The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

Design, Synthesis, and Mode of Action of Thioacetamide Derivatives as the Algicide Candidate Based on Active Substructure Splicing Strategy.

Lakes and reservoirs worldwide are experiencing a growing problem with harmful cyanobacterial blooms (HCBs), which have significant implications for ecosystem health and water quality. Algaecide is an effective way to control HCBs effectively. In this study, we applied an active substructure splicing strategy for rapid discovery of algicides. Through this strategy, we first optimized the structure of the lead compound S5, designed and synthesized three series of thioacetamide derivatives (series A, B, C), and then evaluated their algicidal activities. Finally, compound A3 with excellent performance was found, which accelerated the process of discovering and developing new algicides. The biological activity assay data showed that A3 had a significant inhibitory effect on M. aeruginosa. FACHB905 (EC50 = 0.46 µM) and Synechocystis sp. PCC6803 (EC50 = 0.95 µM), which was better than the commercial algicide prometryn (M. aeruginosa. FACHB905, EC50 = 6.52 µM; Synechocystis sp. PCC6803, EC50 = 4.64 µM) as well as better than lead compound S5 (M. aeruginosa. FACHB905, EC50 = 8.80 µM; Synechocystis sp. PCC6803, EC50 = 7.70 µM). The relationship between the surface electrostatic potential, chemical reactivity, and global electrophilicity of the compounds and their activities was discussed by density functional theory (DFT). Physiological and biochemical studies have shown that A3 might affect the photosynthesis pathway and antioxidant system in cyanobacteria, resulting in the morphological changes of cyanobacterial cells. Our work demonstrated that A3 might be a promising candidate for the development of novel algicides and provided a new active skeleton for the development of subsequent chemical algicides.

A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS.

KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.

Applying Machine Learning Analysis Based on Proximal Femur of Abdominal Computed Tomography to Screen for Abnormal Bone Mass in Femur.

RATIONALE AND OBJECTIVES: To evaluate the performance of machine learning analysis based on proximal femur of abdominal computed tomography (CT) scans in screening for abnormal bone mass in femur. MATERIALS AND METHODS: 222 patients aged 50 years or older who underwent abdominal CT and dual-energy X-ray absorptiometry scans within 14 days were retrospectively enrolled. The patients were randomly assigned to a training cohort (n = 155) and a testing cohort (n = 67) in a ratio of 7:3. A total of 2288 candidate radiomic features were extracted from the volume region of interest - the left proximal femur of the abdominal CT scans. The most valuable radiomic features were selected using minimum-Redundancy Maximum-Relevancy and the least absolute shrinkage and selection operator to construct the radiomics model. The predictive performance was assessed with receiver operating characteristic curve. RESULTS: 13 features were chosen to establish the radiomics model. The radiomics model using logistic regression displayed excellent prediction performance in distinguishing normal bone mass and abnormal bone mass, with the area under the curve (AUC), accuracy, sensitivity and specificity of 0.917 (95% CI, 0.867-0.967), 0.826, 0.935 and 0.780 in the training cohort. The testing cohort indicated a better performance with AUC, accuracy, sensitivity and specificity of 0.963 (95% CI, 0.919-0.999), 0.851, 0.923 and 0.889. CONCLUSION: The radiomics model based on proximal femur of abdominal CT scans had a high predictive performance to identify abnormal bone mass in femur, which can be used as a tool for opportunistic osteoporosis screening.

Correlation between AI-based CT organ features and normal lung dose in adjuvant radiotherapy following breast-conserving surgery: a multicenter prospective study.

BACKGROUND: Radiation pneumonitis (RP) is one of the common side effects after adjuvant radiotherapy in breast cancer. Irradiation dose to normal lung was related to RP. We aimed to propose an organ features based on deep learning (DL) model and to evaluate the correlation between normal lung dose and organ features. METHODS: Patients with pathology-confirmed invasive breast cancer treated with adjuvant radiotherapy following breast-conserving surgery in four centers were included. From 2019 to 2020, a total of 230 patients from four nationwide centers in China were screened, of whom 208 were enrolled for DL modeling, and 22 patients from another three centers formed the external testing cohort. The subset of the internal testing cohort (n = 42) formed the internal correlation testing cohort for correlation analysis. The outline of the ipsilateral breast was marked with a lead wire before the scanning. Then, a DL model based on the High-Resolution Net was developed to detect the lead wire marker in each slice of the CT images automatically, and an in-house model was applied to segment the ipsilateral lung region. The mean and standard deviation of the distance error, the average precision, and average recall were used to measure the performance of the lead wire marker detection model. Based on these DL model results, we proposed an organ feature, and the Pearson correlation coefficient was calculated between the proposed organ feature and ipsilateral lung volume receiving 20 Gray (Gy) or more (V20). RESULTS: For the lead wire marker detection model, the mean and standard deviation of the distance error, AP (5 mm) and AR (5 mm) reached 3.415 ± 4.529, 0.860, 0.883, and 4.189 ± 8.390, 0.848, 0.830 in the internal testing cohort and external testing cohort, respectively. The proposed organ feature calculated from the detected marker correlated with ipsilateral lung V20 (Pearson correlation coefficient, 0.542 with p < 0.001 in the internal correlation testing cohort and 0.554 with p = 0.008 in the external testing cohort). CONCLUSIONS: The proposed artificial Intelligence-based CT organ feature was correlated with normal lung dose in adjuvant radiotherapy following breast-conserving surgery in patients with invasive breast cancer. TRIAL REGISTRATION: NCT05609058 (08/11/2022).

Rapid preparation of high efficiency hydrogen evolution catalyst with hydrophilicity.

The electrolytic water method is an outstanding hydrogen production process because of its high stability and no restriction. A low-priced and efficient catalyst for electro-deposition of Ni-Co microspheres and nanoclusters on carbon steel (Ni-Co/CS) has been prepared by the dynamic hydrogen bubble template. In the 6 M KOH solution, Ni-Co/CS only requires an overpotential of 48 mV to provide a current density of 50 mA cm-2. At the same time, it also has a large electrochemically active specific surface area (ECSA) and a hydrophilic surface. In addition, the study about the influence of carbon steel (CS) on Ni-Co coatings and the comparison experiment for different base materials has been completed. The results prove that CS is an excellent base material for hydrogen production. It can help the Ni-Co catalyst to have a stable electrolysis in 6 M KOH for 500 h. The above properties of Ni-Co/CS catalyst make it a new choice of hydrogen production by electrolysis of water in practical applications.

RNA N6-methyladenosine demethylase FTO inhibits glucocorticoid-induced osteoblast differentiation and function in bone marrow mesenchymal stem cells.

Excess glucocorticoids (GCs) have been reported as key factors that impair osteoblast (OB) differentiation and function. However, the role of RNA N6-methyladenosine (m6 A) in this process has not yet been elucidated. In this study, we report that both the mRNA and protein expression of fat mass and obesity-associated gene (FTO), a key m6 A demethylase, were dose-dependently downregulated during OB differentiation by dexamethasone (DEX) in bone marrow mesenchymal stem cells (BMSCs), and FTO was gradually increased during OB differentiation. Meanwhile, FTO knockdown suppressed OB differentiation and mineralization, whereas overexpression of wide-type FTO, but not mutant FTO (mutated m6 A demethylase active site), reversed DEX-induced osteogenesis impairment. Interfering with FTO inhibited proliferation and the expression of Ki67 and Pcna in BMSCs during OB differentiation, whereas forced expression of wide-type FTO improved DEX-induced inhibition of BMSCs proliferation. Moreover, FTO knockdown reduced the mRNA stability of the OB marker genes Alpl and Col1a1, and FTO-modulated OB differentiation via YTHDF1 and YTHDF2. In conclusion, our results suggest that FTO inhibits the GCs-induced OB differentiation and function of BMSCs.

Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1H)-ones were designed rationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10c exerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.

Design, Synthesis, and Bioassay for the Thiadiazole-Bridged Thioacetamide Compound as Cy-FBP/SBPase Inhibitors Based on Catalytic Mechanism Virtual Screening.

Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase (Cy-FBP/SBPase) was an important regulatory enzyme in cyanobacterial photosynthesis and was a potential target enzyme for screening to obtain novel inhibitors against cyanobacterial blooms. In this study, we developed a novel pharmacophore screening model based on the catalytic mechanism and substrate structure of Cy-FBP/SBPase and screened 26 S series compounds with different structures and pharmacophore characteristics from the Specs database by computer-assisted drug screening. These compounds exhibited moderate inhibitory activity against Cy-FBP/SBPase, with 9 compounds inhibiting >50% at 100 µM. Among them, compound S5 showed excellent inhibitory activity against both Cy-FBP/SBPase and Synechocystis sp. PCC6803 (IC50 = 6.7 ± 0.7 µM and EC50 = 7.7 ± 1.4 µM). The binding mode of compound S5 to Cy-FBP/SBPase was predicted using the molecular docking theory and validated by sentinel mutation and enzyme activity analysis. Physiochemical, gene transcription level, and metabolomic analyses showed that compound S5 significantly reduced the quantum yield of photosystem II and the maximum electron transfer rate, downregulated transcript levels of related genes encoding the Calvin cycle and photosystem, reduced the photosynthetic efficiency of cyanobacteria, thus inhibited metabolic pathways, such as the Calvin cycle and tricarboxylic acid cycle, and eventually achieved an efficient algicide. In addition, compound S5 had a high safety profile for human-derived cells and zebrafish. In summary, the novel pharmacophore screening model obtained from the current work provides an effective solution to the cyanobacterial bloom problem.

Structural insight into the substrate-binding mode and catalytic mechanism for MlrC enzyme of Sphingomonas sp. ACM-3962 in linearized microcystin biodegradation.

Removing microcystins (MCs) safely and effectively has become an urgent global problem because of their extremely hazardous to the environment and public health. Microcystinases derived from indigenous microorganisms have received widespread attention due to their specific MC biodegradation function. However, linearized MCs are also very toxic and need to be removed from the water environment. How MlrC binds to linearized MCs and how it catalyzes the degradation process based on the actual three-dimensional structure have not been determined. In this study, the binding mode of MlrC with linearized MCs was explored using a combination of molecular docking and site-directed mutagenesis methods. A series of key substrate binding residues, including E70, W59, F67, F96, S392 and so on, were identified. Sodium dodecane sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to analyze samples of these variants. The activity of MlrC variants were measured using high performance liquid chromatography (HPLC). We used fluorescence spectroscopy experiments to research the relationship between MlrC enzyme (E), zinc ion (M), and substrate (S). The results showed that MlrC enzyme, zinc ion and substrate formed E-M-S intermediates during the catalytic process. The substrate-binding cavity was made up of N and C-terminal domains and the substrate-binding site mainly included N41, E70, D341, S392, Q468, S485, R492, W59, F67, and F96. The E70 residue involved in both substrate catalysis and substrate binding. In conclusion, a possible catalytic mechanism of the MlrC enzyme was further proposed based on the experimental results and a literature survey. These findings provided new insights into the molecular mechanisms of the MlrC enzyme to degrade linearized MCs, and laid a theoretical foundation for further biodegradation studies of MCs.

Design, synthesis and mechanism research of novel algicide based on bioactive fragments synthesis strategy.

The frequency and intensity of harmful cyanobacterial blooms (HCBs) are increasing all over the world, their prevention and control have become a great challenge. In this paper, a series of 1,3,4-thiadiazole thioacetamides (T series) were designed and synthesized as potential algaecides. Among them, the compound T3 showed its best algacidal activity against Synechocystis sp. PCC 6803 (PCC 6803, EC50 = 1.51 µM) and Microcystis aeruginosa FACHB 905 (FACHB905, EC50 = 4.88 µM), which was more effective than the lead compound L1 (PCC6803, EC50 = 7.7 µM; FACHB905, EC50 = 8.8 µM) and the commercially available herbicide prometryn (PCC6803, EC50 = 4.64 µM；FACHB905, EC50 = 6.52 µM). Meanwhile, T3 showed a lower inhibitory activity (EC50 = 12.76 µM) than prometryn (EC50 = 7.98 µM) to Chlorella FACHB1227, indicating that T3 had selective inhibition to prokaryotic algae (PCC6803, FACHB905) and eukaryotic algae (FACHB1227). Furthermore, the algacidal and anti-algae activities of T3 were significantly better than those of prometryn, while the toxicity of zebrafish and human cells was less than prometryn. Electron microscope, physiological, biochemical and metabonomic analysis showed that T3 interfered with light absorption and light conversion during photosynthesis by significantly reducing chlorophyll content, thus inhibited metabolic pathways such as the Calvin cycle and TCA cycle, and eventually led to the cell rupture of cyanobacteria. These results afforded further development of effective and safe algaecides.

Crystal structural analysis and characterization for MlrC enzyme of Sphingomonas sp. ACM-3962 involved in linearized microcystin degradation.

Microcystinase C (MlrC), one key hydrolase of the microcystinase family, plays an important role in linearized microsystin (L-MC) degradation. However, the three-dimensional structure and structural features of MlrC are still unclear. This study obtained high specific activity and high purity of MlrC by heterologous expression, and revealed that MlrC derived from Sphingomonas sp. ACM-3962 (ACM-MlrC) can degrade linearized products of MC-LR, MC-RR and MC-YR to product 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid (Adda), indicating the degradation function and significance in MC-detoxification. More importantly, this study reported the crystal structure of ACM-MlrC at 2.6 Å resolution for the first time, which provides a basis for further understanding the structural characteristics and functions of MlrC. MlrC had a dual-domain feature, namely N and C terminal domain respectively. The N-terminal domain contained a Glutamate-Aspartate-Histidine-Histidine catalytic quadruplex coordinated with zinc ion in each monomer. The importance of zinc ions and their coordinated residues was analyzed by dialysis and site-directed mutagenesis methods. Moreover, the important influence of the N/C-terminal flexible regions of ACM-MlrC was also analyzed by sequence truncation, and then the higher yield and total activity of variants were obtained, which was beneficial to study the better function and application of MlrC.

A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.

Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strategy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was associated with susceptibility to Zika virus (ZIKV) infection. Loss of NDUFA4 led to decreased sensitivity to ZIKV, dengue virus, and SARS-CoV-2 infection. Isogenic hiPSC lines carrying non-risk alleles of SNPs or deletion of the cis-regulatory region lower sensitivity to viral infection. Mechanistic studies indicated that loss/reduction of NDUFA4 causes mitochondrial stress, which leads to the leakage of mtDNA and thereby upregulation of type I interferon signaling. This study provides proof-of-principle for the application of iPSC arrays in GWAS and identifies NDUFA4 as a previously unknown susceptibility locus for viral infection.

Development of a Potentially New Algaecide for Controlling Harmful Cyanobacteria Blooms Which is Ecologically Safe and Selective.

Harmful cyanobacterial blooms (HCBs) caused by Microcystis aeruginosa are of great concern as they negatively affect the aquatic environment and human health. Chemical methods could rapidly eradicate HCBs and have been used for many decades. However, many chemical reagents are not recommended to eliminate HCBs in the long term, given the possible destructive and toxic effects of the chemicals employed on non-target aquatic organisms. We developed a new algaecide, 2-((1,3,4-thiadiazol-2-yl)thio)-N-(4-chlorophenyl) acetamide (Q2), to control harmful cyanobacteria while being environmentally friendly and selective. In our study, Q2 effectively inhibited cyanobacterial growth, especially of M. aeruginosa, but did not affect eukaryotic algae in test concentrations. A critical mechanism was revealed by transcriptome and metagenomic results showing that Q2 affects multiple cellular targets of cyanobacteria for HCB control, including the destruction of organelles, damage in the photosynthesis center, as well as inhibition of gas vesicle growth, and these changes can be highly relevant to the decrease of quorum-sensing functional KEGG pathways. Furthermore, Q2 did not affect the microbial composition and could recover the disrupted aquatic functional pathways in a short period. This is different from the impact on ecosystem functioning of the traditionally used harmful algaecide diuron. All these results verified that Q2 could be friendly to the aquatic environment, providing a new directional choice in managing HCBs in the future.

Universal Preparation Strategy for Ultradurable Antibacterial Fabrics through Coating an Adhesive Nanosilver Glue.

Microbiological protection textile materials played an important role in the battle against the epidemic. However, the traditional active antimicrobial treatment of textiles suffers from narrow textile applicability, low chemical stability, and poor washability. Here, a high-strength adhesive nanosilver glue was synthesized by introducing nontoxic water-soluble polyurethane glue as a protectant. The as-prepared nanosilver glue could adhere firmly to the fiber surfaces by forming a flexible polymer film and could encapsulate nanosilver inside the glue. The as-prepared nanosilver had a torispherical structure with diameter of ~22 nm, zeta potential of -42.7 mV, and good dispersibility in water, and it could be stored for one year. Further studies indicated that the nanosilver glue had wide applicability to the main fabric species, such as cotton and polyester fabric, surgical mask, latex paint, and wood paint. The antimicrobial cotton and polyester fabrics were prepared by a simple impregnation-padding-baking process. The corresponding antimicrobial activity was positively correlated with nanosilver content. The treated fabrics (500 mg/kg) exhibited ultrahigh washing resistance (maintained over 99% antibacterial rates for 100 times of standard washing) and wear resistance (99% antibacterial rates for 8000 times of standard wearing), equivalent breathability to untreated fabric, improved mechanical properties, and good flexibility, demonstrating a potential in cleanable and reusable microbiological protection textiles.

Strain-boosted hyperoxic graphene oxide efficiently loading and improving performances of microcystinase.

Harmful Microcystis blooms (HMBs) and microcystins (MCs) that are produced by Microcystis seriously threaten water ecosystems and human health. This study demonstrates an eco-friendly strategy for simultaneous removal of MCs and HMBs by adopting unique hyperoxic graphene oxides (HGOs) as carrier and pure microcystinase A (PMlrA) as connecting bridge to form stable HGOs@MlrA composite. After oxidation, HGOs yield inherent structural strain effects for boosting the immobilization of MlrA by material characterization and density functional theory calculations. HGO5 exhibits higher loading capacities for crude MlrA (1,559 mg·g-1) and pure MlrA (1,659 mg·g-1). Moreover, the performances of HGO5@MlrA composite, including the capability of removing MCs and HMBs, the ecological and human safety compared to MlrA or HGO5 treatment alone, have been studied. These results indicate that HGO5 can be used as a promising candidate material to effectively improve the application potential of MlrA in the simultaneous removal of MCs and HMBs.

Clinical features and functions of a novel Lpl mutation C.986A>C (p.Y329S) in patient with hypertriglyceridemia.

OBJECTIVE: To investigate and assess the clinical features and functions of a new lipoprotein lipase (Lpl) gene mutation c.986A>C (p.Y329S) found in hypertriglyceridemia(HTG) patients from a Chinese family. METHODS: Five members of a family with the proband were diagnosed with HTG were investigated, and fasting peripheral blood was collected . The plasma was then used to measure triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein cholesterol (HDL-C), free fatty acids (FFA), and glucose tolerance. Following that, genomic deoxyribonucleic acid (DNA) was extracted from whole-blood samples using the QIAamp whole-blood DNA kit, and the coding exon regions and flanking regions of 95 dyslipidemia-related genes were captured using GenCap liquid-phase target gene capture technology. The activity of LPL and its mutation were then determined using cell assays, and the newly discovered LPL mutant was functionally analyzed. The binding site of fenofibrate and LPL, as well as the mutation, were subjected to predictive analysis. RESULTS: The LPL gene's c.986A>C (p.Y329S) heterozygous mutation was discovered, and patients with the mutation had the typical phenotype of LPL deficiency and weakened LPL activity. Furthermore, this mutant has been treated with fenofibrate, and its triglyceride level is perfectly controlled and stable. The prediction analysis of the fenofibrate and LPL binding sites reveals that the wild-type system, Phe378 contributes most to the binding energy of fenofibrate. In the mutant system, Tyr394, which contributes the most to the binding energy of fenofibrate, the contribution of S329 is greater than that of Y329 (0.9∼0.7 kal/mol) . After Y329 is mutated, the hydrogen bond data of fenofibrate and LPL will also increase to quote H-bond diagrams. CONCLUSIONS: A heterozygous mutation c.986A>C (p.Y329S) in exon 6 of Lpl gene occurs in the proband with familial HTG. Lpl c.986A>C (p.Y329S) mutation weakens the activity of the LPL, which may be the pathogenic mutation of HTG. In addition, The proband has been treated with fenofibrate and the triglyceride level is ideally controlled and stable. The prediction analysis of the fenofibrate and LPL binding site shows that the wild-type system, Phe378 contributes most to the binding energy of fenofibrate. In the mutant system, Tyr394, which contributes the most to the binding energy of fenofibrate, the contribution of S329 is greater than that of Y329 (0.9∼0.7 kal/mol). After Y329 is mutated, the hydrogen bond data of fenofibrate and LPL will also increase, which may be one of the reasons why the mutation has no effect on the therapeutic effect of fenofibrate.

Design, synthesis, high algicidal potency, and putative mode of action of new 2-cyclopropyl-4-aminopyrimidine hydrazones.

Control of cyanobacteria harmful algal blooms remains a global challenge. In the present study, a series of novel 2-cyclopropyl-4-aminopyrimidine hydrazones were designed and synthesized as potential algicides. Compounds 4a, 4b, 4h, 4j, 4k, 4l, and 4m showed potent inhibition against Synechocystis sp. PCC6803 (median effective concentration, EC50 = 1.1 to 1.7 µM) and Microcystis aeruginosa FACHB905 (EC50 = 1.2 to 2.0 µM), more potent than, or comparably with, copper sulfate (PCC6803, EC50 = 1.8 µM; FACHB905, EC50 = 2.2 µM) and prometryne (PCC6803, EC50 = 12.3 µM; FACHB905, EC50 = 7.2 µM). Compound 4k exhibited algicidal activity in an expanded culture system, and was less toxic than copper sulfate to zebrafish. Electron microscope analyses showed that 4k damaged cyanobacterial cells and decreased the number of thylakoid lamellae. Transcriptomic and qPCR analyses suggest that 4k interfered photosynthesis-related pathways. Treatment with 4k significantly decreased the maximum quantum yield of photosystem II and the photosynthetic electron transfer rate, and the resulting reactive oxygen species damaged thylakoid membranes and photosystem I. The results suggest that 4k is a potential lead for further development of effective and safe algicides.

Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulated arc therapy.

PURPOSE: To explore clinical and dosimetric predictors of acute hematologic toxicity (HT) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy (VMAT). METHODS AND MATERIALS: We retrospectively reviewed the clinical data of 184 cervical cancer patients who had concurrent chemotherapy and VMAT. Hematological parameters were collected during the treatment period. The total pelvic bone (TPB) was delineated retrospectively for dose-volume calculations. To compare the differences between two groups, the normality test findings were used to run a paired-samples t-test or Wilcoxon signed-rank test. Pearson's correlation analysis or Spearman's correlation was used to testing the correlation between the two variables. Binary logistic regression analysis was used to analyze associations between HT and possible risk factors. The receiver operating characteristic curve(ROC) was used to evaluate the best cut-off point for dosimetric planning constraints. RESULTS: The nadir of absolute monocyte count (AMC) was found to be positively correlated with the nadir of absolute white blood cells (WBC) count (r = 0.5378, 95% CI 0.4227-0.6357, P < 0.0001) and the nadir of absolute neutrophil count(ANC) (r = 0.5000, 95% CI 0.3794-0.6039, P < 0.0001). The AMC decreased and increased before the ANC and WBC. In multivariate logistic regression analysis, the chemotherapy regimens and the TPB_V20 were independent risk factors for developing grade ≥ 3 HT. The optimal TPB_V20 cut-off value identified by ROC curves and the Youden test was 71% (AUC = 0.788; 95% CI 0.722-0.845; P value < 0.001). CONCLUSIONS: The changing trend of AMC can be used as an effective predictor for the timing and severity of the ANC/WBC nadirs and prophylactic G-CSF administration. Maintain TPB_V20 < 71% and selecting single-agent cisplatin or carboplatin could significantly reduce grade ≥ 3 HT in cervical cancer patients undergoing concurrent chemoradiotherapy.