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HIV-1 transcript function is controlled in part by twinned transcriptional start site usage, where 5' capped RNAs beginning with a single guanosine (1G) are preferentially packaged into progeny virions as genomic RNA (gRNA) whereas those beginning with three sequential guanosines (3G) are retained in cells as mRNAs. In 3G transcripts, one of the additional guanosines base pairs with a cytosine located within a conserved 5' polyA element, resulting in formation of an extended 5' polyA structure as opposed to the hairpin structure formed in 1G RNAs. To understand how this remodeling influences overall transcript function, we applied in vitro biophysical studies with in-cell genome packaging and competitive translation assays to native and 5' polyA mutant transcripts generated with promoters that differentially produce 1G or 3G RNAs. We identified mutations that stabilize the 5' polyA hairpin structure in 3G RNAs, which promote RNA dimerization and Gag binding without sequestering the 5' cap. None of these 3G transcripts were competitively packaged, confirming that cap exposure is a dominant negative determinant of viral genome packaging. For all RNAs examined, conformations that favored 5' cap exposure were both poorly packaged and more efficiently translated than those that favored 5' cap sequestration. We propose that structural plasticity of 5' polyA and other conserved RNA elements place the 5' leader on a thermodynamic tipping point for low-energetic (~3 kcal/mol) control of global transcript structure and function., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose: This study aimed to investigate the effect of remote ischemic preconditioning (RIPC) on the healing of small intestinal anastomoses, evaluated by tensile strength and histologic wound healing on postoperative day 5., Methods: A total of 22 female pigs were randomized 1:1 into either an intervention or control group. The intervention group received 5 cycles of 3-minute ischemia followed by 3-minute reperfusion on the right forelimb. Two end-to-end anastomoses, a distal and a proximal, were created in the small intestine 30 and 60 min after RIPC, respectively. On postoperative day 5, the anastomoses were harvested and underwent a maximal anastomotic tensile strength (MATS) test (MATS 1-3) followed by histologic analyses., Results: MATS 1, when a tear became visible in the serosa, was significantly increased in the proximal anastomoses of the RIPC group compared with the control group (4.91 N vs 3.83 N; P = .005). No other significant differences were found when comparing these 2 groups., Conclusion: Our study showed no convincing results of RIPC on intestinal anastomotic healing to recommend its use in a general clinical setting. Further animal studies on RIPC's effect after relative or absolute intestinal ischemia may be recommended., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

State-of-the-art optical cavities are pivotal in pushing the envelope of laser frequency stability below 10-16. This is often achieved by extending the cavity length or cooling the system to cryogenic temperatures to reduce the thermal noise floor. In our study, we present a 30-cm-long cavity that operates at room temperature and is outfitted with crystalline coatings. The system has a predicted ultralow thermal noise floor of 4.4 × 10-17, comparable to what is observed in cryogenic silicon cavities. A 1397-nm laser is stabilized in this advanced cavity, and the stable frequency is then transferred to the clock transition in strontium optical lattice clocks via a frequency-doubling process. We have meticulously minimized and assessed the technical noise contributions through comparisons with an ultrastable reference laser that is locked to a commercially available 30-cm cavity. The frequency instability of the system is rigorously evaluated using a three-cornered-hat method. The results demonstrate that the laser frequency instability remains below 2 × 10-16 for averaging times ranging from 1 to 50 s. These findings underscore the significant potential of room-temperature cavities with crystalline coatings in high-precision metrology and pave the way for further improvements in optical lattice clocks., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

A method for the synthesis of furans bearing indoline skeletons was developed via an intramolecular palladium-catalyzed 5- exo-dig cyclization/etherification cascade of N -propargyl arylamines containing a 1,3-dicarbonyl side chain. This method realized the first capture of vinyl carbopalladiums by ketones as O -nucleophiles and showed a wide range of substrate tolerability affording trisubstituted furans in various yields. The enantioselective version for this domino process and diverse derivatizations of the reaction products were also studied.

Pathogenic bacteria have consistently posed a formidable challenge to human health, creating the critical need for effective antibacterial solutions. In response, enzyme-metal-organic framework (MOF) composites have emerged as a promising class of antibacterial agents. This study focuses on the development of an enzyme-MOF composite based on HZIF-8, incorporating the advantages of simple synthesis, ZIF-8 antibacterial properties, lysozyme hydrolysis, and high biological safety. Through a one-pot method, core-shell nanoparticles (HZIF-8) were synthesized. This structure enables efficient immobilization of lysozyme and lactoferrin within the HZIF-8, resulting in the formation of the lysozyme-lactoferrin@HZIF-8 (LYZ-LF@HZIF-8) composite. Upon exposure to light irradiation, HZIF-8 itself possessed antibacterial properties. Lysozyme initiated the degradation of bacterial peptidoglycan and lactoferrin synergistically enhanced the antibacterial effect of lysozyme. All of the above ultimately contributed to comprehensive antibacterial activity. Antibacterial assessments demonstrated the efficacy of the LYZ-LF@HZIF-8 composite, effectively eradicating Staphylococcus aureus at a cell density of 1.5 × 10 6 CFU/mL with a low dosage of 200 μg/mL and completely inactivating Escherichia coli at 400 μg/mL with the same cell density. The enzyme-MOF composite exhibited significant and durable antibacterial efficacy, with no apparent cytotoxicity in vitro, thereby unveiling expansive prospects for applications in the medical and food industries.

Objectives: This study aimed to systematically assess the methodological quality and key recommendations of the guidelines for the diagnosis and treatment of liver failure (LF), furnishing constructive insights for guideline developers and equipping clinicians with evidence-based information to facilitate informed decision-making., Data Sources: Electronic databases and manual searches from January 2011 to August 2023., Study Selection: Two reviewers independently screened titles and abstracts, then full texts for eligibility. Fourteen guidelines were included., Data Extraction and Synthesis: Two reviewers extracted data and checked by two others. Methodological quality of the guidelines was appraised using the Appraisal of Guidelines for Research and Evaluation II tool. Of the 14 guidelines, only the guidelines established by the Society of Critical Care Medicine and the American College of Gastroenterology (2023) achieved an aggregate quality score exceeding 60%, thereby meriting clinical recommendations. It emerged that there remains ample room for enhancement in the quality of the guidelines, particularly within the domains of stakeholder engagement, rigor, and applicability. Furthermore, an in-depth scrutiny of common recommendations and supporting evidence drawn from the 10 adult LF guidelines unveiled several key issues: controversy exists in the recommendation, the absence of supporting evidence and confusing use of evidence for recommendations, and a preference in evidence selection., Conclusions: There are high differences in methodological quality and recommendations among LF guidelines. Improving these existing problems and controversies will benefit existing clinical practice and will be an effective way for developers to upgrade the guidelines., Competing Interests: This study was supported by the National Natural Science Foundation of China (no. 82160106) to Dr. Yang and Yunnan's Young Academic and Technical Leaders Reserve Talent Project (no. 202105AC160049) to Dr. Sun. The remaining authors have disclosed that they do not have any potential conflicts of interest, (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Developing coordination complexes (such as metal-organic frameworks, MOFs) with circularly polarized luminescence (CPL) is currently attracting tremendous attention and remains a significant challenge in achieving MOF with circularly polarized afterglow. Herein, MOFs-based circularly polarized afterglow is first reported by combining the chiral induction approach and tuning the afterglow times by using the auxiliary ligands regulation strategy. The obtained chiral R/S-ZnIDC, R/S-ZnIDC(bpy), and R/S-ZnIDC(bpe)(IDC = 1H-Imidazole-4,5-dicarboxylate, bpy = 4,4'-Bipyridine, bpe = trans-1,2-Bis(4-pyridyl) ethylene) containing a similar structure unit display different afterglow times with 3, 1, and <0.1 s respectively which attribute to that the longer auxiliary ligand hinders the energy transfer through the hydrogen bonding. The obtained chiral complexes reveal a strong chiral signal, obvious photoluminescence afterglow feature, and strong CPL performance (g lum up to 3.7 × 10 -2 ). Furthermore, the photo-curing 3D printing method is first proposed to prepare various chiral MOFs based monoliths from 2D patterns to 3D scaffolds for anti-counterfeiting and information encryption applications. This work not only develops chiral complexes monoliths by photo-curing 3D printing technique but opens a new strategy to achieve tunable CPL afterglow in optical applications., (© 2024 Wiley‐VCH GmbH.)

Traditionally, pharmacological mammalian/mechanistic targets of rapamycin (mTOR) kinase inhibitors have been used during transplantation and tumor treatment. Emerging pre-clinical evidence from the last decade displayed the surprising effectiveness of mTOR inhibitors in ameliorating Alzheimer's Disease (AD), a common neurodegenerative disorder characterized by progressive cognitive function decline and memory loss. Research shows mTOR activation as an early event in AD development, and inhibiting mTOR may promote the resolution of many hallmarks of Alzheimer's. Aberrant protein aggregation, including amyloid-beta (Aβ) deposition and tau filaments, and cognitive defects, are reversed upon mTOR inhibition. A closer inspection of the evidence highlighted a temporal dependence and a hallmark-specific nature of such beneficial effects. Time of administration relative to disease progression, and a maintenance of a functional lysosomal system, could modulate its effectiveness. Moreover, mTOR inhibition also exerts distinct effects between neurons, glial cells, and endothelial cells. Different pharmacological properties of the inhibitors also produce different effects based on different blood-brain barrier (BBB) entry capacities and mTOR inhibition sites. This questions the effectiveness of mTOR inhibition as a viable AD intervention strategy. In this review, we first summarize the different mTOR inhibitors available and their characteristics. We then comprehensively update and discuss the pre-clinical results of mTOR inhibition to resolve many of the hallmarks of AD. Key pathologies discussed include Aβ deposition, tauopathies, aberrant neuroinflammation, and neurovascular system breakdowns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Zheng, Han, Chen and Mao.)

Towards realizing the future quantum internet 1,2 , a pivotal milestone entails the transition from two-node proof-of-principle experiments conducted in laboratories to comprehensive multi-node set-ups on large scales. Here we report the creation of memory-memory entanglement in a multi-node quantum network over a metropolitan area. We use three independent memory nodes, each of which is equipped with an atomic ensemble quantum memory 3 that has telecom conversion, together with a photonic server where detection of a single photon heralds the success of entanglement generation. The memory nodes are maximally separated apart for 12.5 kilometres. We actively stabilize the phase variance owing to fibre links and control lasers. We demonstrate concurrent entanglement generation between any two memory nodes. The memory lifetime is longer than the round-trip communication time. Our work provides a metropolitan-scale testbed for the evaluation and exploration of multi-node quantum network protocols and starts a stage of quantum internet research., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yi-Long Wu reports grants and personal fees from AstraZeneca, BMS, and Pfizer; and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, and Roche, outside the submitted work. Qing Zhou reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi outside the submitted work. Wen-Zhao Zhong received speech honoraria from AstraZeneca, Roche, Eli Lilly, and Pfizer, outside the submitted work. The other authors have no competing interest to declare., (Copyright © 2023 Science China Press. Published by Elsevier B.V. All rights reserved.)

Aim: To compare the surgical outcomes of glaucoma drainage device implantation (GDI) and trans-scleral neodymium:YAG cyclophotocoagulation (CPC) in the management of refractory glaucoma after Descemet-stripping automated endothelial keratoplasty (DSAEK)., Methods: This retrospective study on observational case series enrolled 29 patients who underwent DSAEK and posterior anti-glaucoma surgery (15 with GDI and 14 with CPC). The main outcome measures were intraocular pressure (IOP), glaucoma surgery success rate (defined as IOP of 6-21 mm Hg without additional anti-glaucoma operation), number of glaucoma medications, endothelial graft status, and best-corrected visual acuity (BCVA)., Results: The mean follow-up time was 34.1 and 21.0mo for DSAEK or glaucoma surgeries, both for the GDI and CPC groups. Both groups showed significant IOP reduction after glaucoma surgery. The GDI group presented a significantly higher success rate in IOP control than the CPC group (60% vs 21.4%, P =0.03). Both procedures significantly decreased the number of glaucoma medications ( P =0.03). Forty percent and 57% of cases in the GDI and the CPC group, respectively, experienced endothelial graft failure during follow-up ( P =0.36). Significantly worse BCVA after surgery was observed in the CPC group but not in the GDI group., Conclusion: Both GDI and CPC significantly decrease IOP in eyes with glaucoma after DSAEK. GDI is preferable to CPC in refractory glaucoma cases after DSAEK, as it manifests a significantly higher success rate for IOP control, similar endothelial graft failure rate, and relatively preserves BCVA than CPC., Competing Interests: Conflicts of Interest: Wang MS, None; Dong XC, None; Zheng MY, None; Fan X, None; Xiao GG, None; Hong J, None; Wu LL, None., (International Journal of Ophthalmology Press.)

In the process of preparing presonalized concentrated watered pills, the decoction needs to be concentrated by heat and mixed with medicinal slices or powder to prepare a wet mass. However, some of the traditional Chinese medicine(TCM) components are easily decomposed or transformed by heat. In order to optimize the preparation process of presonalized TCM concentrated watered pills and reduce the loss of heat-unstable components in prescriptions, this study uses five compound TCM prescriptions containing heat-unstable components as model prescriptions, namely the Linggui Zhugan Formula, Xiaochengqi Formula, Sanpian Formula, Xiaoer Qixing Formula, and Xiaoyao Formula. Based on the two kinds of preparation process of presonalized concentrated watered pills previously established by our research group, whole extract concentrated watered pills and concentrated watered pills without excipients are prepared, respectively. Characteristic maps are measured and compared with those of the corresponding decoction. The results show that the characteristic maps of the concentrated watered pills without excipients of the five model prescriptions are very close to those of the decoction, and the number of characteristic peaks and peak areas are higher than those of whole extract concentrated watered pills. In addition, the peak area of some peaks is higher than that of the corresponding decoction. Thus, it is recommended to select the preparation process of prescription-based concentrated watered pills without excipients based on the &quot;unification of medicines and excipients&quot; to preserve those heat-unstable components more effectively when the prescription contains a heat-unstable component of TCM. This study provides a basis for the subsequent reasonable development and application of presonalized TCM pills.

This study aims to optimize the composite excipients suitable for the preparation of concentrated water pills of personalized traditional Chinese medicine prescriptions by the extruding-rounding method and investigate the roles of each excipient in the preparation process. The fiber materials and powder materials were taken as the standard materials suitable as excipients in the preparation of personalized concentrated water pills without excipient. Water absorption properties and torque rheology were used as indicators for selecting the materials of composite excipients. The ratio of composite excipients was optimized by D-optimal mixture design. Moreover, to demonstrate the universal applicability of the optimal composite excipients, this study selected three traditional Chinese medicine prescriptions with low, medium, and high extraction rates to verify the optimal ratio. Finally, the effects of each selected excipient on the molding of personalized concentrated water pills were investigated with the four parameters of the pill molding quality as indicators. The optimized composite excipients were dextrin∶microcrystalline cellulose(MCC)∶low-substituted hydroxypropyl cellulose(L-HPC) at a ratio of 1∶2∶4. The composite excipients were used for the preparation of personalized concentrated water pills with stable process, good quality, and a wide range of application. Dextrin acted as a diluent and accelerated the speed of extruding. MCC mainly served as an adhesive, increasing the cohesion and viscosity of the pills. L-HPC as a water absorbent and disintegrating agent can absorb and hold the water of the concentrate and has a strong disintegration effect.

In recent years, as people's living standards continue to improve, and the pace of life accelerates dramatically, the demand and quality of traditional Chinese medicine(TCM) services from patients continue to rise. As an essential supplement to the existing forms of TCM application, such as Chinese patent medicine, decoction, and formulated granules, presonalized TCM preparations is facing an increasing market demand. Currently, manual and semi-mechanized production are the primary production ways in presonalized TCM preparations. However, the production process control level is low, and digitalization and informatization need to be improved, which restricts the automated and intelligent development of presonalized TCM preparations. Presonalized TCM preparations faces a significant opportunity and challenge in integrating with intelligent manufacturing through research and development of intelligent equipment and core technology. This paper overviews the connotation and characteristics of intelligent manufacturing and summarizes the application of intelligent manufacturing technologies such as &quot;Internet of things&quot; &quot;big data&quot;, and &quot;artificial intelligence&quot; in the TCM industry. Based on the innovative research and development model of &quot;intelligent classification of TCM materials, intelligent decision making of prescription and process, and online control and intelligent production&quot; of presonalized TCM preparations, the research practice and achievements from our research group in the field of intelligent manufacturing of presonalized TCM preparations are introduced. Ultimately, the paper proposes the direction for developing intelligent manufacturing of presonalized TCM preparations, which will provide a reference for the research and application of automation and intelligence of presonalized TCM preparations.

Background: The transformation of epidermal growth factor receptor ( EGFR )-mutant lung adenocarcinoma (LUAD) into small cell lung cancer (SCLC) accounts for 3-14% of the resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). At present, there is no relevant research to explore the dynamic expression of EGFR -mutant proteins and genomic evolution in EGFR -mutant transformed SCLC/neuroendocrine carcinoma (NEC)., Methods: Genetic analysis and protein level analysis by next-generation sequencing (NGS), Whole-exome sequencing (WES) and immunohistochemistry were performed to explore expression of EGFR -mutant proteins and genomic evolution in EGFR -mutant transformed SCLC. The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment. According to the subsequent treatment regimens after SCLC/NEC transformation, 35 patients were divided into chemo (n=21) and combo (n=14) groups., Results: EGFR L858R and EGFR E746-750 del protein expression by immunohistochemistry was 80.0% (4/5) and 100% (6/6), respectively (P=0.455) in initially-transformed tissues. Meanwhile, EGFR -mutant proteins were expressed in 85.7% (6/7) of dynamic rebiopsy tissues or effusion samples after the first transformation. Then, by the pathway enrichment analysis of tissue and plasma NGS, the EGFR-related pathways were still activated after SCLC/NEC transformation. Moreover, WES analysis revealed that transformed SCLC shared a common clonal origin from the baseline LUAD. The drug sensitivity of three PDOs demonstrated potent anti-cancer activity of EGFR-TKIs plus chemo, compared with chemo or TKI alone. There were significant differences in objective response rate (ORR) between the combo and chemo groups [42.9 % vs. 4.8%, P=0.010, 95% confidence interval (CI): 1.5-145.2]. Furthermore, the median post-transformation progression-free survival (pPFS) was significantly prolonged in the combo group, with 5.4 (95% CI: 3.4-7.4) versus 3.5 (95% CI: 2.7-4.3, P=0.012) months., Conclusions: EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR -mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-161/coif). YLW reports that he receives funding support for Key Lab System Project of Guangdong Science and Technology Department-Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (No. 2017B030314120). JJY reports that he receives funding support for the High-Level Hospital Construction Project (No. DFJH201809), the National Natural Science Foundation of China (No. 81972164) and the Natural Science Foundation of Guangdong Province (No. 2019A1515010931). The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration., Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR -mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts., Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively., Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR -mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option., Funding: Chinese Thoracic Oncology Group (CTONG)., Competing Interests: Prof. Yi-Long Wu reports grants and personal fees from AstraZeneca, BMS, Pfizer; and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, Roche, outside the submitted work. Prof. Qing Zhou reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. Prof. Wen-Zhao Zhong reports speech honoraria from AstraZeneca, Roche, Eli Lilly and Pfizer. Dr. Chong-Rui Xu reports grants from Hengrui Pharmaceutical and Pfizer. The other authors have no competing interests to declare., (© 2023 The Author(s).)

Colorectal cancer (CRC) is one of highly prevalent cancer. Immunotherapy with immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of treatment for many advanced cancers, but CRC still exhibits suboptimal response to immunotherapy. The gut microbiota can affect both anti-tumor and pro-tumor immune responses, and further modulate the efficacy of cancer immunotherapy, particularly in the context of therapy with ICIs. Therefore, a deeper understanding of how the gut microbiota modulates immune responses is crucial to improve the outcomes of CRC patients receiving immunotherapy and to overcome resistance in nonresponders. The present review aims to describe the relationship between the gut microbiota, CRC, and antitumor immune responses, with a particular focus on key studies and recent findings on the effect of the gut microbiota on the antitumor immune activity. We also discuss the potential mechanisms by which the gut microbiota influences host antitumor immune responses as well as the prospective role of intestinal flora in CRC treatment. Furthermore, the therapeutic potential and limitations of different modulation strategies for the gut microbiota are also discussed. These insights may facilitate to better comprehend the interplay between the gut microbiota and the antitumor immune responses of CRC patients and provide new research pathways to enhance immunotherapy efficacy and expand the patient population that could be benefited by immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Frailty, which predicts high dependency and mortality, is a major challenge for healthcare systems in nations that are rapidly aging and is receiving increasing attention. Cirrhosis is often combined with frailty, which has a significant impact on patient health outcomes. Understanding the risk factors for frailty, elucidating the mechanism of cirrhosis combined with frailty, and early recognition and slowing down the occurrence and development of frailty are of great significance for the prognosis of cirrhotic patients. This article reviews the current research status of cirrhosis combined with frailty, including the definition and risk factors, mechanism, correlation, and intervention measures, in order to improve understanding and provide assistance for strengthening early identification, management, and intervention.

To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician's therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n = 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n = 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n = 8) had no responses to physician's therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402 . RWS, clinicaltrials.gov identifier: NCT03605602 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The KRAS G12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRAS G12C -mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRAS G12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRAS G12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRAS G12C mutation. 143D selectively inhibited cell proliferation and induced G 1 -phase cell cycle arrest and apoptosis by downregulating KRAS G12C -dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (C max ) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRAS G12C -mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRAS G12C mutation., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Purpose: Rearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown., Methods: Data from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs)., Results: Patients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation., Conclusion: Selective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting., (© 2022. The Author(s).)

Due to the unclear quality of the current guidelines, users may be confused about how to diagnose and treat achalasia. The objective of this work is to systematically evaluate the methodological quality of the current guidelines for diagnosing and treating achalasia and to determine the heterogeneity among recommendations. We systematically searched literature databases to retrieve relevant guidelines for the diagnosis and treatment of achalasia. The Appraisal of Guidelines for Research and Evaluation II tool was used to evaluate the quality of the included guidelines. Key recommendations in the guidelines were extracted, and the reasons for the heterogeneity of the key recommendations between different guidelines were further analyzed. Seven guidelines on the diagnosis and treatment of achalasia are included in this study. The overall score of three guidelines exceeded 60%. The average score in domain 5 was the lowest, at 41.8%. The average scores in domain 2, domain 3, and domain 6 were also low, at 45.4%, 57.1% and 56.9%, respectively. The main recommendations and quality of evidence for different guidelines vary greatly, mainly due to the different emphases among different guidelines, the lack of systematic retrieval, or the unfairness of evidence use in some guidelines. There are considerable differences in the methodological quality of diagnosis and treatment guidelines for achalasia. Additionally, the differences in the main recommendations and evidence support among guidelines are also obvious. Guideline developers should improve the above related factors to decrease the heterogeneity, and they should further formulate or update the guidelines for the diagnosis and treatment of achalasia., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PP i ase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

BackgroundAntiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.MethodsWe undertook an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5'-leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.ResultsClones carrying proviruses with 5'-leader defects can cause persistent NSV up to approximately 103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope.ConclusionThese findings show that proviruses with 5'-leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-leader can help in understanding failure to completely suppress viremia.FundingOffice of the NIH Director and National Institute of Dental and Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases (NIAID), NIH, to the PAVE, BEAT-HIV, and DARE Martin Delaney collaboratories.

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL‑2‑dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models., Results: We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients., Conclusion: Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair. Video Abstract., (© 2023. The Author(s).)

Objective: To systematically evaluate the guidelines for the diagnosis and treatment of radioactive enteritis, compare their differences and reasons and provide some reference for updating them., Methods: This study used guidelines related to radiation enteritis by searching a database. Four independent reviewers used the AGREE II evaluation tool to evaluate the quality of the included guidelines, collate their main recommendations, and analyze the highest evidence supporting the main recommendations., Results: Six diagnostic and therapeutic guidelines for radiation enteritis were included in this study, one of which, the American Society for Gastrointestinal Endoscopy guidelines, had an overall score of over 60%, which is worthy of clinical recommendation. In the diagnosis and treatment of radioactive rectal injury, the recommendations for hemorrhagic endoscopic treatment are mature and mainly include (I) argon plasma coagulation; (II) formalin treatment; (III) bipolar electrocoagulation; (IV) heater probe; (V) radiofrequency ablation; and (VI) cryoablation., Conclusion: The methodological quality of radioactive enteritis guidelines is unequal; even in the same guidelines, different domains have a large difference. For radioactive rectal damage diagnosis, a type of endoscopic treatment recommendation is more mature, but the overall diagnosis and treatment of radioactive enteritis still lacks high-quality research evidence., (© 2023. The Author(s).)

Objectives: Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC., Methods: Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis., Results: All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P ＜ 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies., Conclusion: Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Based on network pharmacology, molecular docking, and in vitro experimental verification, this study aims to explore the effect of Albiziae Cortex-Tribuli Fructus combination on HSC-LX2 pyroptosis. Specifically, the targets of Albiziae Cortex, Tribuli Fructus, and hepatic fibrosis were retrieved from an online database and CNKI, and &quot;drug-component-target&quot; network and &quot;drug-component-target-disease&quot; network were constructed. Protein-protein interaction(PPI) network was established based on STRING. Metascape was employed for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and the mechanism of Albiziae Cortex-Tribuli Fructus combination against liver fibrosis was predicted. Molecular docking was used to verify some of the results of network pharmacology, and in vitro experiment was carried out to further verify the above conclusions. According to the results of network pharmacological analysis, 25 active components and 439 targets of Albiziae Cortex-Tribuli Fructus combination and 152 anti-liver fibrosis targets were screened out, including nucleotide-binding oligomerization domain and leucine-rich-repeat-and pyrin-domain-containing 3(NLRP3) and caspase-1. The key targets were involved in 194 KEGG pathways in which the NOD-like receptor signaling pathway topped. The binding common targets were related to pyroptosis. The results of in vitro experiment showed that the pair-containing serum reduced the proliferation rate of HSC-LX2 and the content of reactive oxygen species(ROS), interleukin-18(IL-18), and interleukin-1β(IL-1β)(P&lt;0.05). Western blot and qRT-PCR suggested that the protein and gene expression of NLRP3, caspase-1, α-smooth muscle actin(α-SMA), and gasdermin D(GSDMD) in HSC-LX2 increased after AngⅡ stimulation, and the expression decreased after the intervention of pair-containing serum(P&lt;0.05). In summary, the pair-containing serum can inhibit the classic pathway of pyroptosis, which may be the anti-liver fibrosis mechanism. This is consistent with the predicted results of network pharmacology.

Introduction: While phosphodiesterase type 5 inhibitors (PDE5is) and others are used to treat Erectile dysfunction (ED), many patients are either unresponsive or resistant to it. Stem cell therapy (SCT) is a promising alternative approach. Numerous preclinical trials have demonstrated improved erectile function in animal models using SCT, although the number of clinical trials investigating SCT for men with ED is limited. Nonetheless, findings from human clinical trials suggest that SCT may be a useful treatment option., Areas Covered: Biomedical literature, including PubMed, ClinicalTrials.gov, and European Union Clinical Trials Registry, were analyzed to summarize and synthesize information on stem cell therapy for ED in this narrative review. The achievements in preclinical and clinical evaluations are presented and critically analyzed., Expert Opinion: SCT has demonstrated some benefits in improving erectile function, while further studies are urgently needed. Such studies would provide valuable insights into the optimal use of stem cell therapy and its potential as a therapeutic option for ED. Taking advantage of different mechanisms of action involved in various regenerative therapies, combination therapies such as SCT and low-energy shock waves or platelet-rich plasma may provide a more effective therapy and warrant further research.

To evaluate the knowledge of, participation in, attitudes towards, and experiences with "doing the month" (DTM), a traditional Chinese and Vietnamese postpartum practice, at a federally qualified health center that serves predominantly Asian immigrants. DTM practices revolve around the balance between yin and yang and include practices such as the mother remaining on bed rest for as long as possible, restricting diet to certain foods, and avoiding visitors and social activities. A cross-sectional survey in Chinese, Vietnamese, and English was developed to determine the prevalence of women who have heard of and participated in DTM. 154 respondents participated. The mean age of respondents was 40.1 years. Without prompting of what DTM was, 58 (37.7%) responded that they had heard of DTM. After an explanatory paragraph, this increased to 117 (76.6%) participants. Out of 107 patients who have children, 65 (60.7%) "did the month" after giving birth. Participation rates were highest for women who identified as Chinese or Vietnamese. Likert-type scale questions showed that respondents believed DTM was stressful but enjoyable and helpful for recovery from childbirth. In conclusion, DTM is a common practice that health providers should be aware of., (© 2021. The Author(s).)

Aims: China has the largest number of adults with diabetes. Although multiple metabolic risk factors (MRFs) are implicated in the development of diabetes, it remains unclear how they progress during the development of diabetes among Chinese. We examined trajectories of multiple MRFs among Chinese and identified the critical period when drastic changes occurred during the development of diabetes., Methods: This prospective cohort study included participants since 2006-2007 in the Kailuan study. People attended biennial examinations until 2017 with additions of new participants at each examination cycle. The time when a participant first completed the examination was served as the baseline. A total of 122,659 participants without prevalent diabetes at baseline and with complete follow-up data were included. MRFs were collected via biennial physical examinations and laboratory measures. Incident diabetes cases were identified via biennial fasting glucose tests and self-reported physician-diagnosis., Results: During up to 12 years of follow-up, 14,922 incident diabetes cases were identified. Compared with participants who did not develop diabetes, those who developed diabetes had more adverse levels of most MRFs at baseline and during follow-up. Abrupt increases in multiple MRFs (including fasting glucose, surrogate insulin resistance indicators, lipids, systolic blood pressure, pulse pressure, heart rate, alanine aminotransferase, and C-reactive protein) were observed 3 years before the diagnosis of diabetes., Conclusions: We identified 3 years before diabetes diagnosis as a critical period when multiple MRFs experienced drastic changes. This would have implications for early monitoring and timely prevention for individuals who experience sudden adverse progression of multiple MRFs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Cerebral small vessel disease (CSVD) is a common syndrome in the older population, with a prevalence ranging from 5% in subjects aged 50 years to almost 100% in those aged 90 years and older. It is regarded to be a major cause of vascular cognitive impairment. Existing prevention and treatment approaches have not yet shown ideal clinical outcomes. Dengyinnaotong Capsule has shown great potential for improving cognitive function. This trial (De-CSVD trial) is designed to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive function in patients with CSVD ., Methods: This multicenter, randomized, open-label, controlled trial is planned to recruit at least 270 patients with mild cognitive impairment related to CSVD in 25 centers in China. Recruitment started on 10 May 2021 and is foreseen to end on 31 December 2022. The final follow-up of participants will be completed by the end of March 2023. Participants will be randomized in a ratio of 1:1 to the experimental group (routine basic treatment plus Dengyinnaotong Capsule) or the control group (routine basic treatment). The primary outcome is the change in the Montreal Cognitive Assessment score from baseline to week 12. Secondary outcomes are changes in Shape Trail Test, Activities of Daily Living, Geriatric Depression Scale, and Dizziness Handicap Inventory score from baseline to week 12, new vascular events, and the changes in serum level of homocysteine, high-sensitivity C-reactive protein, and D-dimer from baseline to week 4 and 12, respectively. The exploratory outcome is the changes in the Tinetti performance-oriented mobility assessment score from baseline to week 12. Safety assessment is performed by monitoring vital signs, general biochemical examinations, 12-lead electrocardiogram examinations, and incidence of cardiovascular and cerebrovascular ischemia or bleeding events. Visits will be performed at week 0 (baseline, pre-randomization), week 4, and week 12 in the treatment period (post-randomization)., Discussion: This trial is the first to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive impairment in patients with CSVD. The findings of this study might provide convincing evidence regarding the efficacy of Dengyinnaotong Capsule in patients with mild cognitive impairment related to CSVD., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100045831. Registered on 25 April 2021., (© 2022. The Author(s).)

Inhibitors targeting the antiapoptotic molecule BCL-2 have therapeutic potential for the treatment of acute myeloid leukaemia (AML); however, BCL-2 inhibitors such as venetoclax exhibit limited monotherapy efficacy in relapsed or refractory human AML. PI3Kδ/AKT signalling has been shown to be constitutively active in AML patients. Here, we demonstrate that the combination of BCL-2 and PI3Kδ inhibitors exerts synergistic antitumour effects both in vitro and in vivo in AML. Cotreatment with venetoclax and the specific PI3Kδ inhibitor idelalisib significantly enhanced antiproliferative effects and induced caspase-dependent apoptosis in a panel of AML cell lines. The synergistic effects were mechanistically based on the inactivation of AKT/4E-BP-1 signalling and the reduction of MCL-1 expression, which diminished the binding of Bim to MCL-1. Notably, compared with the parental FLT3-ITD-positive MV-4-11, the acquired FLT3 inhibitor quizartinib-resistant xenograft model carrying the F691L mutation, exhibited a markedly higher sensitivity to venetoclax. Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3Kδ may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations., Competing Interests: None., (AJCR Copyright © 2022.)

Quantum internet gives the promise of getting all quantum resources connected, and it will enable applications far beyond a localized scenario. A prototype is a network of quantum memories that are entangled and well separated. In this Letter, we report the establishment of postselected entanglement between two atomic quantum memories physically separated by 12.5 km directly. We create atom-photon entanglement in one node and send the photon to a second node for storage via electromagnetically induced transparency. We harness low-loss transmission through a field-deployed fiber of 20.5 km by making use of frequency down-conversion and up-conversion. The final memory-memory entanglement is verified to have a fidelity of 90% via retrieving to photons. Our experiment makes a significant step forward toward the realization of a practical metropolitan-scale quantum network.

Objective: To rank percentages of underrepresented residents in surgical subspecialties and understand the experience of mentees and mentors who participated in the inaugural University of California, San Francisco Urology UnderRepresented Trainees Entering Residency (UReTER) Mentorship Program for Black, Indigenous, and/or LatinX medical students applying into urology., Methods: Medical student mentees across the country were recruited via social media and email listservs. Demographic information and photos of mentors were presented on the UReTER website. Medical students could choose a mentor, and once matched, both parties were notified. A survey was emailed to all participants on Urology Match Day 2021., Result: The 2018 -2019 ACGME Databook showed underrepresented minority residents made up 7.6% of urology residents, lagging behind neurosurgery, vascular surgery, general surgery, and obstetrics and gynecology. 71 mentees and 101 mentors volunteered for the UReTER Mentorship Program (71 mentor-mentee couplets). Overall response rate was 51% [33 mentors and 32 mentees]. Of mentees who completed the survey, 16 (47%) participated in the 2021 Urology Match; 15 (94%) matched and 6 (38%) felt that UReTER helped them match., Conclusion: Feedback on this pilot program was very positive including a high match rate among those who participated. Future changes to the program include expanded student outreach, increased structure, broadened mentor network. The implementation of a low-cost program to increase underrepresented applicants into Urology has great potential to increase representation and improve the field. This program can and should be replicated in all subspecialties., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this paper, water-soluble green fluorescent carbon dots (G-CDs) were prepared using p -phenylenediamine and glutathione (GSH) as the precursors. The G-CDs exhibit excellent optical properties, and the maximum emission wavelength is located at 522 nm (under 410 nm excitation), which greatly overlaps with the absorption spectrum of AuNPs. Consequently, an effective "off-on" fluorescent sensing platform involved in G-CDs and AuNPs for detection of clenbuterol (CLB) was constructed. The fluorescence of G-CDs was strongly quenched by AuNPs due to the inner filter effect (IFE). As CLB was introduced, the quenched fluorescence intensity was recovered due to the specific interaction between the AuNPs and CLB. The recovered fluorescence intensity is linear to CLB concentration in the range of 13-270 ng mL -1 with a low detection limit of 3.75 ng mL -1 . The prepared sensor has been successfully applied for CLB detection in pork liver and could be utilized in food analysis., Competing Interests: The researcher claims no conflicts of interests., (This journal is © The Royal Society of Chemistry.)

There exists a complex relationship between liver and thyroid hormones. Liver plays an important role in the activation, inactivation, transportation, and metabolism of thyroid hormones. At the same time, thyroid hormones also affect hepatocytes activity and liver metabolism, such as lipid and bilirubin metabolism. Importantly, thyroid hormone levels often change abnormally in patients with liver cirrhosis. Therefore, studying the change of thyroid hormone levels in patients with liver cirrhosis has a certain clinical value for assessing the severity, prognosis, diagnosis and treatment. This paper reviews the research progress on the relationship between liver cirrhosis and thyroid hormone.

Objective: The California Department of Public Health investigates compliance with hospital licensure and issues an administrative penalty when there is an immediate jeopardy. Immediate jeopardies are situations in which a hospital's noncompliance of licensure requirements causes serious injury or death to patient. In this study, we critically examine immediate jeopardies between 2007 and 2017 in California., Methods: All immediate jeopardies reported between 2007 and 2017 were abstracted for hospital, location, date, details of noncompliance, and patient's health outcome., Results: Of 385 unique immediate jeopardies, 141 (36.6%) caused mortality, 120 (31.2%) caused morbidity, 96 (24.9%) led to a second surgery, 9 (2.3%) caused emotional trauma without physical trauma, and 19 (4.9%) were caught before patients were harmed. Immediate jeopardy categories included the following: surgical (34.2%), medication (18.9%), monitoring (14.2%), falls (7.8%), equipment (5.4%), procedural (5.4%), resuscitation (4.4%), suicide (3.9%), MD/RN miscommunication (3.4%), and abuse (2.3%)., Conclusions: Noncompliance to hospital licensure causes significant morbidity and mortality. Statewide hospital licensure policies should focus on enacting standardized reporting requirements of immediate jeopardies into an Internet-based form that public health officials can regularly analyze to improve hospital safety., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples., Method: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1 PE-sDNA., Result: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy., Conclusion: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To investigate the risk factors for necrotizing enterocolitis (NEC) in preterm infants, and to establish a scoring model that can predict the development and guide the prevention of NEC., Methods: A retrospective analysis was performed on the medical data of preterm infants who were admitted to the Department of Neonatology,Bethune First Hospital of Jilin University, from January 2011 to December 2020. These infants were divided into two groups: NEC (298 infants with Bell II stage or above) and non-NEC (300 infants). Univariate and multivariate analyses were performed to identify the factors influencing the development of NEC. A nomogram for predicting the risk of NEC was established based on the factors. The receiver operator characteristic (ROC) curve and the index of concordance (C-index) were used to evaluate the predictive performance of the nomogram., Results: The multivariate logistic regression analysis showed that grade ≥2 intracranial hemorrhage, peripherally inserted central catheterization, breast milk fortifier, transfusion of red cell suspension, hematocrit >49.65%, mean corpuscular volume >114.35 fL, and mean platelet volume >10.95 fL were independent risk factors for NEC ( P <0.05), while the use of pulmonary surfactant, the use of probiotics, and the platelet distribution width >11.8 fL were protective factors against NEC ( P <0.05). The nomogram showed good accuracy in predicting the risk of NEC, with a bootstrap-corrected C-index of 0.844. The nomogram had an optimal cutoff value of 171.02 in predicting the presence or absence of NEC, with a sensitivity of 74.7% and a specificity of 80.5%., Conclusions: The prediction nomogram for the risk of NEC has a certain clinical value in early prediction, targeted prevention, and early intervention of NEC.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-β stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics., (© 2021 AlphaMed Press.)

Background: Tumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvironment. Turning the TAMs against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically "cold" tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells' immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype., Results: Nano-DOX were first shown to stimulate the tumor cells and the TAMs to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAMs. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1's action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAMs both by blocking Nano-DOX-induced PD-L1 in the TAMs and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAMs with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX's action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner., Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAMs to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAMs, achieves enhanced activation of TAM-mediated anti-tumor response., (© 2021. The Author(s).)

Chlorin e6 (Ce6) is a promising photosensitizer for tumor photodynamic therapy (PDT). However, the efficacy of Ce6 PDT is limited by Ce6's poor water solubility, rapid blood clearance, and inadequate accumulation in the tumor tissue. This problem is tackled in this work, wherein functionalized superparamagnetic iron oxide nanoparticles (IO-NPs) were used as carriers to deliver Ce6 to melanoma. The IO-NPs were coated with polyglycerol (PG) to afford good aqueous solubility. The chemotherapeutic agent doxorubicin (DOX) was attached to the PG coating via the hydrazone bond to afford affinity to the cell membrane and thereby promote the cell uptake. The hydrophobic nature of DOX also induced the aggregation of IO-NPs to form nanoclusters. Ce6 was then loaded onto the IO nanoclusters through physical adsorption and coordination with surface iron atoms, yielding the final composites IO-PG-DOX-Ce6. In vitro experiments showed that IO-PG-DOX-Ce6 markedly increased Ce6 uptake in mouse melanoma cells, leading to much-enhanced photocytotoxicity characterized by intensified reactive oxygen species production, loss of viability, DNA damage, and stimulation of tumor cell immunogenicity. In vivo experiments corroborated the in vitro findings and demonstrated prolonged blood clearance of IO-PG-DOX-Ce6. Importantly, IO-PG-DOX-Ce6 markedly increased the Ce6 distribution and retention in mouse subcutaneous melanoma grafts and significantly improved the efficacy of Ce6-mediated PDT. No apparent vital organ damage was observed at the same time. In conclusion, the IO-PG-DOX NPs provide a simple and safe delivery platform for efficient tumor enrichment of Ce6, thereby enhancing antimelanoma PDT.

Doxorubicin (DOX) has been widely incorporated in various delivery forms for tareted treatment of malignant tumors such as triple-negative breast cancer (TNBC), with numerous studies reporting higher therapeutic efficacy and lower toxicity at the same time. However, little attention has been paid to whether DOX in a delivery form acts with the same actions and processes as in free form at the cellular level. This question was investigated in the present study wherein DOX conjugated with polyglycerol-coated nanodiamonds through the pH-sensitive hydrazone bond (Nano-DOX) was compared with DOX in free form on the 4T1 mouse TNBC model. We first found Nano-DOX to have a distinct intracellular distribution profile from DOX. Internalized Nano-DOX mainly stayed in the lysosomes slowly releasing DOX into the cytoplasm and then the nucleus whereas DOX displayed both nuclear and lysosomal distribution after cell uptake. Next, Nano-DOX was shown to induce endoplasmic reticulum (ER) stress without substantial DNA damage while DOX caused massive DNA damage as well as ER stress. Consequently, Nano-DOX only caused minimal activation of pro-inflammatory signaling mediated by MAPK/ERK, NF-κB and STAT3 as seen in response to DOX-inflicted DNA damage. Consistently, DOX-induced activities of ABC transporters, CXCL-1, GM-CSF and IL-6, which are tumor protective events downstream to the pro-inflammatory signaling, were also minimal in Nano-DOX-treated cancer cells. These findings are compelling proof that a chemotherapy in nano form can have distinct intracellular pharmacokinetics from its free from, which can result in altered cellular effects of the drug. Implications of these findings are discussed with an emphasis on nano-drug design, tumor pharmacology and chemoresistance., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Interferometers are widely used in imaging technologies to achieve enhanced spatial resolution, but require that the incoming photons be indistinguishable. In previous work, we built and analyzed color erasure detectors, which expand the scope of intensity interferometry to accommodate sources of different colors. Here we demonstrate experimentally how color erasure detectors can achieve improved spatial resolution in an imaging task, well beyond the diffraction limit. Utilizing two 10.9-mm-aperture telescopes and a 0.8 m baseline, we measure the distance between a 1063.6 and a 1064.4 nm source separated by 4.2 mm at a distance of 1.43 km, which surpasses the diffraction limit of a single telescope by about 40 times. Moreover, chromatic intensity interferometry allows us to recover the phase of the Fourier transform of the imaged objects-a quantity that is, in the presence of modest noise, inaccessible to conventional intensity interferometry.