An Investigation of the Anisotropic Mechanical Properties of Additive-Manufactured 316L SS with SLM.

Selective laser melting (SLM) forms specimens that often exhibit anisotropic mechanical properties. Most existing research only explains that the mechanical properties of specimens perpendicular to the build direction are superior to those parallel to the build direction. In this paper, the mechanical properties of SLM 316L SS specimens with different surfaces and different directions are compared. Finally, it was found that the mechanical properties of specimens on Face 3 are stronger than those on Face 1 and Face 2, while the mechanical properties of specimens on Face 1 and Face 2 are similar. For specimens in different directions on the same surface, the mechanical properties of Face 1 and Face 2 exhibit clear anisotropy, while the mechanical properties of Face 3 tend to be isotropic. In this paper, the EBSD technique was used to analyze the specimens. It was found that the anisotropy of the mechanical properties of Face 1 and Face 2 are attributed to the presence of texture and columnar crystals in the sample. This paper can provide accurate and reliable material performance data for the practical application of SLM 316L SS, thereby guiding the optimization of engineering design and manufacturing processes.

Study of Anisotropic Behavior in Sheet Metal Forming.

Since sheet metal exhibits significant anisotropy in processing and forming, which has a significant impact on its performance during processing, forming, and use, we explore the anisotropic behavior of materials in the forming process of sheet metal. The ability of the Yld2000-2d criterion to describe anisotropic behavior is analyzed, and its accuracy for characterization of the anisotropic behavior of metal plates is improved, based on which anisotropic behavior is predicted in three-dimensional space. Theoretical and experimental results on the anisotropy of sheet metal are compared, and two materials, 5754O aluminum alloy and DP980 steel plate, are tested and analyzed, and the anisotropic behaviors, such as three-point bending and cylindrical deep-drawing, are well predicted.

Preperitoneal pelvic balloon tamponade-an effective intervention to control pelvic injury hemorrhage in a swine model.

Objective: This study aimed to estimate the effects of the volume of preperitoneal balloon (PPB) on arterial and venous hemorrhage in a swine pelvic fracture model. Methods: Twenty-four swine were randomized into 0-mL, 500-mL, 800-mL, and 1000-mL intra-hematoma PPB groups. They were subjected to open-book pelvic fracture and reproducible injuries in the external iliac artery and vein. The pelvic binder and IH-PPBs with different volumes of fluid were applied to control the active hemorrhage after arterial and venous injuries. The survival time and rate during 60-min observation and digital subtraction angiography (DSA) images were the primary endpoints in this study. Secondary endpoints included survival rate within 70 min, peritoneal pressure, hemodynamics, blood loss, infusion fluid, blood pH, and lactate concentration. Results: Our results indicated that the 800-mL and 1000-mL groups had a higher survival rate (0%, 50%, 100% and 100% for 0, 500, 800, and 1000-mL groups respectively; p < 0.0001) and longer survival time (13.83 ± 2.64, 24.50 ± 6.29, 55.00 ± 6.33, and 60.00 ± 0.00 min for 0, 500, 800, and 1,000 groups respectively; p < 0.0005) than the 0-mL or 500-mL groups during the 60 min observation. Contrastingly, survival rate and time were comparable between 800-mL and 1000-mL groups during the 60-min observation. The IH-PPB volume was associated with an increase in the pressure of the balloon and the preperitoneal pressure but had no effect on the bladder pressure. Lastly, the 1000-mL group had a higher mean arterial pressure and systemic vascular resistance than the 800-mL group. Conclusion: IH-PPB volume-dependently controls vascular bleeding after pelvic fracture in the swine model. IH-PPB with a volume of 800 mL and 1000 mL efficiently managed pelvic fracture-associated arterial and venous hemorrhage and enhanced survival time and rate in the swine model without evidences of visceral injury.

Repair of a "long and narrow" skin defect of the upper extremity with a modified design of a compound SCIP flap: a series of 12 cases.

BACKGROUND: Large skin lesions of the upper extremity tend to be ''long and narrow'' in shape, and the currently used repair and reconstruction protocols still have some drawbacks, including difficulty in closure of the donor area, poor cosmetic appearance of the donor and recipient areas, and low flap survival rates. The ilioinguinal flap has been more widely used for repair and reconstruction of various complex conditions. In order to improve the versatility of the flap design and to achieve better aesthetic results, we report a study on the improved design of Compound SCIP flap for repairing "long and narrow" large skin defects of the upper extremity by using a modified design of the ilioinguinal flap for the procurement of perforating blood vessels and flap excision. METHODS: From April 2005 to August 2015, a total of 12 patients underwent this modified design procedure, in which the anterior branch of the fourth lumbar artery or the posterior intercostal artery was selected to provide blood supply for the perforator flap together with the superficial branch of the superficial iliac artery to meet the blood supply needs of the flap for the one-time repair of a large "long and narrow" skin defect in the upper limb. Patient demographics, flap characteristics, and associated complications were retrospectively analyzed. RESULTS: 3 females and 9 males were included in this study, the mean age of the patients was 31.7 years (range, 22-44 years), the mean follow-up period was 15.3 ± 5.6 months (range, 7-24 months), and all patients had complete closure of the defect site and donor area, and all flaps survived. CONCLUSIONS: The Compound SCIP flap presents some advantages in repairing 'long and narrow' skin defects in the upper limb. While ensuring the survival rate of the elongated ilioinguinal flap, it amplifies the benefits of the ilioinguinal flap and enhances skin utilization. This can serve as a beneficial choice for repairing 'long and narrow' skin defects in the upper limb.

Neoadjuvant Chemotherapy Is Effective in Those Infected With SARS-CoV-2: The Real-World Experience of a Large Chinese Breast Cancer Center.

PURPOSE: During the major shift in China's policies on coronavirus disease 2019 (COVID-19), many residents will be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) over a short period, including a few patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). Moreover, it is unknown whether this comorbidity affects the efficacy of NAC for breast cancer and the patient's psychological state and quality of life (QOL). This study aims to answer these questions. METHODS: The clinical data of 2,793 patients with breast cancer who received NAC at The Affiliated Hospital of Qingdao University were retrospectively collected. The infected and non-infected groups were divided according to whether they were infected with COVID-19 during NAC. Propensity score matching was used to reduce patient selection bias. The effectiveness, psychological well-being, and QOL of the two groups were compared. RESULTS: No discernible differences were observed in the pathological complete response rates (p = 0.307) and major histological responses rate (p = 0.398) between the infected and non-infected groups. Following the full course of NAC, the Functional Assessment of Cancer Treatment General (p < 0.001) and Functional Assessment of Cancer Therapy for Breast Cancer (p < 0.001) were lower in the infected group than the non-infected group, the Hospital Anxiety and Depression Scale (HADS) anxiety scale (p < 0.001) and HADS depression scale (p < 0.001) were considerably higher in the infected group than the non-infected group. CONCLUSION: With timely treatment and effective medical management, SARS-CoV-2 does not appear to affect the efficacy of NAC; however, it can significantly affect the QOL of patients and increase their psychological distress. Therefore, in addition to a timely assessment of the efficacy of NAC, it is necessary to dynamically understand the patient's psychological state and QOL.

Graphiumisides A-D, Monoterpene Glycosides from an Animal-Derived Endophytic Fungus Graphium sp. GD-11.

 Four new monoterpene rhamnosides, graphiumisides A-D (1-4), along with four known steroid compounds (5-8) were isolated from the fermentation extract of animal-derived endophytic fungus, Graphium sp. GD-11. The chemical structures of all compounds were elucidated using 1D and 2D NMR, HRESIMS spectroscopic analyses, and other spectroscopic methods. Compounds 1-4 exhibit a distinctive structure connected by one p-menthane type monoterpene and one L-rhamnose. This is the first report of monoterpene glycosides from Graphium sp. All compounds (1-8) were tested for cytotoxic activities against four cancer cell lines (HepG2, SMMC7721, SW480, and A549), and only compound 1 showed weak anti-tumor activity against SMMC7721 cells.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Background: Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. Methods: (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. Results: The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. Conclusions: This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

Expanded ROS Generation and Hypoxia Reversal: Excipient-free Self-assembled Nanotheranostics for Enhanced Cancer Photodynamic Immunotherapy.

The efficacy of photodynamic therapy (PDT)-related cancer therapies is significantly restricted by two irreconcilable obstacles, i.e., low reactive oxygen species (ROS) generation capability and hypoxia which constrains the immune response. Herein, this work develops a self-assembled clinical photosensitizer indocyanine green (ICG) and the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) nanoparticles (ISDN) without any excipient. This work discovers that the hydrophobic interaction forces between ICG and 17-DMAG promote the photostability of ICG and its intersystem crossing (ISC) process, thereby improving the ROS quantum yield from 0.112 to 0.46. Augmented ROS generation enhances PDT efficacy and further enhances immunogenic cell death (ICD) effects. 17-DMAG inhibits the HSP90/hypoxia-inducible factor 1α (HIF-1α) axis to dramatically reverse the immunosuppressive tumor microenvironment caused by PDT-aggravated hypoxia. In a mouse model of pancreatic cancer, ISDN markedly improve cytotoxic T lymphocyte infiltration and MHC I and MHC II activation, demonstrating the superior ICD effects in situ tumor and the powerful systematic antitumor immunity generation, eventually achieving vigorous antitumor and recurrence resistance. This study proposes an unsophisticated and versatile strategy to significantly improve PDT efficacy for enhancing systemic antitumor immunity and potentially extending it to multiple cancers.

Research on the mechanism and application of wedge cutting blasting with hole-inner delay.

To increase the efficiency of deep-hole blasting driving in mine rock tunnels, an innovative pattern of wedge cutting blasting with hole-inner delay was proposed. First, the blasting mechanisms of conventional and innovative wedge cutting patterns were theoretically investigated. The results showed that the resistance from large upper rock blocks and the clamping action from the surrounding rock were the major challenges of conventional cutting methods. For the innovative cutting pattern, under the conversion of the spatial distribution and release sequence of blasting energy, the first blasting of the upper charge can strengthen the breaking of the upper rock mass and create a new free surface, which provides favorable conditions for the delayed blasting of the bottom charge. Second, finite element models of two cutting patterns were established and solved, and the simulation results visually revealed the propagation of a stress wave. Critically, the stress strength in the upper cavity increased by 66-83% under the action of the upper charge, which was conducive to the breaking of the upper rock mass and the generation of a new free surface. Therefore, the rock mass in the bottom cavity can be readily broken and discharged. Ultimately, field applications were executed in a rock tunnel. Compared with a conventional cutting pattern, the proposed innovative cutting pattern can prominently increase the cycle advance and hole utilization and greatly reduce the unit consumption of explosives and detonators. This research confirms the usability of the innovative wedge cutting pattern with hole-inner delay in deep-hole blasting driving of rock tunnels.

Impact of changes in collagen construction and molecular state on integrin - binding properties.

The interaction between the integrin and collagen is important in cell adhesion and signaling. Collagen, as the main component of extracellular matrix, is a base material for tissue engineering constructs. In tissue engineering, the collagen structure and molecule state may be altered to varying degrees in the process of processing and utilizing, thereby affecting its biological properties. In this work, the impact of changes in collagen structure and molecular state on the binding properties of collagen to integrin α2ß1 and integrin specific cell adhesion were explored. The results showed that the molecular structure of collagen is destroyed under the influence of heating, freeze-grinding and irradiation, the triple helix integrity is reduced and molecular breaking degree is increased. The binding ability of collagen to integrin α2ß1 is increased with the increase of triple helix integrity and decays exponentially with the increase of molecular breaking degree. The collagen molecular state can also influences the binding ability of collagen to cellular receptor. The collagen fibrils binding to integrin α2ß1 and HT1080 cells is stronger than to collagen monomolecule. Meanwhile, the hybrid fibril exhibits a different cellular receptor binding performance from corresponding single species collagen fibril. These findings provide ideas for the design and development of new collagen-based biomaterials and tissue engineering research.

Malaria cases in China acquired through international travel, 2013-2022.

BACKGROUND: Despite the World Health Organisation certifying China malaria-free in 2021, the risk of local transmission caused by imported malaria cases remains a significant clinical and public health issue. It is necessary to present the changing trends of malaria in China and discuss the role of travel medicine services in consolidating malaria elimination. METHODS: This study systematically reviewed articles and reports related to human malaria from 2013 to 2022 published in international and Chinese databases. Data on malaria (i.e. number of cases, Plasmodium spp., diagnostic method, country of acquisition, provinces with high risk of re-introduction and transmission) were collected and synthesised, then summarised using descriptive statistics. RESULTS: Overall, 24 758 cases of malaria (>99.5% laboratory confirmed, > 99.2% imported, 0.5% fatal) were reported in China from 2013 to 2022, with a downward trend over the years (4128 cases in 2013 compared to 843 cases in 2022; χ2 trend p-value = 0.005). The last locally acquired case was reported in 2017. P. falciparum (65.5%) was the most common species identified, followed by P. vivax (20.9%) and P. ovale (10.0%). Two Pheidole knowlesi cases were also identified in 2014 and 2017 in returned travellers from Malaysia and Indonesia, respectively. The most common countries of malaria acquisition were Ghana, Angola, and Myanmar. P. vivax was mainly detected in returned travellers from Myanmar, while P. falciparum and P. ovale were detected in travellers from Sub-Saharan Africa. Imported cases were mainly reported in Yunnan, Jiangsu, Sichuan, Guangxi, Shandong, Zhejiang, and Henan provinces, where large numbers of Chinese people travel overseas for work. CONCLUSION: Returned travellers from malaria-endemic countries pose a significant risk of malaria re-introduction to China. Travel medicine should be strengthened to improve the capacity and accessibility of both pre- and post-travel services, including malaria prophylaxis and prompt diagnosis of illness in returned travellers.

Pediatric Ménière's disease with disassociated cochlear and vestibular symptoms: a case report.

Background: Typical Ménière's disease (MD) rarely occurs in childhood. Compared to adults, age-associated changes in vestibular function can occur during infancy and childhood. Previous case reports may have lacked some audiovestibular tests in children. It is worthwhile to follow a child with MD to observe how vertigo and hearing loss could progress under an insufficient vestibular system. Case Description: A 14-year-old pediatric patient with disassociated episodes between vertigo and hearing loss was finally diagnosed with MD. He was diagnosed with probable MD due to lack of objective evidence of hearing loss in his first two admissions. However, in his third admission, he had hearing loss even without attack of vertigo and was finally diagnosed. By listing the patient's audiovestibular auxiliary tests in a chronological order, we might follow the progress of pediatric MD. Gadolinium-enhanced magnetic resonance imaging (Gd-MRI) might be sensitive to reflect endolymphatic hydrops (EH). Medications including corticosteroids might be effective for both hearing loss and vertigo. Conclusions: In pediatric MD, vestibular and cochlear symptoms may occur and progress independently. Audiovestibular evaluation, especially caloric tests and cervical vestibular evoked myogenic potential (cVEMP), can be useful for pediatric MD. Gd-MRI can be sensitive for detecting EH. Both systemic and postauricular administration of corticosteroids might be effective in alleviating vertigo and improving hearing. Prolongation of the follow-up period of pediatric MD is warranted.

In vitro anti-Helicobacter pylori activity and antivirulence activity of cetylpyridinium chloride.

The primary treatment method for eradicating Helicobacter pylori (H. pylori) infection involves the use of antibiotic-based therapies. Due to the growing antibiotic resistance of H. pylori, there has been a surge of interest in exploring alternative therapies. Cetylpyridinium chloride (CPC) is a water-soluble and nonvolatile quaternary ammonium compound with exceptional broad-spectrum antibacterial properties. To date, there is no documented or described specific antibacterial action of CPC against H. pylori. Therefore, this study aimed to explore the in vitro activity of CPC against H. pylori and its potential antibacterial mechanism. CPC exhibited significant in vitro activity against H. pylori, with MICs ranging from 0.16 to 0.62 µg/mL and MBCs ranging from 0.31 to 1.24 µg/mL. CPC could result in morphological and physiological modifications in H. pylori, leading to the suppression of virulence and adherence genes expression, including flaA, flaB, babB, alpA, alpB, ureE, and ureF, and inhibition of urease activity. CPC has demonstrated in vitro activity against H. pylori by inhibiting its growth, inducing damage to the bacterial structure, reducing virulence and adherence factors expression, and inhibiting urease activity.

Hysteresis-Free and Bias-Stable Organic Transistors Fabricated by Dip-Coating with a Vertical-Phase-Separation Structure.

The morphology of organic films plays a pivotal role in determining the performance of transistor devices. While the dip-coating technique is capable of producing highly oriented organic films, it often encounters challenges such as limited coverage and the presence of defects in gaps between strips, adversely affecting device performance. In this study, we address these challenges by increasing solution viscosity through the incorporation of a substantial proportion of dielectric polymers, thereby enhancing the participation of additional molecules during the film formation process when pulled up. This method produces continuous and oriented organic films with a notable absence of gaps, significantly improving the carrier mobility of transistor devices by more than twofold. Importantly, the fabricated devices exhibit remarkable reliability, showing no hysteresis even after 200 cycles of measurement. Furthermore, the current and threshold voltages of the devices demonstrate exceptional stability, maintaining steady after 10,000 s of bias measurement. This approach provides a solution for the cost-effective and large-scale production of organic transistors, contributing significantly to the advancement of organic electronics.

Advances in the pharmacological effects and mechanisms of Nelumbo nucifera gaertn. Extract nuciferine.

ETHNOPHARMACOLOGIC RELEVANCE: The leaves of Nelumbo nucifera Gaertn. Are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Nuciferine, one of N. nucifera Gaertn. leaf extracts, has been shown to possess several pharmacological properties, including but not limited to ameliorating hyperlipidemia, stimulating insulin secretion, inducing vasodilation, reducing blood pressure, and demonstrating anti-arrhythmic properties. AIM OF THE STUDY: In light of the latest research findings on nuciferine, this article provides a comprehensive overview of its chemical properties, pharmacological activities, and the underlying regulatory mechanisms. It aims to serve as a dependable reference for further investigations into the pharmacological effects and mechanisms of nuciferine. MATERIALS AND METHODS: Use Google Scholar, Scifinder, PubMed, Springer, Elsevier, Wiley, Web of Science and other online database search to collect the literature on extraction, separation, structural analysis and pharmacological activity of nuciferine published before November 2023. The key words are "extraction", "isolation", "purification" and "pharmacological action" and "nuciferine". RESULTS: Nuciferine has been widely used in the treatment of ameliorating hyperlipidemia and lose weight, Nuciferine is a monomeric aporphine alkaloid extracted from the leaves of the plant Nymphaea caerulea and Nelumbo nucifera Gaertn. Nuciferine has pharmacological activities such as relaxing smooth muscles, improving hyperlipidemia, stimulating insulin secretion, vasodilation, inducing hypotension, antiarrhythmic effects, and antimicrobial and anti-HIV activities. These pharmacological properties lay a foundation for the treatment of tumors, inflammation, hyperglycemia, lipid-lowering and weight-loss, oxidative stress and other diseases with nuciferine. CONCLUSION: Nuciferine has been clinically used to treat hyperlipidemia and aid in weight loss due to its effects on lipid levels, insulin secretion, vasodilation, blood pressure reduction, anti-tumor properties, and immune enhancement. However, other potential benefits of nuciferine have not yet been fully explored in clinical practice. Future research should delve deeper into its molecular structure, toxicity, side effects, and clinical pharmacology to uncover its full range of effects and pave the way for its safe and expanded clinical use.

Two New Phenylpropanoid Compounds from Lilium Brownii and Their Anti-monoamine Oxidase Activity.

Baihe is a commonly used Chinese medicine for the treatment of neurological disorders. Clinically, the bulbs of Lilium brownii are used to act as Baihe. In the study, two new phenylpropanoid compounds including 3-O-acetyl-1-O-caffeoylglycerol (1) and 3-O-acetyl-1-O-p-coumaroylglycerol (2) were isolated from the bulbs of L. brownii. Their structures were identified by spectroscopic method and the effect on monoamine oxidase activity was determined using an enzyme labeling method. The results show 1 and 2 have anti-monoamine oxidase activity with 20.96 % and 22.31 % inhibition rates at 50 µg/ml, respectively.

Effect of Celastrus Orbiculatus Extract on proliferation and apoptosis of human Burkitt lymphoma cells.

The lymphoma incidence rate is on the rise, with invasive forms particularly prone to relapse following conventional treatment, posing a significant threat to human life and wellbeing. Numerous studies have shown that traditional Chinese botanical drug medicine offers promising therapeutic benefits for various malignancies, with previous experimental findings indicating that Celastrus orbiculatus extract effectively combats digestive tract tumors. However, its impact on lymphoma remains unexplored. This study aims to investigate the impact and underlying mechanisms of COE on the proliferation and apoptosis of Burkitt lymphoma cells. We diluted COE in RPMI-1640 medium to create various working concentrations and introduced it to human Burkitt lymphoma Raji and Ramos cells. To evaluate cell viability, we used the CCK-8 assay, and we observed morphological changes using HE staining. We also conducted Annexin V-PI and JC-1 staining experiments to assess apoptosis. By combining the cell cycle experiment with the EDU assay, we gained insights into the effects of COE on DNA replication in lymphoma cells. Using Western blotting, we detected alterations in apoptosis-related proteins. In vivo experiments revealed that following COE intervention, tumor volume decreased, survival time was prolonged, spleen size reduced, and the expression of tumor apoptosis-related proteins changed. Our findings indicate that COE effectively inhibits lymphoma cell proliferation and promotes apoptosis by regulating these apoptosis-related proteins.

Seco-cyclic phorbol derivatives and their anti-HIV-1 activities.

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C (PKC). The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20, C3/C4, and C9 of phorbol. Concurrently, the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex. The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration. This research entailed the hydrolysis of phorbol, producing seco-cyclic phorbol derivatives. The anti-HIV-1 efficacy of these derivatives was assessed, and the affinity constant (Kd) for PKC-δ protein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry. The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity. Remarkably, compound S11, with an EC50 of 0.27 µmol·L-1 and a CC50 of 153.92 µmol·L-1, demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription (ssDNA and 2LTR), likely acting at the viral entry stage, yet showed no affinity for the PKC-δ protein. These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).