRI-based analysis of brain structural changes in patients with hypertension via a privileged information learning algorithm.

Hypertension can lead to changes in the brain structure and function, and different blood pressure levels (2017ACC/AHA) have different effects on brain structure. It is important to analyze these changes by machine learning methods, and various characteristics can provide rich information for the analysis of these changes. However, multiple feature extraction involves complex data processing. How to make a single feature achieve the same diagnosis effect as multiple features do is worth of study. Kernel ridge regression (KRR) is a kind of machine learning method, which shows faster learning speed and generalization ability in classification tasks. In order to knowledge transfer, we use privileged information (PI) to transfer information of multiple types of feature to single feature. This allows only one feature type to be used during the test stage. In the process of feature fusion, we need to consider all the samples' attribution making the classifier better. In this work, we propose a multi-kernel KRR+ framework based on self-paced learning to analyze the changes of the brain structure in patients with different blood pressure levels. Specifically, one kind of a feature is taken as main feature, and other features are input into the multi-kernel KRR as PI. These two inputs are fed into the final KRR classifier together. In addition, a self-paced learning method is introduced into sample selecting to avoid training the classifier using samples with a large loss value firstly, which improves the generalization performance of the classifier. Experimental results show that the proposed method can make full use of the information of various features and achieve better classification performance. This shows self-paced learning based KRR can help analyze brain structure of patients with different blood pressure levels. The discriminative features may help clinicians to make judgments of hypertension degrees on brain MRI images.

Optogenetics in taste research: A decade of enlightenment.

The electrophysiological function of the tongue involves complicated activities in taste sense, producing the perceptions of salty, sweet, bitter, and sour. However, therapies and prevention of taste loss arising from dysfunction in electrophysiological activity require further fundamental research. Optogenetics has revolutionized neuroscience and brought the study of sensory system to a higher level in taste. The year 2022 marks a decade of developments of optogenetics in taste since this technology was adopted from neuroscience and applied to the taste research. This review summarizes a decade of advances that define near-term translation with optogenetic tools, and newly-discovered mechanisms with the applications of these tools. The main limitations and opportunities for optogenetics in taste research are also discussed.

Effectiveness and safety of intracardiac electrocardiogram guidance for epicutaneo-cava catheters via the lower extremity in preterm infants: a retrospective study.

INTRODUCTION: In recent years, intracardiac electrocardiogram (IC-ECG) technology has been widely used for epicutaneo-cava catheter (ECC) placement and has shown many potential advantages. However, evidence about the quantitative changes, effectiveness, and safety of IC-ECG for lower extremity ECC is sparse. This study aimed to explore the quantitative changes in IC-ECG for lower extremity ECC and determine its effectiveness and safety. METHODS: A retrospective study was conducted on 303 premature infants who underwent successful IC-ECG-guided lower extremity ECC placement between January 2019 and December 2021. All patients underwent chest X-ray postoperatively to verify the position of the catheter tip. The amplitudes of the surface electrocardiogram and IC-ECG QRS waves and the difference between the two amplitudes were measured. The effectiveness (matching rate between IC-ECG and chest X-ray) and safety (incidence of catheter-related complications) of IC-ECG for lower extremity ECC were evaluated. RESULTS: The matching rate between IC-ECG and chest X-ray was 95.0%. When the catheter tip was optimally positioned, the QRS amplitude of the IC-ECG was 0.85 ± 0.56 mv higher than that of the surface electrocardiogram. The overall incidence of catheter-related complications was 10.6%. The actual ECC insertion length was associated with a noticeably increased risk of catheter-related complications. CONCLUSIONS: This study suggests that IC-ECG is an effective and safe method by observing the dynamic changes in both QRS complexes and P wave to locate the tip of lower extremity ECC in preterm infants. Our findings would facilitate the application of IC-ECG for ECC localization.

Evaluation of the in vitro performance of generic and original adapalene gel.

OBJECTIVE: The aim was to evaluate the difference of the in vitro behavior between the commercially available generic adapalene gel and original product with Topical Classification System (TCS), and to analyze the effect of changes of excipients on the release behavior. SIGNIFICANCE: Establishing in vitro performance assays to understand the impact of formulation variables on the critical quality attributes (CQA) is critical for the quality assessment of semi-solid generic drug. METHODS: In vitro release (IVR), in vitro permeation (IVP), viscosity, and pH measurement methods for adapalene gels were established and validated. The differences between generic adapalene gel from 7 companies and original products were evaluated by correlation analysis (CA) and principal component analysis (PCA), and the relationship among 4 parameters was elucidated. The effect of excipients on the above variables was examined by univariate tests. RESULTS: There were some differences between the gels of 5 of the 7 imitation enterprises and reference listed drug (RLD). There were varying degrees of correlation between viscosity, pH, the adapalene amount retained in skin and release rate. The result validated the key role of IVR, and identified that pH value, type of suspending agent, the amount of carbomer, etc. had certain effects on the release rate. CONCLUSIONS: The factors mentioned above should be considered when developing and manufacturing generic adapalene gels, and the application of TCS in the evaluation of generic topical drugs was advanced. Additionally, our research revealed some discrepancies from USP<1724>, which could be valuable information for the revision.

Effectiveness of a novel traction device in endoscopic submucosal dissection for colorectal lesions.

BACKGROUND: Among all types of superficial gastrointestinal (GI) neoplasms, colorectal lesions are recognized as one of the most difficult locations to operate, due to the limited operation space, physiological bends, poor visualization of the submucosal dissection plane sheltered by colorectal crinkle wall, and the thin intestinal mucosa layer which is easy to perforation. The purpose of this prospective study is to evaluate the feasibility, efficacy, and safety of a novel endoscopic traction technique in assisting the endoscopic submucosal dissection (ESD) procedure in colorectal lesions. METHOD: A total of 117 patients with colonic lesions who underwent endoscopic treatment were enrolled between August 2020 and January 2021 at the endoscopic center of Beijing Chao-yang Hospital of Capital Medical University. Based on whether traction device was used during the operation, 60 and 57 patients were assigned to the conventional ESD group and clips and rubber band triangle traction-assisted ESD group (CRT-ESD, in which three clips and a rubber band were used to form an elastic triangular traction device), respectively. The total procedure time (TPT), submucosal dissection time (SDT), submucosal dissection speed (SDS), and rate of adverse events of the two groups were analyzed. RESULTS: After excluding patients who did not undergo treatment (conventional ESD, 1; CRT-ESD, 4), 112 patients were included in the study (conventional ESD, 59; CRT-ESD, 53). The baseline characteristics of the patients were well balanced between the two groups. The TPT (58.71 ± 26.22 min vs 33.58 ± 9.88 min, p < 0.001) and SDT (49.24 ± 23.75 min vs 26.34 ± 8.75 min, p < 0.001) were significantly different between the conventional ESD group and CRT-ESD group. The CRT-ESD group had significantly higher SDS than that of the traditional ESD group (0.54 ± 0.42 cm2/min vs 0.89 ± 0.40 cm2/min, p < 0.001). There were 4 (6.8%) cases of perforation in the traditional ESD group, and no perforation occurred in traction-assisted ESD. CONCLUSIONS: Compared with traditional ESD, CRT-ESD with clip and rubber band is both safer and more effective in the treatment of colorectal lesions.

Automated software-assisted diagnosis of esophageal squamous cell neoplasia using high-resolution microendoscopy.

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is an optical biopsy technology that provides subcellular imaging of esophageal mucosa but requires expert interpretation of these histopathology-like images. We compared endoscopists with an automated software algorithm for detection of esophageal squamous cell neoplasia (ESCN) and evaluated the endoscopists' accuracy with and without input from the software algorithm. METHODS: Thirteen endoscopists (6 experts, 7 novices) were trained and tested on 218 post-hoc HRME images from 130 consecutive patients undergoing ESCN screening/surveillance. The automated software algorithm interpreted all images as neoplastic (high-grade dysplasia, ESCN) or non-neoplastic. All endoscopists provided their interpretation (neoplastic or non-neoplastic) and confidence level (high or low) without and with knowledge of the software overlay highlighting abnormal nuclei and software interpretation. The criterion standard was histopathology consensus diagnosis by 2 pathologists. RESULTS: The endoscopists had a higher mean sensitivity (84.3%, standard deviation [SD] 8.0% vs 76.3%, P = .004), lower specificity (75.0%, SD 5.2% vs 85.3%, P < .001) but no significant difference in accuracy (81.1%, SD 5.2% vs 79.4%, P = .26) of ESCN detection compared with the automated software algorithm. With knowledge of the software algorithm, the specificity of the endoscopists increased significantly (75.0% to 80.1%, P = .002) but not the sensitivity (84.3% to 84.8%, P = .75) or accuracy (81.1% to 83.1%, P = .13). The increase in specificity was among novices (P = .008) but not experts (P = .11). CONCLUSIONS: The software algorithm had lower sensitivity but higher specificity for ESCN detection than endoscopists. Using computer-assisted diagnosis, the endoscopists maintained high sensitivity while increasing their specificity and accuracy compared with their initial diagnosis. Automated HRME interpretation would facilitate widespread usage in resource-poor areas where this portable, low-cost technology is needed.

Risk factors for complications after endoscopic treatment in Chinese patients with early esophageal cancer and precancerous lesions.

BACKGROUND: This study aimed to analyze the risk factors for complications after endoscopic treatment of early esophageal cancer and precancerous lesions and provides evidence for developing preventive measures against these complications. METHODS: The clinical data of patients with early esophageal cancer and precancerous lesions treated in the Department of Endoscopy, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College from January 2009 to December 2015 were analyzed. The risk factors related to delayed bleeding, perforation, and stenosis were assessed. RESULTS: Of 459 patients, 15 (3.3%) had delayed bleeding, 16 (3.5%) had perforation, and 82 (17.9%) had stenosis. Conservative treatment was performed for patients with bleeding and perforation, and endoscopic dilation was performed to relieve stenosis. The independent risk factors for delayed bleeding were lesion size (OR = 1.51, P = 0.020), circumferential diameter [odds ratio (OR) = 1.24, P = 0.037]. The kind of operation method [endoscopic submucosal dissection (ESD)/cap-based endoscopic resection (EMR-Cap): OR = 15.38, P = 0.013) was the independent risk factor for perforation. The independent predictors of stenosis were circumferential diameter (OR = 1.58, P < 0.001), lesion in the neck (OR = 0.12, P = 0.003), and surgical time (OR = 1.02, P = 0.007). CONCLUSION: Few complications occur after the endoscopic treatment of early esophageal cancer and precancerous lesions which can be treated by endoscopic and conservative medical therapies. Strict operational training is required for ESD treatment.

Integrating Fluorinated Polymer and Manganese-Layered Double Hydroxide Nanoparticles as pH-activated 19 F MRI Agents for Specific and Sensitive Detection of Breast Cancer.

19 F magnetic resonance imaging (19 F MRI) agents capable of being activated upon interactions with cancer triggers are attracting increasing attention, although challenges still remain for precise and specific detection of cancer tissues. In this study, a novel hybrid 19 F MRI agent for pH-sensitive detection of breast cancer tissues is reported, a composite system designed by conjugating a perfluoropolyether onto the surface of manganese-incorporated layered double hydroxide (Mn-LDH@PFPE) nanoparticles. The 19 F NMR/MRI signals from aqueous solutions of Mn-LDH@PFPE nanoparticles are quenched at pH 7.4, but "turned on" following a reduction in pH to below 6.5. This is due to partial dissolution of Mn2+ from the Mn-LDH nanoparticles and subsequent reduction in the effect of paramagnetic relaxation. Significantly, in vivo experiments reveal that an intense 19 F MR signal can be detected only in the breast tumor tissue after intravenous injection of Mn-LDH@PFPE nanoparticles due to such a specific activation. Thus pH-activated Mn-LDH@PFPE nanoparticles are a potential "smart" 19 F MRI agent for precise and specific detection of cancer diseases.

Durability of radiofrequency ablation for treatment of esophageal squamous cell neoplasia: 5-year follow-up of a treated cohort in China.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is an accepted treatment for flat Barrett's neoplasia. Less is known about RFA for esophageal squamous cell neoplasia (ESCN). Our group has reported several prospective studies of RFA for ESCN in China with promising results through 12 months of follow-up. In this cohort study we aimed to evaluate longer term outcomes after RFA for ESCN. METHODS: Patients with flat unstained lesions (USLs) on Lugol's endoscopy containing moderate-/high-grade intraepithelial neoplasia (MGIN/HGIN) or mucosal cancer were treated with RFA every 3 months until complete remission (CR; no MGIN or a worse histologic grade). Patients with CR at 12 months (CR12) were included for follow-up and underwent annual Lugol's endoscopy with biopsy sampling and re-RFA for flat USLs. The clinical course of patients with persistent ESCN at 12 months (treatment failures) is also reported. RESULTS: Among the 78 patients in CR12, 67 (86%) had sustained CR during a median of 48 months (interquartile range, 48-48) of follow-up and 5 endoscopies (interquartile range, 4-6). Recurrence occurred in 7 of 78 patients (9%; MGIN, n = 6; HGIN, n = 1); all lesions were managed with RFA. Four other patients (5%) had progression (to HGIN, n = 1; submucosal esophageal squamous cell carcinoma, n = 3). During follow-up protocol violations occurred in 46 of 78 patients (59%). Of the 12 treatment failures, progression occurred in 6. Overall, 2 patients developed subepithelial disease that was not visible after Lugol's endoscopy. Based on post-hoc analysis, the pink-color sign at baseline (a pink color change after Lugol's endoscopy) significantly predicted failure after RFA. CONCLUSIONS: RFA is relatively easy to apply and can efficiently treat large areas with ESCN. Despite protocol violations that may have interfered with the efficacy of RFA in 59% of patients, most patients with CR12 had sustained CR during follow-up. However, some patients progressed to advanced disease and 2 developed subepithelial disease, not visible after Lugol's endoscopy. Based on currently available data, we advise the restriction of the use of RFA for flat MGIN and HGIN without the pink-color sign on Lugol's chromoendoscopy. (Clinical trial registration number: NCT02047305.).

Analyzing brain structural differences associated with categories of blood pressure in adults using empirical kernel mapping-based kernel ELM.

BACKGROUND: Hypertension increases the risk of angiocardiopathy and cognitive disorder. Blood pressure has four categories: normal, elevated, hypertension stage 1 and hypertension stage 2. The quantitative analysis of hypertension helps determine disease status, prognosis assessment, guidance and management, but is not well studied in the framework of machine learning. METHODS: We proposed empirical kernel mapping-based kernel extreme learning machine plus (EKM-KELM+) classifier to discriminate different blood pressure grades in adults from structural brain MR images. ELM+ is the extended version of ELM, which integrates the additional privileged information about training samples in ELM to help train a more effective classifier. In this work, we extracted gray matter volume (GMV), white matter volume, cerebrospinal fluid volume, cortical surface area, cortical thickness from structural brain MR images, and constructed brain network features based on thickness. After feature selection and EKM, the enhanced features are obtained. Then, we select one feature type as the main feature to feed into KELM+, and the rest of the feature types are PI to assist the main feature to train 5 KELM+ classifiers. Finally, the 5 KELM+ classifiers are ensemble to predict classification result in the test stage, while PI is not used during testing. RESULTS: We evaluated the performance of the proposed EKM-KELM+ method using four grades of hypertension data (73 samples for each grade). The experimental results show that the GMV performs observably better than any other feature types with a comparatively higher classification accuracy of 77.37% (Grade 1 vs. Grade 2), 93.19% (Grade 1 vs. Grade 3), and 95.15% (Grade 1 vs. Grade 4). The most discriminative brain regions found using our method are olfactory, orbitofrontal cortex (inferior), supplementary motor area, etc. CONCLUSIONS: Using region of interest features and brain network features, EKM-KELM+ is proposed to study the most discriminative regions that have obvious structural changes in different blood pressure grades. The discriminative features that are selected using our method are consistent with the existing neuroimaging studies. Moreover, our study provides a potential approach to take effective interventions in the early period, when the blood pressure makes minor impacts on the brain structure and function.

A tablet-interfaced high-resolution microendoscope with automated image interpretation for real-time evaluation of esophageal squamous cell neoplasia.

BACKGROUND AND AIMS: In recent years high-resolution microendoscopy (HRME) has shown potential to improve screening for esophageal squamous cell neoplasia. Furthering its utility in a clinical setting, especially in lower-resource settings, could be accomplished by reducing the size and cost of the system as well as incorporating the ability of real-time, objective feedback. This article describes a tablet-interfaced HRME with fully automated, real-time image analysis. METHODS: The performance of the tablet-interfaced HRME was assessed by acquiring images from the oral mucosa in a normal volunteer. An automated, real-time analysis algorithm was developed and evaluated using training, test, and validation images from a previous in vivo study of 177 patients referred for screening or surveillance endoscopy in China. The algorithm was then implemented in a tablet HRME that was used to obtain and analyze images from esophageal tissue in 3 patients. Images were displayed alongside the probability that the imaged region was neoplastic. RESULTS: The tablet-interfaced HRME demonstrated comparable imaging performance at a lower cost compared with first-generation laptop-interfaced HRME systems. In a post-hoc quantitative analysis, the algorithm identified neoplasia with a sensitivity and specificity of 95% and 91%, respectively, in the validation set compared with 84% and 95% achieved in the original study. CONCLUSIONS: The tablet-based HRME is a low-cost tool that provides quantitative diagnostic information to the endoscopist in real time. This could be especially beneficial in lower-resource settings for operators with less experience interpreting HRME images.

[Clinical characteristics of multiple primary cancer associated with esophageal squamous carcinoma].

OBJECTIVE: To examine the characteristics of esophageal squamous cancers with multiple primary cancers in another organ. METHODS: Between January 2012 and December 2014, 3 104 patients with esophageal squamous cell carcinoma treated in Cancer Institute and Hospital, Chinese Academy of Medical Sciences, were reviewed for the presence of an additional primary cancer retrospectively. The patients were divided into two groups according to whether they had multiple primary cancer. RESULTS: Totally 369 (11.9%) patients were found multiple primary cancer in the other organs. Among these patients, 72.4% was found synchronously, another primary cancer was found in the head and neck region in 211 (6.8%), in the stomach in 140 (4.2%), and in the lung, colon, breast, and other locations in the remaining patients. Of the 211 patients with another primary cancer in the head and neck region, 156 (73.2%) had hypopharyngeal cancer. Furthermore, the incidence of intraesophageal multiple cancerous lesion in the patients with primary cancer in the head and neck region was significantly higher than that in those whose other primary cancers were gastric cancer or in those with non-multiple primary cancer (P<0.01). CONCLUSION: There is a high incidence of multiple primary cancers in patients with esophageal squamous carcinoma, mostly found synchronously. The leading multiple primary cancers were head and neck cancer and stomach cancer. Intraesophageal multiple cancerous lesion is an indicator for a second primary cancer in head and neck. A better knowledge of the relationships between esophageal carcinoma and cancers in other organs may lead to earlier detection of other primary cancers and improved therapeutic results.

[Effects of enteral nutrition starting time on digestive function and growth rate in very low birth weight infants].

OBJECTIVE: To study the appropriate time of starting enteral nutrition and observe the effects of different enteral nutrition starting times on the digestive function, growth rate, and nosocomial infection rate in very low birth weight infants (VLBWI). METHODS: All the VLBWI admitted to the neonatal intensive care unit between February and December, 2012 were selected. Depending on different times of starting enteral nutrition, these infants were divided into three groups: ≤ 3 days (n=116), 4-6 days (n=36), and ≥ 7 days (n=26). The effects of different enteral nutrition starting times on digestive function, growth rate and nosocomial infection rate were analyzed. RESULTS: The ≤ 3 days group had significantly higher milk intake than the other two groups at one week after birth; the ≤ 3 days and 4-6 days group had significantly higher milk intake than the ≥ 7 days group at two and three weeks after birth. The growth rate showed no significant differences between the three groups. The ≤ 3 days group had a significantly shorter time of central venous catheterization than the other two groups, and the ≥ 7 days group had a significantly longer time to full enteral feeding than the other two groups. The nosocomial infection rate of the ≤ 3 days group (13.8%) was significantly lower than that of the ≥ 7 days group (46.2%). CONCLUSIONS: For VLBWI, the time of starting enteral nutrition has no impact on growth rate, but starting enteral nutrition early can promote the development of gastrointestinal function, increase milk intake, shorten the time to full enteral feeding, reduce the time of central venous catheterization, and significantly reduce nosocomial infection rate.

Effects of Telemedicine on Informal Caregivers of Patients in Palliative Care: Systematic Review and Meta-Analysis.

Background: Telemedicine technology is a rapidly developing field that shows immense potential for improving medical services. In palliative care, informal caregivers assume the primary responsibility in patient care and often face challenges such as increased physical and mental stress and declining health. In such cases, telemedicine interventions can provide support and improve their health outcomes. However, research findings regarding the use of telemedicine among informal caregivers are controversial, and the efficacy of telemedicine remains unclear. Objective: This study aimed to evaluate the impacts of telemedicine on the burden, anxiety, depression, and quality of life of informal caregivers of patients in palliative care. Methods: A systematic literature search was conducted using the PubMed, Embase, Web of Science, CENTRAL, PsycINFO, CINAHL Plus with Full Text, CBM, CNKI, WanFang, and VIP databases to identify relevant randomized controlled trials published from inception to March 2023. Two authors independently screened the studies and extracted the relevant information. The methodological quality of the included studies was assessed using the Cochrane risk-of-bias tool. Intervention effects were estimated and sensitivity analysis was conducted using Review Manager 5.4, whereas 95% prediction intervals (PIs) were calculated using R (version 4.3.2) and RStudio. Results: A total of 9 randomized controlled trials were included in this study. The meta-analysis indicated that telemedicine has reduced the caregiving burden (standardized mean differences [SMD] -0.49, 95% CI -0.72 to -0.27; P<.001; 95% PI -0.86 to -0.13) and anxiety (SMD -0.23, 95% CI -0.40 to -0.06; P=.009; 95% PI -0.98 to 0.39) of informal caregivers; however, it did not affect depression (SMD -0.21, 95% CI -0.47 to 0.05; P=.11; 95% PI -0.94 to 0.51) or quality of life (SMD 0.35, 95% CI -0.20 to 0.89; P=.21; 95% PI -2.15 to 2.85). Conclusions: Although telemedicine can alleviate the caregiving burden and anxiety of informal caregivers, it does not significantly reduce depression or improve their quality of life. Further high-quality, large-sample studies are needed to validate the effects of telemedicine. Furthermore, personalized intervention programs based on theoretical foundations are required to support caregivers.

PhotoPyro-Induced cGAS-STING Pathway Activation Enhanced Anti-Melanoma Immunotherapy via a Manganese-Coordinated Nanomedicine.

Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti-melanoma immunotherapy based on a manganese-coordinated nanomedicine is provided. Supplemented with photoirradiation, photon-mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon-controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation-triggered double-stranded DNA generation in the cytosol would activate the Mn2+ -sensitized cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro-induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage-associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation-triggered PhotoPyro and cGAS-STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.

Cuproptotic nanoinducer-driven proteotoxic stress potentiates cancer immunotherapy by activating the mtDNA-cGAS-STING signaling.

Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA-cGAS-STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu+. Cu+ thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS-STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

Dual-Epigenetically Relieving the MYC-Correlated Immunosuppression via an Advanced Nano-Radiosensitizer Potentiates Cancer Immuno-Radiotherapy.

Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.

Klippel-Trenaunay syndrome and pregnancy: A Case-Report.

Klippel-Trenaunay Syndrome is a benign disease with a low incidence rate. Pregnant women with KTS may be at increased risk of thrombosis and coagulopathy due to normal hemodynamic changes during pregnancy. The choice of delivery route for KTS pregnant woman needs rigorous evaluation. This study reported a case of successful delivery by oxytocin combined with balloon catheter induction for the first time, providing more options for KTS pregnant woman. At the same time, this study reported a successful case of labor induced by oxytocin combined with balloon catheter for the first time, which further explored the obstetric management of pregnant women with KTS and provided them with more delivery options.

Metal-Phenolic Nanomedicines Regulate T-Cell Antitumor Function for Sono-Metabolic Cancer Therapy.

Cancer cells outcompete tumor-infiltrating T lymphocytes (TILs) for glucose uptake, manipulating a glucose-deprived tumor microenvironment (TME) with high accumulation of lactate, which impairs CD8+ TIL effector function, however supports the immune suppression of regulatory T (Treg) cells. Aerobic glycolysis inhibition coupled with mitochondrial dysfunction in cancer cells may reprogram TME to destabilize Treg cells and, more importantly, facilitate CD8+ T cell activation and cytotoxic killing. Here, a sono-metabolic cancer therapy via hyaluronic acid (HA)-modified metal-phenolic nanomedicine (HPP-Ca@GSK) is proposed to accomplish the aforementioned goals. Abrogating lactate dehydrogenase A (LDHA) by delivering GSK2837808A (GSK, LDHA inhibitor) successfully suppresses aerobic glycolysis in cancer cells and creates high-glucose, low-lactate conditions, satisfying the glucose nutrition required by CD8+ TILs but destabilizing Treg cells. Meanwhile, depending on ultrasound-mediated oxidative stress, more than 3-fold of calcium (from HPP-Ca@GSK) is mitochondrion-overloaded, amplifying mitochondrial dysfunction and promoting the cancer cellular release of damage-associated molecular patterns for more CD8+ T cell activation and tumor infiltration. In vitro and in vivo studies demonstrate that HPP-Ca@GSK-based sono-metabolic treatment exhibits impressive anticancer activity. Cooperating with anticytotoxic T lymphocyte-associated protein-4 antibodies for enhanced Treg cell destabilization further improves therapeutic efficacy. These findings provide a metabolic intervention strategy for cancer immunotherapy.