Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target.

Heat shock protein 70 (HSP70) is a highly conserved protein functioning as a "molecular chaperone", which is integral to protein folding and maturation. In addition to its high expression within cells upon stressful challenges, HSP70 can be translocated to the cell membrane or released from cells in free form or within extracellular vesicles (EVs). Such trafficking of HSP70 is also present in cancer cells, as HSP70 is overexpressed in various types of patient samples across a range of common malignancies, signifying that extracellular HSP70 (eHSP70) can serve as a tumor biomarker. eHSP70 is involved in a broad range of cancer-related events, including cell proliferation and apoptosis, extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), angiogenesis, and immune response. eHSP70 can also induce cancer cell resistance to various treatments, such as chemotherapy, radiotherapy, and anti-programmed death-1 (PD-1) immunotherapy. Though the role of eHSP70 in tumors is contradictory, characterized by both pro-tumor and anti-tumor effects, eHSP70 serves as a promising target in cancer treatment. In this review, we comprehensively summarized the current knowledge about the role of eHSP70 in cancer progression and treatment resistance and discussed the feasibility of eHSP70 as a cancer biomarker and therapeutic target.

Synergistic Redox Modulation for High-Performance Nickel Oxide-Based Inverted Perovskite Solar Modules.

Nickel oxide (NiOx )-based inverted perovskite solar cells stand as promising candidates for advancing perovskite photovoltaics towards commercialization, leveraging their remarkable stability, scalability, and cost-effectiveness. However, the interfacial redox reaction between high-valence Ni4+ and perovskite, alongside the facile conversion of iodide in perovskite into I2 , significantly deteriorates the performance and reproducibility of NiOx -based perovskite photovoltaics. Here, potassium borohydride (KBH4 ) is introduced as a dual-action reductant, which effectively avoids the Ni4+ /perovskite interface reaction and mitigates the iodide-to-I2 oxidation within perovskite film. This synergistic redox modulation significantly suppresses nonradiative recombination and increases the carrier lifetime. As a result, an impressive power conversion efficiency of 24.17% for NiOx -based perovskite solar cells is achieved, and a record efficiency of 20.2% for NiOx -based perovskite solar modules fabricated under ambient conditions. Notably, when evaluated using the ISOS-L-2 standard protocol, the module retains 94% of its initial efficiency after 2000 h of continuous illumination under maximum power point at 65 °C in ambient air.

Lead-free Cs2AgBiBr6 double perovskite microcrystals for effective visible-light photocatalytic thio/selenocyanation.

Lead-free perovskite microcrystals (MCs) have been regarded as promising potential photocatalysts, owing to their high molar extinction coefficient, low economic cost, adjustable light absorption range, and ample surface-active sites. Herein, C-3 thio/selenocyanation of indoles is demonstrated in high selectivity and yield by using lead-free double perovskite Cs2AgBiBr6 MCs under visible light irradiation. Moreover, the photocatalyst can be recycled at least 5 times without a significant decrease in catalytic activity.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Integration of Network Pharmacology and Experimental Validation to Explore Jixueteng - Yinyanghuo Herb Pair Alleviate Cisplatin-Induced Myelosuppression.

Jixueteng, the vine of the bush Spatholobus suberectus Dunn., is widely used to treat irregular menstruation and arthralgia. Yinyanghuo, the aboveground part of the plant Epimedium brevicornum Maxim., has the function of warming the kidney to invigorate yang. This research aimed to investigate the effects and mechanisms of the Jixueteng and Yinyanghuo herbal pair (JYHP) on cisplatin-induced myelosuppression in a mice model. Firstly, ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) screened 15 effective compounds of JYHP decoction. Network pharmacology enriched 10 genes which may play a role by inhibiting the apoptosis of bone marrow (BM) cells. Then, a myelosuppression C57BL/6 mice model was induced by intraperitoneal (i.p.) injection of cis-Diaminodichloroplatinum (cisplatin, CDDP) and followed by the intragastric (i.g.) administration of JYHP decoction. The efficacy was evaluated by blood cell count, reticulocyte count, and histopathological analysis of bone marrow and spleen. Through the vivo experiments, we found the timing of JYHP administration affected the effect of drug administration, JYHP had a better therapeutical effect rather than a preventive effect. JYHP obviously recovered the hematopoietic function of bone marrow from the peripheral blood cell test and pathological staining. Flow cytometry data showed JYHP decreased the apoptosis rate of BM cells and the western blotting showed JYHP downregulated the cleaved Caspase-3/Caspase-3 ratios through RAS/MEK/ERK pathway. In conclusion, JYHP alleviated CDDP-induced myelosuppression by inhibiting the apoptosis of BM cells through RAS/MEK/ERK pathway and the optimal timing of JYHP administration was after CDDP administration.

Neutral nickel-catalyzed dehydrosulfonylation of unactivated allylic alcohols under mild conditions.

Allyl sulfones are important sulfur-containing compounds that have widespread applications in organic synthesis, medicinal chemistry and materials science. Herein, nickel-catalysed dehydrosulfonylation of unactivated allyl alcohols with aryl sulfonyl hydrazides without additional active agents under mild conditions was developed. A variety of functional allyl sulfones could be efficiently synthesized in the presence of air-stable Ni(acac)2 as the catalyst and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) as the ligand.

Visible-light-driven EDA complex-promoted cascade cyclization to construct 4-cyanoalkyl isoquinoline-1,3-diones.

Visible-light-induced EDA complex-promoted ring-opening of cycloketone oxime esters to synthesise various cyanoalkylated products with N-methacryloyl benzamides was developed. Various radical receptors were compatible with the current reaction system to furnish diverse heterocyclic compounds. Mechanistic analysis shows that the formation of an EDA complex was crucial to the photocatalytic strategy. Importantly, 4-cyanoalkyl isoquinoline-1,3-diones were obtained in high yields by using a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) through prolonging the reaction time, which provided a practical approach to give a variety of isoquinoline-1,3-dione derivatives.

Knowledge mapping of digital medicine in cardiovascular diseases from 2004 to 2022: A bibliometric analysis.

Objective: To review studies on digital medicine in cardiovascular diseases (CVD), discuss its development process, knowledge structure and research hotspots, and provide a perspective for researchers in this field. Methods: The relevant literature in recent 20 years (January 2004 to October 2022) were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used to demonstrate our knowledge of keywords, co-references and speculative frontiers. VOSviewer was used to chart the contributions of authors, institutions and countries and incorporates their link strength into the table. Results: A total of 5265 English articles in set timespan were included. The number of publications increased steadily annually. The United States (US) produced the highest number of publications, followed by England. Most publications were from Harvard Medicine School, followed by Massachusetts General Hospital and Brigham Women's Hospital. The most authoritative academic journal was JMIR mHealth and uHealth. Noseworthy PA may have the highest influence in this intersected field with the highest number of citations and total link strength. The utilization of wearable mobile devices in the context of CVD, encompassing the identification of risk factors, diagnosis and prevention of diseases, as well as early intervention and remote management of diseases, has been widely acknowledged as a knowledge base and an area of current interest. To investigate the impact of various digital medicine interventions on chronic care and assess their clinical effectiveness, examine the potential of machine learning (ML) in delivering clinical care for atrial fibrillation (AF) and identifying early disease risk factors, as well as explore the development of disease prediction models using neural networks (NNs), ML and unsupervised learning in CVD prognosis, may emerge as future trends and areas of focus. Conclusion: Recently, there has been a significant surge of interest in the investigation of digital medicine in CVD. This initial bibliometric study offers a comprehensive analysis of the research landscape pertaining to digital medicine in CVD, thereby furnishing related scholars with a dependable reference to facilitate further progress in this domain.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFß Signaling.

PURPOSE: Intratumoral nerve infiltration relates to tumor progression and poor survival in oral squamous cell carcinoma (OSCC). How neural involvement regulates antitumor immunity has not been well characterized. This study aims to investigate molecular mechanisms of regulating tumor aggressiveness and impairing antitumor immunity by nerve-derived factors. EXPERIMENTAL DESIGN: We performed the surgical lingual denervation in an immunocompetent mouse OSCC model to investigate its effect on tumor growth and the efficacy of anti-PD-1 immunotherapy. A trigeminal ganglion neuron and OSCC cell coculture system was established to investigate the proliferation, migration, and invasion of tumor cells and the PD-L1 expression. Both the neuron-tumor cell coculture in vitro model and the OSCC animal model were explored. RESULTS: Lingual denervation slowed down tumor growth and improved the efficacy of anti-PD-1 treatment in the OSCC model. Coculturing with neurons not only enhanced the proliferation, migration, and invasion but also upregulated TGFß-SMAD2 signaling and PD-L1 expression of tumor cells. Treatment with the TGFß signaling inhibitor galunisertib reversed nerve-derived tumor aggressiveness and downregulated PD-L1 on tumor cells. Similarly, lingual denervation in vivo decreased TGFß and PD-L1 expression and increased CD8+ T-cell infiltration and the expression of IFNγ and TNFα within tumor. CONCLUSIONS: Neural involvement enhanced tumor aggressiveness through upregulating TGFß signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, downregulated TGFß signaling, enhanced activities of CD8+ T cells, and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC. SIGNIFICANCE: This study revealed the specific mechanisms for nerve-derived cancer progression and impaired antitumor immunity in OSCC, providing a novel insight into the cancer-neuron-immune network as well as pointing the way for new strategies targeting nerve-cancer cross-talk as a potential adjuvant therapeutic approach for OSCC.

AutoMolDesigner for Antibiotic Discovery: An AI-Based Open-Source Software for Automated Design of Small-Molecule Antibiotics.

Discovery of small-molecule antibiotics with novel chemotypes serves as one of the essential strategies to address antibiotic resistance. Although a considerable number of computational tools committed to molecular design have been reported, there is a deficit in holistic and efficient tools specifically developed for small-molecule antibiotic discovery. To address this issue, we report AutoMolDesigner, a computational modeling software dedicated to small-molecule antibiotic design. It is a generalized framework comprising two functional modules, i.e., generative-deep-learning-enabled molecular generation and automated machine-learning-based antibacterial activity/property prediction, wherein individually trained models and curated datasets are out-of-the-box for whole-cell-based antibiotic screening and design. It is open-source, thus allowing for the incorporation of new features for flexible use. Unlike most software programs based on Linux and command lines, this application equipped with a Qt-based graphical user interface can be run on personal computers with multiple operating systems, making it much easier to use for experimental scientists. The software and related materials are freely available at GitHub (https://github.com/taoshen99/AutoMolDesigner) and Zenodo (https://zenodo.org/record/10097899).

Secondary metabolites from the Actinomadura sp. and their cytotoxic activity.

Actinomadura sp., which is usually found in muddy habitats, produces various secondary metabolites with biological activities. In this study, five new compounds named formosensin A (1), formosensin B (2), oxanthroquinone-3-O-α-d-mannose (8), oxanthromicin A (9), and oxanthromicin B (10) were isolated from the culture of Actinomadura sp. together with five known compounds (3-7). Their structures were elucidated by extensive spectroscopic methods including NMR and MS. In particular, the absolute configurations of compounds 1 and 2 were determined using computational methods. Moreover, compounds 1-2 and 8-10 were screened for cytotoxic activity using a panel of human tumor cell lines. Compound 9 induced significant cytotoxicity in five human tumor cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480) with IC50 values of 8.7, 17.5, 15.0, 17.8, and 14.6 µM, respectively. These findings suggested that compound 9 could provide therapeutic benefits in the treatment of tumor-related diseases.

Visible-light-induced decarboxylative cascade cyclization of acryloylbenzamides with N-hydroxyphthalimide esters via EDA complexes.

A visible-light-induced decarboxylative cascade reaction of acryloylbenzamides with alkyl N-hydroxyphthalimide (NHP) esters for the synthesis of various 4-alkyl isoquinolinediones mediated by triphenylphosphine (PPh3) and sodium iodide (NaI) was developed. This operationally simple protocol proceeded via the photoactivation of electron donor-acceptor (EDA) complexes between N-hydroxyphthalimide esters and NaI/PPh3, resulting in multiple carbon-carbon bond formations without the use of precious metal complexes or synthetically elaborate organic dyes, which provided an alternative practical approach to synthesize diverse isoquinoline-1,3(2H,4H)-dione derivatives.

Clinical Experience of External Application of Clearing Heat and Removing Dampness in Relieving Grade 2 to 3 Rash Caused by Programed Cell Death Protein 1 (PD-1)/Programed Cell Death Ligand 1 (PD-L1) Inhibitors: A Single-Center Retrospective Study.

OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Ruggedized Self-Propelling Hemostatic Gauze Delivers Low Dose of Thrombin and Systemic Tranexamic Acid and Achieves High Survival in Swine With Junctional Hemorrhage.

INTRODUCTION: Hemorrhage is responsible for 91% of preventable prehospital deaths in combat. Bleeding from anatomic junctions such as the groin, neck, and axillae make up 19% of these deaths, and reports estimate that effective control of junctional hemorrhage could have prevented 5% of fatalities in Afghanistan. Hemostatic dressings are effective but are time-consuming to apply and are limited when proper packing and manual pressure are not feasible, such as during care under fire. CounterFlow-Gauze is a hemostatic dressing that is effective without compression and delivers thrombin and tranexamic acid into wounds. Here, an advanced prototype of CounterFlow-Gauze, containing a range of low thrombin doses, was tested in a lethal swine model of junctional hemorrhage. Outcomes were compared with those of Combat Gauze, the current dressing recommended by Tactical Combat Casualty Care. MATERIALS AND METHODS: CounterFlow-Gauze containing thrombin doses of 0, 20, 200, and 500 IU was prepared. Swine received femoral arteriotomies, and CounterFlow-Gauze was packed into wounds without additional manual compression. In a separate study using a similar model of junctional hemorrhage without additional compression, CounterFlow-Gauze containing 500 IU thrombin was tested and compared with Combat Gauze. In both studies, the primary outcomes were survival to 3 h and volume of blood loss. RESULTS: CounterFlow-Gauze with 200 and 500 IU had the highest 3-h survival, achieving 70 and 75% survival, respectively. CounterFlow-Gauze resulted in mean peak plasma tranexamic acid concentrations of 9.6 ± 1.0 µg/mL (mean ± SEM) within 3 h. In a separate study with smaller injury, CounterFlow-Gauze with 500 IU achieved 100% survival to 3 h compared with 92% in Combat Gauze animals. CONCLUSIONS: An advanced preclinical prototype of CounterFlow-Gauze formulated with a minimized thrombin dose is highly effective at managing junctional hemorrhage without compression. These results demonstrate that CounterFlow-Gauze could be developed into a feasible alternative to Combat Gauze for hemorrhage control on the battlefield.

Visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization to construct α-chromone substituted α-amino acid derivatives.

Organophotocatalytic cascade cross-dehydrogenative-coupling/cyclization reaction of o-hydroxyarylenaminones with α-amino acid derivatives for the construction of α-chromone substituted α-amino acid derivatives was developed. Various N-arylglycine esters, amides and dipeptides underwent the cascade cyclization reaction well with o-hydroxyarylenaminones to afford the corresponding 3-aminoalkyl chromones in good to excellent yields. This approach consists of visible-light-promoted oxidation of α-amino acid derivatives, the Mannich reaction, and intramolecular nucleophilic cyclization under acidic conditions, and features a wide reaction scope, a simple operation and mild reaction conditions, which may have the potential to be used for the synthesis of bioactive molecules.