Lightweight safflower cluster detection based on YOLOv5.

The effective detection of safflower in the field is crucial for implementing automated visual navigation and harvesting systems. Due to the small physical size of safflower clusters, their dense spatial distribution, and the complexity of field scenes, current target detection technologies face several challenges in safflower detection, such as insufficient accuracy and high computational demands. Therefore, this paper introduces an improved safflower target detection model based on YOLOv5, termed Safflower-YOLO (SF-YOLO). This model employs Ghost_conv to replace traditional convolution blocks in the backbone network, significantly enhancing computational efficiency. Furthermore, the CBAM attention mechanism is integrated into the backbone network, and a combined L C I O U + N W D loss function is introduced to allow for more precise feature extraction, enhanced adaptive fusion capabilities, and accelerated loss convergence. Anchor boxes, updated through K-means clustering, are used to replace the original anchors, enabling the model to better adapt to the multi-scale information of safflowers in the field. Data augmentation techniques such as Gaussian blur, noise addition, sharpening, and channel shuffling are applied to the dataset to maintain robustness against variations in lighting, noise, and visual angles. Experimental results demonstrate that SF-YOLO surpasses the original YOLOv5s model, with reductions in GFlops and Params from 15.8 to 13.2 G and 7.013 to 5.34 M, respectively, representing decreases of 16.6% and 23.9%. Concurrently, SF-YOLO's mAP0.5 increases by 1.3%, reaching 95.3%. This work enhances the accuracy of safflower detection in complex agricultural environments, providing a reference for subsequent autonomous visual navigation and automated non-destructive harvesting technologies in safflower operations.

High Spatial-Resolution and Acquisition-Efficiency Cardiac MR T1 Mapping Based on Radial bSSFP and a Low-Rank Tensor Constraint.

BACKGROUND: Cardiac T1 mapping is valuable for evaluating myocardial fibrosis, yet its resolution and acquisition efficiency are limited, potentially obscuring visualization of small pathologies. PURPOSE: To develop a technique for high-resolution cardiac T1 mapping with a less-than-100-millisecond acquisition window based on radial MOdified Look-Locker Inversion recovery (MOLLI) and a calibrationless space-contrast-coil locally low-rank tensor (SCC-LLRT) constrained reconstruction. STUDY TYPE: Prospective. SUBJECTS/PHANTOM: Sixteen healthy subjects (age 25 ± 3 years, 44% females) and 12 patients with suspected cardiomyopathy (age 57 ± 15 years, 42% females), NiCl2-agar phantom. FIELD STRENGTH/SEQUENCE: 3-T, standard MOLLI, radial MOLLI, inversion-recovery spin-echo, late gadolinium enhancement. ASSESSMENT: SCC-LLRT was compared to a conventional locally low-rank (LLR) method through simulations using Normalized Root-Mean-Square Error (NRMSE) and Structural Similarity Index Measure (SSIM). Radial MOLLI was compared to standard MOLLI across phantom, healthy subjects, and patients. Three independent readers subjectively evaluated the quality of T1 maps using a 5-point scale (5 = best). STATISTICAL TESTS: Paired t-test, Wilcoxon signed-rank test, intraclass correlation coefficient analysis, linear regression, Bland-Altman analysis. P < 0.05 was considered statistically significant. RESULTS: In simulations, SCC-LLRT demonstrated a significant improvement in NRMSE and SSIM compared to LLR. In phantom, both radial MOLLI and standard MOLLI provided consistent T1 estimates across different heart rates. In healthy subjects, radial MOLLI exhibited a significantly lower mean T1 (1115 ± 39 msec vs. 1155 ± 36 msec), similar T1 SD (74 ± 14 msec vs. 67 ± 23 msec, P = 0.20), and similar T1 reproducibility (28 ± 18 msec vs. 22 ± 15 msec, P = 0.34) compared to standard MOLLI. In patients, the proposed method significantly improved the sharpness of myocardial boundaries (4.50 ± 0.65 vs. 3.25 ± 0.43), the conspicuity of papillary muscles and fine structures (4.33 ± 0.74 vs. 3.33 ± 0.47), and artifacts (4.75 ± 0.43 vs. 3.83 ± 0.55). The reconstruction time for a single slice was 5.2 hours. DATA CONCLUSION: The proposed method enables high-resolution cardiac T1 mapping with a short acquisition window and improved image quality. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Principles and Methods for Improving the Thermoelectric Performance of SiC: A Potential High-Temperature Thermoelectric Material.

Thermoelectric materials that can convert thermal energy to electrical energy are stable and long-lasting and do not emit greenhouse gases; these properties render them useful in novel power generation devices that can conserve and utilize lost heat. SiC exhibits good mechanical properties, excellent corrosion resistance, high-temperature stability, non-toxicity, and environmental friendliness. It can withstand elevated temperatures and thermal shock and is well suited for thermoelectric conversions in high-temperature and harsh environments, such as supersonic vehicles and rockets. This paper reviews the potential of SiC as a high-temperature thermoelectric and third-generation wide-bandgap semiconductor material. Recent research on SiC thermoelectric materials is reviewed, and the principles and methods for optimizing the thermoelectric properties of SiC are discussed. Thus, this paper may contribute to increasing the application potential of SiC for thermoelectric energy conversion at high temperatures.

Deciphering the pollution risks, sources and their links of heavy metals in soils.

Heavy metals in soils pose serious ecological and health risks. To make efficient strategies for mitigating the underlying hazards, it is critical to reveal the pollution sources and their links with the risks. Researchers have investigated source identification and risk evaluation of heavy metals in soils, yet few have systematically deciphered the source-sink relationship of soil metals and the links between source apportionment and risk assessment. In the study, an integrated technological framework has been proposed to address the gaps, and applied to characterize the pollution risks, sources and their links of soil metals in a typical coal resource city in China. The assessment using geochemical tool and ecological risk index shows the soils in study area are polluted by Cd, Hg, Cr, As and Pb in varied degrees, and particularly, Cd and Hg present significant ecological risk. Two advanced receptor models (multivariate curve resolution-weighted alternating least-squares and multilinear engine 2) are comparatively applied for apportioning the potential sources of soil metals, and the results suggest the two models have identified similar sources (r2 > 0.90), including agricultural activities, atmospheric depositions and industrial discharges with contributions of 35.5 %-38.3 %, 30.3 %-35.1 %, and 26.6 %-34.1 %, respectively. Then, apportionment results of the two models are jointly employed for evaluating the source-specific health risks of metals in the environment using a probabilistic risk assessment model. The risk levels within the area are overall acceptable or tolerable, and relatively, the industrial discharges present higher contribution on the non-carcinogenic and carcinogenic risks of soil metals to public. Findings will help the managers to design targeted policies for reducing the risks of soil metals, and the framework proposed provides a useful guideline to better understand the source-risk relationship of soil metals in other environments worldwide.

Distinct species turnover patterns shaped the richness of antibiotic resistance genes on eight different microplastic polymers.

Elucidating the formation mechanism of plastisphere antibiotic resistance genes (ARGs) on different polymers is necessary to understand the ecological risks of plastisphere ARGs. Here, we explored the turnover and assembly mechanism of plastisphere ARGs on 8 different microplastic polymers (4 biodegradable (bMPs) and 4 non-biodegradable microplastics (nMPs)) by metagenomic sequencing. Our study revealed the presence of 479 ARGs with abundance ranging from 41.37 to 58.17 copies/16S rRNA gene in all plastispheres. These ARGs were predominantly multidrug resistance genes. The richness of plastisphere ARGs on different polymers had a significant correlation with the contribution of species turnover to plastisphere ARGs ß diversity. Furthermore, polymer type was the most critical factor affecting the composition of plastisphere ARGs. More opportunistic pathogens carrying diverse ARGs on BMPs (PBAT, PBS, and PHA) with higher horizontal gene transfer potential may further magnify the ecological risks and human health threats. For example, the opportunistic pathogens Riemerella anatipestifer, Vibrio campbellii, and Vibrio cholerae are closely related to human production and life, which were the important potential hosts of many plastisphere ARGs and mobile genetic elements on BMPs. Thus, we emphasize the urgency of developing the formation mechanism of plastisphere ARGs and the necessity of controlling BMPs and ARG pollution, especially BMPs, with ever-increasing usage in daily life.

Gut Microbiota and Its Metabolites: The Emerging Bridge Between Coronary Artery Disease and Anxiety and Depression?

The increasing studies indicated that cardiovascular diseases, such as coronary artery disease (CAD), usually induce and exacerbate psychological problems, including anxiety and depression. These psychological issues are admitted as independent risk factors of heart disease as well. The interaction between CAD and anxiety and depression deteriorates the development and prognosis of CAD, which severely threatens the quality of life of patients. Although the existing mechanisms revealed the pathological relationship between CAD and anxiety and depression, there are few studies investigating the correlation between CAD and anxiety and depression from the aspect of gut microbiota (GM) and its metabolites. Therefore, in this review, we summarized whether GM and its metabolites are the emergent bridge between CAD and anxiety and depression. The results showed that there are four kinds of jointly up-regulated bacteria (i.e., Staphylococcus, Escherichia coli, Helicobacter pylori, and Shigella) and five kinds of jointly down-regulated bacteria (i.e., Prevotella, Lactobacillus, Faecalibacterium prausnitzii, Collinsella, and Bifidobacterium) in CAD as well as anxiety and depression. In addition, in CAD and anxiety and depression, the dysbiosis of the former four kinds of bacterium frequently leads to the outburst of inflammatory response, and the dysbiosis of the latter five kinds of bacterium is usually related to the metabolic abnormality of short-chain fatty acids, bile acids, and branched-chain amino acids. Therefore, we believe that GM and its metabolites act as the emergent bridge between CAD and anxiety and depression. The findings of this review provide novel insights and approaches for the clinical treatment of patients with both CAD and anxiety and depression.

Metamagnetic phase transition induced large magnetocaloric effect in a Dy0.5Ho0.5MnO3 single crystal.

Magnetic refrigeration based on the magnetocaloric effect is gaining interest in orthogonal or hexagonal rare-earth manganite. However, a more comprehensive understanding of the underlying mechanism is still required. We grew a high-quality single crystal of Dy0.5Ho0.5MnO3 using the optical floating zone method, since the parent crystals DyMnO3 and HoMnO3 have orthogonal and hexagonal structures, respectively. The magnetic and magnetocaloric properties and refrigeration mechanisms are thoroughly investigated. Doping modifies the magnetism according to the results obtained from the investigation of magnetic and dielectric properties and heat capacity. The spin reorientation transition shifts towards low temperature in comparison to HoMnO3. Near the Néel temperature of rare-earth sublattices (5 K), the highest changes in negative magnetic entropy under 0-70 kOe are 18 J kg-1 K-1 and 13 J kg-1 K-1 along the a- and c-axes, respectively. The low-temperature metamagnetic phase transition caused by the alterations in the magnetic symmetry of Ho3+ contributes to an increased magnetocaloric effect in comparison to the parent crystals, rendering it a promising choice for magnetic refrigeration applications. Dy0.5Ho0.5MnO3 exhibits a clear magnetocrystalline anisotropy with enhanced refrigeration capacity and negative magnetic entropy change along the a-axis. The adiabatic temperature change of Dy0.5Ho0.5MnO3 is 8.5 K, larger than that of HoMnO3, rendering it a promising choice for low-temperature magnetic refrigeration applications.

Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration.

Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.

MicroRNA-3061 downregulates the expression of PAX7/Wnt/Ca2+ signalling axis genes to induce premature ovarian failure in mice.

The in-depth mechanisms of microRNA regulation of premature ovarian failure (POF) remain unclear. Crispr-cas9 technology was used to construct transgenic mice. The qPCR and Western blot was used to detect the expression level of genes. H&E staining were used to detect ovarian pathological phenotypes. We found that the expression levels of microRNA-3061 were significantly higher in ovarian granulosa cells (OGCs) of POF mouse models than in controls. The miR-3061+/-/AMH-Cre+/- transgenic mice manifested symptoms of POF. RNA-Seq and luciferase reporter assay confirmed that the PAX7 was one of the target genes negatively regulated by microRNA-3061 (miR-3061-5p). Moreover, PAX7 mediated the expression of non-canonical Wnt/Ca2+ signalling pathway by binding to the motifs of promoters to stimulate the transcriptional activation of Wnt5a and CamK2a. In contrast, specific knock-in of microRNA-3061 in OGCs significantly downregulated the expression levels of PAX7 and inhibited the expression of downstream Wnt/Ca2+ signalling pathway. We also discerned a correlation between the expression levels of mRNAs of the Wnt/Ca2+ signalling pathway and the levels of E2 and FSH in POF patients by examining gene expression in the follicular fluid-derived exosomes of women. We confirmed that overexpression of microRNA-3061 induced proliferative inhibition of OGCs and ultimately induced POF in mice by suppressing the transcription factor PAX7 and downregulating expression levels of its downstream Wnt/Ca2+ signalling pathway genes.

Adar Regulates Drosophila melanogaster Spermatogenesis via Modulation of BMP Signaling.

The dynamic process of Drosophila spermatogenesis involves asymmetric division, mitosis, and meiosis, which ultimately results in the production of mature spermatozoa. Disorders of spermatogenesis can lead to infertility in males. ADAR (adenosine deaminase acting on RNA) mutations in Drosophila cause male infertility, yet the causative factors remain unclear. In this study, immunofluorescence staining was employed to visualize endogenous ADAR proteins and assess protein levels via fluorescence-intensity analysis. In addition, the early differentiation disorders and homeostatic alterations during early spermatogenesis in the testes were examined through quantification of transit-amplifying region length, counting the number of GSCs (germline stem cells), and fertility experiments. Our findings suggest that deletion of ADAR causes testicular tip transit-amplifying cells to accumulate and become infertile in older male Drosophila. By overexpressing ADAR in early germline cells, male infertility can be partially rescued. Transcriptome analysis showed that ADAR maintained early spermatogenesis homeostasis through the bone-morphogenetic-protein (BMP) signaling pathway. Taken together, these findings have the potential to help explore the role of ADAR in early spermatogenesis.

PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

Turning Ultra-Low Coercivity and Ultra-High Temperature Stability Within 897 K via Continuous Crystal Ordering Fluctuations.

High-performance soft magnetic materials are important for energy conservation and emission reduction. One challenge is achieving a combination of reliable temperature stability, high resistivity, high Curie temperature, and high saturation magnetization in a single material, which often comes at the expense of intrinsic coercivity-a typical trade-off in the family of soft magnetic materials with homogeneous microstructures. Herein, a nanostructured FeCoNiSiAl complex concentrated alloy is developed through a hierarchical structure strategy. This alloy exhibits superior soft magnetic properties up to 897 K, maintaining an ultra-low intrinsic coercivity (13.6 A m-1 at 297 K) over a wide temperature range, a high resistivity (138.08 µΩ cm-1 at 297 K) and the saturation magnetization with only a 16.7% attenuation at 897 K. These unusual property combinations are attributed to the dual-magnetic-state nature with exchange softening due to continuous crystal ordering fluctuations at the atomic scale. By deliberately controlling the microstructure, the comprehensive performance of the alloy can be tuned and controlled. The research provides valuable guidance for the development of soft magnetic materials for high-temperature applications and expands the potential applications of related functional materials in the field of sustainable energy.

Stereoscopic Polymer Network for Developing Mechanically Robust Flexible Perovskite Solar Cells with an Efficiency Approaching 25.

Flexible perovskite solar cells (pero-SCs) have the potential to overturn the application scenario of silicon photovoltaic technology. However, their mechanical instability severely impedes their practical applicability, and the corresponding intrinsic degradation mechanism remains unclear. In this study, the degradation behavior of flexible pero-SCs is systematically analyzed under mechanical stress and it is observed that the structural failure first occurs in the polycrystal perovskite film, then extend to interfaces. To suppress the structural failure, pentaerythritol triacrylate, a crosslinked molecule with three stereoscopic crosslink sites, is employed to establish a 3D polymer network in both the interface and bulk perovskite. This network reduced the Young's modulus of the perovskite and simultaneously enhanced the interfacial toughness. As a result, the formation of cracks and delamination, which occur under a high mechanical stress, is significantly suppressed in the flexible pero-SC, which consequently retained 92% of its initial power conversion efficiency (PCE) after 20 000 bending cycles. Notably, the flexible device also shows a record PCE of 24.9% (certified 24.48%).

Gut Microbiota-Derived 3-Hydroxybutyrate Blocks GPR43-Mediated IL6 Signaling to Ameliorate Radiation Proctopathy.

Radiation proctopathy (RP) is a common complication of radiotherapy for pelvic malignancies with high incidence. RP accompanies by microbial dysbiosis. However, how the gut microbiota affects the disease remains unclear. Here, metabolomics reveals that the fecal and serous concentrations of microbiota-derived 3-hydroxybutyrate (3HB) are significantly reduced in RP mice and radiotherapeutic patients. Moreover, the concentration of 3HB is negatively associated with the expression of proinflammatory IL6 that is increased along with the severity of radiation damage. 3HB treatment significantly downregulates IL6 expression and alleviates IL6-mediated radiation damage. Irradiated cell-fecal microbiota co-culture experiments and in vivo assays show that such a radioprotection of 3HB is mediated by GPR43. Microbiome analysis reveals that radiation leads to a distinct bacterial community compared to untreated controls, in which Akkermansia muciniphila is significantly reduced in RP mice and radiotherapeutic patients and is associated with lower 3HB concentration. Gavage of A. muciniphila significantly increases 3HB concentration, downregulates GPR43 and IL6 expression, and ameliorates radiation damage. Collectively, these results demonstrate that the gut microbiota, including A. muciniphila, induce higher concentrations of 3HB to block GPR43-mediated IL6 signaling, thereby conferring radioprotection. The findings reveal a novel implication of the gut-immune axis in radiation pathophysiology, with potential therapeutic applications.

Low field controllable continuous spin switching in the thulium-ytterbium single crystal.

We report the spin reorientation transition (SRT) and the low field controllable continuous spin switching (SSW) of the Tm0.75Yb0.25FeO3 (TYFO) single crystal in this study. The SRT, characterized by the transition from Γ2(Fx, Cy, Gz)-Γ4(Gx, Ay, Fz), occurs within the temperature range of 20-27 K. Under an external magnetic field of 50 Oe, the SSW occurs along the c-axis at approximately 98 K due to the reversal of Tm3+ magnetic moment induced by the magnetic coupling change between Tm3+ and Fe3+, transitioning from a parallel to an antiparallel alignment. Notably, a continuous SSW is observed along the a-axis at low temperatures, which has not been previously reported in rare earth orthoferrites. This unique behavior can be easily manipulated by low magnetic fields within the temperature range of 2-20 K. Both the spin reorientation transition and spin switching phenomena in the TYFO single crystal arise from interactions between rare earth ions and iron ions and can be effectively regulated by applied low magnetic fields, making it a promising material for low-field spin devices.

Mitochondrial dynamics dysfunction: Unraveling the hidden link to depression.

Depression is a common mental disorder and its pathogenesis is not fully understood. However, more and more evidence shows that mitochondrial dynamics dysfunction may play an important role in the occurrence and development of depression. Mitochondria are the centre of energy production in cells, and are also involved in important processes such as apoptosis and oxidative stress. Studies have found that there are abnormalities in mitochondrial function in patients with depression, including mitochondrial morphological changes, mitochondrial dynamics disorders, mitochondrial DNA damage, and impaired mitochondrial respiratory chain function. These abnormalities may cause excessive free radicals and oxidative stress in mitochondria, which further damage cells and affect the balance of neurotransmitters, causing or aggravating depressive symptoms. Studies have shown that mitochondrial dynamics dysfunction may participate in the occurrence and development of depression by affecting neuroplasticity, inflammation and neurotransmitters. This article reviews the effects of mitochondrial dynamics dysfunction on the pathogenesis of depression and its potential molecular pathway. The restorers for the treatment of depression by regulating the function of mitochondrial dynamics were summarized and the possibility of using mitochondrial dynamics as a biomarker of depression was discussed.

Novel CAR-T cells targeting TRKB for the treatment of solid cancer.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.

An auxiliary strategy of partial least squares regression in pharmacokinetic/pharmacodynamic studies: A case of application of guhong injection in myocardial ischemia/reperfusion rats.

Guhong injection (GHI) has been applied in the therapy of cardio-cerebrovascular disease in clinic, but there is no report about the pharmacokinetic/pharmacodynamic (PK/PD) research on GHI treating myocardial ischemia/reperfusion (MI/R) injury in rats. In this study, eight compounds of GHI in plasma, including N-acetyl-L-glutamine (NAG), chlorogenic acid (CGA), hydroxysafflor yellow A (HSYA), p-coumaric acid ( pCA), rutin, hyperoside, kaempferol-3-O-rutinoside, and kaempferol-3-O-glucoside, were quantified by LC-MS/MS. We discovered that the values of t1/2ß, k12, V2, and CL2 were larger than those of t1/2α, k21, V1, and CL1 for all compounds. The levels of four biomarkers, creatine kinase-MB (CK-MB), cardiac troponin I (cTn I), ischemia-modified albumin (IMA), and alpha-hydroxybutyrate dehydrogenase (α-HBDH) in plasma were determined by ELISA. The elevated level of these biomarkers induced by MI/R was declined to different degrees via administrating GHI and verapamil hydrochloride (positive control). The weighted regression coefficients of NAG, HSYA, CGA, and pCA in PLSR equations generated from The Unscrambler X software (version 11) were mostly minus, suggesting these four ingredients were positively correlated to the diminution of the level of four biomarkers. Emax and ED50, two parameters in PK/PD equations that were obtained by adopting Drug and Statistics software (version 3.2.6), were almost enlarged with the rise of GHI dosage. Obviously, all analytes were dominantly distributed and eliminated in the peripheral compartment with features of rapid distribution and slow elimination. With the enhancement of GHI dosage, the ingredients only filled in the central compartment if the peripheral compartment was replete. Meanwhile, high-dose of GHI generated the optimum intrinsic activity, but the affinity of compounds with receptors was the worst, which may be caused by the saturation of receptors. Among the eight analytes, NAG, HSYA, CGA, and pCA exhibited superior cardioprotection, which probably served as the pharmacodynamic substance basis of GHI in treating MI/R injury.

Sintilimab plus anlotinib as second or further-line therapy for extensive disease small cell lung cancer: a phase 2 investigator-initiated non-randomized controlled trial.

Background: Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. Methods: The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1-14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Findings: Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9-28.2). The median PFS was 6.1 months (95% CI: 5.0-7.3). The OS was 12.7 months (95% CI: 7.1-18.2). The ORR was 56.8% (21/37, 95% CI: 40.0-73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7-99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Interpretation: Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Funding: Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.