In Situ Closing the van der Waals Gap of Two-Dimensional Materials.

Self-intercalation in two-dimensional (2D) materials, converting 2D materials into ultrathin covalently bonded materials, presents great possibilities for studying a new family of quantum-confined materials with the potential to realize multifunctional behavior. However, understanding the mechanisms and associated in situ kinetics of synthesizing self-intercalated 2D (ic-2D) materials, particularly at the atomic scale, remains elusive, greatly hindering the practical applications of ic-2D crystals. Here, we successfully in situ synthesized ic-2D thin films via thermal annealing of their parental TMDCs inside an electron microscope. We atomically visualized the evolution from TaS2 and NbS2 into the corresponding ic-2D Ta1+xS2 and ic-2D Nb1+xS2, respectively, by in situ scanning transmission electron microscopy (STEM). The self-intercalation process in TaS2 is atomically realized by metal adatom edge adsorption and subsequent diffusion in an atom-by-atom manner. On the other hand, MoS2 and MoSe2 tend to coalesce into metal crystals under the same annealing conditions, suggesting that the self-intercalation process is predominantly controlled by thermodynamic factors as further verified by density functional theory (DFT). By varying the ramping rate and annealing temperature, the coverage and spatial arrangement of the filling sites can be precisely tuned, ranging from 2a × 3a, 3a × 3a, or Ta trimers, as predominantly gauged by kinetic factors. Our work sheds light on the thermodynamics and growth kinetics involved in ic-2D formation and paves the way for growing highly crystalline ic-2D materials with intercalation concentration and topology-dependent properties.

Efficiency and safety of laparoscopic left hemihepatectomy: A study of intrathecal vs extrathecal Glissonean pedicle techniques.

BACKGROUND: Selective hemihepatic vascular occlusion is utilized in both right and left hemihepatectomies to preserve blood supply to the intact lobe, maintain hemodynamic stability, and mitigate surgical risks. While this technique encompasses both intrathecal and extrathecal Glissonean pedicle transection methods, there is a lack of systematic comparative reports on these two approaches. AIM: To retrospectively analyze the clinical data of patients with hepatocellular carcinoma (HCC) undergoing laparoscopic anatomical hepatectomy in our hospital to explore the feasibility, safety, and short- and long-term efficacy of extrathecal and intrathecal Glissonean pedicle transection methods in laparoscopic left hemihepatectomy. METHODS: A retrospective study was performed to analyze the clinical data of 49 HCC patients who underwent laparoscopic left hemihepatectomy from January 2019 to December 2022 in our hospital. These patients were divided into extrathecal Glissonean pedicle transection (EGP) group (n = 24) and intrathecal Glissonean pedicle transection (IGP) group (n = 25) according to the different approaches used for selective hemihepatic vascular occlusion. The perioperative indicators, liver function indexes, complications, and follow-up findings were compared between these two groups. RESULTS: The surgeries were smooth in both groups, and no perioperative death was noted. The hepatic pedicle transection time and the operation time were (16.1 ± 2.3) minutes and (129.6 ± 19.0) minutes, respectively, in the EGP group, which were significantly shorter than those in the IGP group [(25.5 ± 2.4) minutes and (184.8 ± 26.0) minutes, respectively], both P < 0.01. There were no significant differences in intraoperative blood loss, time to anal exhaust, hospital stay, drain indwelling time, and postoperative liver function between the two groups (all P > 0.05). The incidence of postoperative complications showed no significant difference [16.67% (4/24) vs 16.0% (4/25), P > 0.05). All the 49 HCC patients were followed up after surgery (range: 11.2-53.3 months; median: 36.4 months). The overall survival rate and disease-free survival rate were not significantly different (both P > 0.05). CONCLUSION: Both extrathecal and intrathecal Glissonean pedicle approaches are effective and safe hepatic inflow occlusion techniques in laparoscopic left hemihepatectomy for HCC. However, the extrathecal approach simplifies the hepatic pedicle transection, shortens the operation time, and increases the surgical efficiency, making it a more feasible technique.

MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

BACKGROUND: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. METHODS: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. OBJECTIVES: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. RESULTS: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). CONCLUSIONS: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

Advances in Surgical Treatments of Left Ventricular Aneurysms.

Despite improvements in the early intervention of myocardial infarction (MI) in recent decades, left ventricular aneurysms (LVA) remain a major health concern, particularly in developing nations. The progression of MI can lead to the thinning of the myocardial wall and the formation of a ventricular wall bulge, characteristic of an LVA. Furthermore, cardiac magnetic resonance (CMR) has emerged as the gold standard for LVA diagnosis due to its superior imaging capabilities. Notably, surgical ventricular reconstruction (SVR) is an effective treatment for LVA, aiming to restore the normal volume and structure of the left ventricle, thereby improving cardiac function. However, the criteria for selecting patients for SVR treatment remains a subject of debate. This review focuses on the current understanding of surgical indications, procedures, and prognostic risk factors that influence outcomes in left ventricular reconstruction, highlighting the need for precise patient selection to optimize surgical benefits.

Construction of Lentiviral Vectors Carrying Six Pluripotency Genes in Yak to Obtain Yak iPSC Cells.

Yak is an excellent germplasm resource on the Tibetan Plateau and is able to live in high-altitude areas with hypoxic, cold, and harsh environments. Studies on induced pluripotent stem cells (iPSCs) in large ruminants commonly involve a combination strategy involving six transcription factors, Oct4, Sox2, Klf4, c-Myc, Nanog, and Lin28 (OSKMNL). This strategy tends to utilize genes from the same species to optimize pluripotency maintenance. In this study, we cloned the six pluripotency genes (OSKMNL) from yak and constructed a multi-cistronic lentiviral vector carrying these genes. This vector efficiently delivered the genes into yak fibroblasts, aiming to promote the reprogramming process. We verified that the treated cells had several pluripotency characteristics, marking the first successful construction of a lentiviral system carrying yak pluripotency genes. This achievement lays the foundation for subsequent establishment of yak iPSCs and holds significant implications for yak-breed improvement and germplasm-resource conservation.

Mechanism for Adsorption, Dissociation, and Diffusion of Hydrogen in High-Entropy Alloy AlCrTiNiV: First-Principles Calculation.

To investigate hydrogen behaviors in the high-entropy alloy AlCrTiNiV, density functional theory and transition state theory were used to explore the molecular H2 absorption and dissociation and the atomic H adsorption, diffusion, and penetration progress. The H2 molecule, where the H-H band is parallel to the surface layer, is more inclined to absorb on the top site of the Ti atom site of first atomic layer on the AlCrTiNiV surface, then diffuse into the hollow sites, through the bridge site, after dissociating into two H atoms. Atomic H is more likely to be absorbed on the hollow site. The absorption capacity for atomic H on the surface tends to decline with the increase in H coverage. By calculating the energy barriers of atomic H penetration in AlCrTiNiV, it was indicated that lattice distortion may be one important factor that impacts the permeation rate of hydrogen. Our theory research suggests that high-entropy alloys have potential for use as a hydrogen resistant coating material.

Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study.

BACKGROUND: The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. METHODS: In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. FINDINGS: Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7-40·1). In approach 1, 22 of 50 patients (44% [95% CI 30-59]) had an objective response. In approach 2, 19 of 25 patients (76% [55-91] had an objective response. 23 (46%) of 50 patients had a grade 3-5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). INTERPRETATION: Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. FUNDING: Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.

Harnessing Lecanicillium attenuatum: A novel strategy for combatting Nilaparvata lugens in rice fields.

Nilaparvata lugens is a notorious rice pest causing significant annual yield and economic losses. The use of entomopathogenic fungi offers a promising and eco-friendly approach to sustainable pest management programs. However, research in this area is currently limited to a few specific types of insects and other arthropods. This study aimed to analyze the biocontrol potential of Lecanicillium attenuatum against N. lugens. Bioassays showed that L. attenuatum 3166 induced >80% mortality in N. lugens following 7 d exposure. Greenhouse and field investigations demonstrated that L. attenuatum 3166 application leads to a substantial reduction in N. lugens populations. Under greenhouse conditions, fluorescence was detected in GFP-labeled L. attenuatum 3166 hyphae enveloping the bodies of N. lugens. In field trials, L. attenuatum 3166 treatment exhibited a control efficacy of up to 68.94% at 14 d post-application, which was comparable to that of the commercial entomopathogenic fungal agent. Genomic sequencing of L. attenuatum 3166 revealed a comprehensive array of genes implicated in its infestation and lethality. Further, the transcriptome sequencing analysis highlighted the elevated expression levels of genes encoding proteases, chitinases, cutinases, and phospholipases. Our findings highlight the potential of L. attenuatum 3166 as an effective biological control agent against N. lugens.

Analysis of the diagnostic value of coagulation markers and coagulation function indices on the occurrence of DIC in sepsis and its prognosis.

Sepsis is a life-threatening condition that has the potential to multiple organ dysfunction and mortality. One of its frequent complications is disseminated intravascular coagulation (DIC), characterized by hyperactive clotting mechanisms that cause widespread clot formation and tissue damage. This study aimed to investigate early diagnostic markers of sepsis-associated DIC by comparing inflammatory factor levels, 28-day survival rates, coagulation function, and markers between patients with sepsis (non-DIC group) and those with sepsis-induced DIC (DIC group). The study analyzed the diagnostic efficacy of coagulation function and markers in predicting the occurrence and prognosis of sepsis-associated DIC, presenting survival curves. Results indicated significantly increased levels of APTT, TAT, tPAIC, PIC, and sTM in the DIC group compared to the non-DIC group. Sequential Organ Failure Assessment (SOFA) scores on days 1, 3, and 7 were notably lower in the non-DIC group. Correlation analysis revealed positive associations between PT, APTT, TAT, tPAIC, PIC, sTM levels, and SOFA scores, as well as negative associations with Fib and SOFA scores. Survival curves showed substantially lower mortality rates in the non-DIC group, highlighting significant survival disparities between groups. Combining all four coagulation indicators (TAT+ tPAIC + PIC + sTM) showed promising diagnostic value in evaluating disease severity, early DIC diagnosis, and sepsis prognosis.

[Chemical constituents from stem bark of Aquilaria sinensis and their antibacterial activity against Helicobacter pylori].

The stem bark of Aquilaria sinensis(Thymelaeaceae), with the local name of "Li-Wa-Zi-Xing", is used in traditional Yi medicine for treating chronic gastritis and other diseases. However, its active ingredients remain currently unknown. In this study, Helicobacter pylori(Hp) is used in anti-bacterial experiments to test the active compounds derived from A. sinensis stem bark. Nineteen compounds were isolated from the stem bark of A. sinensis by column chromatography, high-performance liquid chromatography, recrystallization, etc. Aquilaridiester(1) is a new lignan. The other eighteen compounds were reported before, including docosyl caffeate(2), 6-hydroxy-2-[2-(4-methoxyphenyl)ethyl]-4H-1-benzopyran-4-one(3), qinanone A(4), 6-hydroxy-2-(2-phenylethyl)chromone(5), 6-hydroxy-2-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-4H-1-benzopyran-4-one(6), 6-hydroxy-2-[2-(3-methoxy-4-hydroxyphenyl)ethyl]-4H-1-benzopyran-4-one(7), 6-hydroxy-2-[2-(3,4-dimethoxyphenyl)ethyl]chromone(8), 6-hydroxy-2-[(1E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-4H-1-benzopyran-4-one(9), genkwanin(10), 5-hydroxy-2-(4-hydroxy-3,5-dimethoxyphenyl)-7-methoxy-4H-1-benzopyran-4-one(11), 3-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone(12),(+)-syringaresinol(13), zhebeiresinol(14), aquilarin A(15), caruilignan D(16),(-)-ficusal(17), pistaciamide(18), and protocatechuic acid(19). The anti-bacterial results show that compounds 2-7, 10-11, and 13 have inhibitory activity against Hp. Among them, 6-hydroxy-2-(2-phenylethyl)chromone(5) and 6-hydroxy-2-[2-(3-methoxy-4-hydroxyphenyl)ethyl]-4H-benzopyran-4-one(7) have superior inhibitory effects on Hp to others, with the same minimum inhibitory concentration(MIC) of 6.25 µmol·L~(-1). The 2-(2-phenylethyl)chromones are the major active ingredients in A. sinensis stem bark.

Rapid and direct detection of m6A methylation by DNAzyme-based and smartphone-assisted electrochemical biosensor.

m6A methylation detection is crucial for understanding RNA functions, revealing disease mechanisms, guiding drug development and advancing epigenetics research. Nevertheless, high-throughput sequencing and liquid chromatography-based traditional methods still face challenges to rapid and direct detection of m6A methylation. Here we report a DNAzyme-based and smartphone-assisted electrochemical biosensor for rapid detection of m6A. We initially identified m6A methylation-sensitive DNAzyme mutants through site mutation screening. These mutants were then combined with tetrahedral DNA to modify the electrodes, creating a 3D sensing interface. The detection of m6A was accomplished by using DNAzyme to capture and cleave the m6A sequence. The electrochemical biosensor detected the m6A sequence at nanomolar concentrations with a low detection limit of 0.69 nM and a wide detection range from 10 to 104 nM within 60 min. As a proof of concept, the 3'-UTR sequence of rice was selected as the m6A analyte. Combined with a smartphone, our biosensor shows good specificity, sensitivity, and easy-to-perform features, which indicates great prospects in the field of RNA modification detection and epigenetic analysis.

Assessing osteoporosis and bone mineral density through 18F-NaF uptake at lumbar spine.

OBJECTIVES: The use of 18F-Sodium fluoride (NaF) PET/CT is established in the detection of metastatic bone disease, yet its utility in osteoporosis remains underexplored. This research aims to assess the variations in 18F-NaF uptake among individuals with differing bone mineral density (BMD) and to examine the relationship between 18F-NaF uptake and BMD. METHODS: In this retrospective study, 199 patients (average age 56 ± 6, comprising 52 males and 147 females) with a history of cancer were analyzed. Each participant underwent both 18F-NaF PET/CT and lumbar dual-energy X-ray absorptiometry (DXA) scans within a span of 7 days. Based on DXA outcomes, patients and their lumbar vertebrae were categorized into normal BMD, osteopenia, and osteoporosis groups. The lumbar 18F-NaF uptake across these groups were compared, and to explore the association between lumbar standardized uptake values (SUV) values and BMD. The efficacy of 18F-NaF uptake in diagnosing osteoporosis or osteopenia was also evaluated. Analysis was conducted using Mann-Whitney U tests, Spearman regression, and receiver operating characteristic (ROC) curve analysis through GraphPad Prism 10.0. RESULTS: A total of 796 lumbar vertebrae from 199 patients were measured. It was observed that osteoporotic patients had significantly lower 18F-NaF uptake than those with osteopenia and normal BMD across the L1-L4 lumbar vertebrae (P < 0.0001). In a vertebra-based analysis, normal BMD vertebrae exhibited the highest maximum SUV(SUVmax) compared to osteopenic (8.13 ± 1.28 vs. 6.61 ± 1.01, P < 0.0001) and osteoporotic vertebrae (8.13 ± 1.28 vs. 4.82 ± 1.01, P < 0.0001). There was a positive correlation between lumbar 18F-NaF uptake and BMD across all vertebrae, with correlation coefficients exceeding 0.5 (range: 0.57-0.8). The area under the ROC curve values were notably high, at 0.96 for osteoporosis and 0.83 for osteopenia diagnosis. CONCLUSION: This study demonstrates distinct 18F-NaF uptake patterns among individuals with varying BMD levels, with a positive correlation between 18F-NaF uptake and BMD. These findings highlight the potential of 18F-NaF PET/CT as a supportive diagnostic method in the management of osteoporosis.

Characteristics and phylogenetic analysis of the complete chloroplast genome of Mesembryanthemum cordifolium L. F. (Aizoaceae).

Mesembryanthemum cordifolium, a perennial plant with crassulacean acid metabolism (CAM) in the Aizoaceae family, has significant ornamental and medicinal values. In this study, we reported the first complete chloroplast genome sequence of this species. The total genome size was 153,734 bp in length, including a large single-copy (LSC) region of 85,692 bp, a small single-copy (SSC) region of 18,212 bp, and a pair of inverted repeat (IR) regions of 24,915 bp by each. The overall GC content of the M. cordifolium chloroplast genome was 37.08%. The genome encodes 131 genes, comprising 87 protein-coding genes (PCGs), 36 transfer RNA genes (tRNAs), and eight ribosomal RNA genes (rRNAs). Phylogenetic analysis shows this species was relatively close to M. crystallinum. This chloroplast genome sequence will be valuable for species discrimination and for understanding phylogenetic relationships within the genus Mesembryanthemum.

PICKLE-mediated nucleosome condensing drives H3K27me3 spreading for the inheritance of Polycomb memory during differentiation.

Spreading of H3K27me3 is crucial for the maintenance of mitotically inheritable Polycomb-mediated chromatin silencing in animals and plants. However, how Polycomb repressive complex 2 (PRC2) accesses unmodified nucleosomes in spreading regions for spreading H3K27me3 remains unclear. Here, we show in Arabidopsis thaliana that the chromatin remodeler PICKLE (PKL) plays a specialized role in H3K27me3 spreading to safeguard cell identity during differentiation. PKL specifically localizes to H3K27me3 spreading regions but not to nucleation sites and physically associates with PRC2. Loss of PKL disrupts the occupancy of the PRC2 catalytic subunit CLF in spreading regions and leads to aberrant dedifferentiation. Nucleosome density increase endowed by the ATPase function of PKL ensures that unmodified nucleosomes are accessible to PRC2 catalytic activity for H3K27me3 spreading. Our findings demonstrate that PKL-dependent nucleosome compaction is critical for PRC2-mediated H3K27me3 read-and-write function in H3K27me3 spreading, thus revealing a mechanism by which repressive chromatin domains are established and propagated.

[Spatial Heterogeneity and Key Influencing Factors of Soil Organic Carbon, Soil Total Nitrogen, and Carbon to Nitrogen Ratio in main plantations of Torreya grandis cv. Merrillii].

Soil organic carbon （SOC） and soil total nitrogen （STN） serve as important indicators of the elemental balance within forest ecosystems reflecting soil fertility and quality. Accurate knowledge regarding the spatial variability of regional SOC, STN, and C∶N ratio and their influencing factors is of great significance for precise fertilization and soil health. In this study, a total of 117 topsoil samples （0-20 cm in depth） based on a 1 km×1 km grid were collected in the Torreya grandis cv. Merrillii plantation in Zhejiang Province. A combination of multi-dimensional statistical approaches （random forest model, structural equation model, redundancy analysis, and variation partitioning analysis） and diverse spatial analytical techniques （geostatistics, Moran's I index, etc.） were applied to reveal the spatial distributions and influencing factors of SOC, STN, and C∶N ratio in the Torreya. grandis cv. Merrillii region. The results showed that the average ω（SOC）, ω（STN）, and C∶N ratio were 17.63 g·kg-1, 1.48 g·kg-1, and 12.65, respectively, and their coefficients of variation were 68.08%, 67.41%, and 46.03%, respectively, indicating a moderate degree of variability. In general, the SOC, STN, and C∶N ratio of the Torreya grandis cv. Merrillii plantations were at an intermediate level in the national plantation. The semi-variance results showed that the nugget/sill values of SOC, STN, and C∶N ratio were 49.98%, 45.88%, and 49.93%, respectively, demonstrating a moderate level of spatial autocorrelation. The spatial distribution results showed that SOC, STN, and C∶N ratio decreased from northeast to southwest, with the majority of the region exhibiting above-medium fertility levels of SOC. The results of correlation analysis and redundancy analysis indicated that AN, AP, and AK were significantly correlated with both SOC, STN, and C∶N ratio （P<0.05）. The results of random forest, structural equation model, and variation partitioning analysis evidenced that the main influencing factors of SOC and STN were soil-available nutrients （AN, AP, and AK）. Therefore, our results could provide important insights for enhancing soil carbon and nitrogen pools in special plantations in Zhejiang Province, enhancing the capacity of plantations to adapt to regional climate change through ecological measures such as appropriate fertilization practices and strategic understory vegetation cultivation.

Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC.

In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator's choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

Zearalenone Triggers Programmed Cell Death and Impairs Milk Fat Synthesis via the AKT-mTOR-PPARγ-ACSL4 Pathway in Bovine Mammary Epithelial Cells.

Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 µM and 20 µM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.

Phosphorus dynamics in volcanic soils of Weizhou Island, China: implications for environmental and agricultural applications.

The dynamics of phosphorus are intricately governed by geological and ecological processes. Examining phosphorus dynamics in volcanic islands can enhance our comprehension of its behavior within such unique geological systems. However, research on phosphorus dynamics in volcanic islands remains limited. We investigated the phosphorus content of volcaniclastic rocks and basalt soils from Weizhou Island, China, to understand the influencing factors on phosphorus dynamics. The results indicate that in the volcaniclastic profile, phosphorus concentrates at 20-40 cm (17 mg/kg), decreases at 40-60 cm (11.9 mg/kg), and increases at 80-200 cm up to 46.4 mg/kg proximate to the bedrock, for the basalt profile, phosphorus content increases from the surface (80.2 mg/kg) towards the bedrock (83.9 mg/kg). The differences in phosphorus distribution between volcaniclastic rocks and basalts reflect the influence of parent material, rock weathering degree, carbonate content, topographic elevation, sea level changes, and geological activities. A strong positive correlation (R = 0.96907) between total and available phosphorus has been observed, suggesting that total phosphorus content effectively predicts available phosphorus content. Volcaniclastic rocks in wharves and high-elevation areas show low total phosphorus, while forest land with dense vegetation and neutral to alkaline soil supports higher total phosphorus due to enhanced bioavailability for plant absorption and utilization. Overall, the basalt soil of the volcanic island Weizhou Island demonstrates superior long-term fertility compared to the volcaniclastic soil. Despite its low total phosphorus content, it mainly exists in a highly bioavailable form, facilitating plant absorption, which is crucial for enhancing agricultural yields and ecosystem restoration on volcanic islands.