Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Macrophages in CRSwNP: Do they deserve more attention?

Chronic rhinosinusitis (CRS) represents a heterogeneous disorder primarily characterized by the persistent inflammation of the nasal cavity and paranasal sinuses. The subtype known as chronic rhinosinusitis with nasal polyposis (CRSwNP) is distinguished by a significantly elevated recurrence rate and augmented challenges in the management of nasal polyps. The pathogenesis underlying this subtype remains incompletely understood. Macrophages play a crucial role in mediating the immune system's response to inflammatory stimuli. These cells exhibit remarkable plasticity and heterogeneity, differentiating into either the pro-inflammatory M1 phenotype or the anti-inflammatory and reparative M2 phenotype depending on the surrounding microenvironment. In CRSwNP, macrophages demonstrate reduced production of Interleukin 10 (IL-10), compromised phagocytic activity, and decreased autophagy. Dysregulation of pro-resolving mediators may occur during the inflammatory resolution process, which could potentially hinder the adequate functioning of anti-inflammatory macrophages in facilitating resolution. Collectively, these factors may contribute to the prolonged inflammation observed in CRSwNP. Additionally, macrophages may enhance fibrin cross-linking through the release of factor XIII-A (FAXIII), promoting fibrin deposition and plasma protein retention. Macrophages also modulate vascular permeability by releasing Vascular endothelial growth factor (VEGF). Moreover, they may disrupt the balance between Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs), which favors extracellular matrix (ECM) degradation, edema formation, and pseudocyst development. Accumulating evidence suggests a close association between macrophage infiltration and CRSwNP; however, the precise mechanisms underlying this relationship warrant further investigation. In different subtypes of CRSwNP, different macrophage phenotypic aggregations trigger different types of inflammatory features. Increasing evidence suggests that macrophage infiltration is closely associated with CRSwNP, but the mechanism and the relationship between macrophage typing and CRSwNP endophenotyping remain to be further explored. This review discusses the role of different types of macrophages in the pathogenesis of different types of CRSwNP and their contribution to polyp formation, in the hope that a better understanding of the role of macrophages in specific CRSwNP will contribute to a precise and individualized understanding of the disease.

Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney, and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways.

BACKGROUND: Jianpi Gushen Huayu Decoction (JPGS) has been used to clinically treat diabetic nephropathy (DN) for many years. However, the protective mechanism of JPGS in treating DN remains unclear. AIM: To evaluate the therapeutic effects and the possible mechanism of JPGS on DN. METHODS: We first evaluated the therapeutic potential of JPGS on a DN mouse model. We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics. Furthermore, we examined the effects of JPGS on c-Jun N-terminal kinase (JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3). RESULTS: The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress. Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice. A total of 51 differential metabolites were screened. Pathway analysis results indicated that nine pathways significantly changed between the control and model groups, while six pathways significantly altered between the model and JPGS groups. Pathways related to cysteine and methionine metabolism; alanine, tryptophan metabolism; aspartate and glutamate metabolism; and riboflavin metabolism were identified as the key pathways through which JPGS affects DN. Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors. CONCLUSION: JPGS could markedly treat mice with streptozotocin (STZ)-induced DN, which is possibly related to the regulation of several metabolic pathways found in kidneys. Furthermore, JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathway-mediated apoptosis in DN mice.

Development and validation of nomogram models for predicting postoperative prognosis of early-stage laryngeal squamous cell carcinoma.

BACKGROUND: We aimed to investigate the postoperative prognosis in patients with early-stage laryngeal squamous cell carcinoma (LSCC) in association with the preoperative blood markers and clinicopathological characteristics and to develop nomograms for individual risk prediction. METHODS: The clinical data of 353 patients with confirmed early-stage LSCC between 2009 and 2018 were retrospectively retrieved from the First Affiliated Hospital with Nanjing Medical University. All patients were randomly divided into the training and testing groups in a 7:3 ratio. Univariate and multivariate analyses were performed, followed by the construction of nomograms to predict recurrence-free survival (RFS) and overall survival (OS). Finally, the nomograms were verified internally, and the predictive capability of the nomograms was evaluated and compared with that of tumour T staging. RESULTS: Univariate and multivariate analyses identified platelet counts (PLT), fibrinogen (FIB), and platelet to lymphocyte ratio (PLR) were independent factors for RFS, and FIB, systemic immune-inflammation index (SII), and haemoglobin (HGB) were independent prognostic factors for OS. The nomograms showed higher predictive C-indexes than T staging. Furthermore, decision curve analysis (DCA) revealed that the net benefit of the nomograms' calculation model was superior to that of T staging. CONCLUSIONS: We established and validated nomograms to predict postoperative 1-, 3- and 5-year RFS and OS in patients with early-stage LSCC based on significant blood markers and clinicopathological characteristics. These models might help clinicians make personalized treatment decisions.

[Systematic review and Meta-analysis of efficacy and safety of Bidouyan Oral Liquid in treatment of rhinosinusitis].

This study aimed to systematically review the efficacy and safety of Bidouyan Oral Liquid in the treatment of rhinosinu-sitis(RS). CNKI, Wanfang, SinoMed, VIP, Cochrane Library, PubMed, EMbase, Web of Science, and Ovid were searched for the randomized controlled trial(RCT) of Bidouyan Oral Liquid for the treatment of RS patients. Moreover, the reference lists and the grey literature were searched manually. Two researchers independently screened the literature and extracted data. The Cochrane collaboration's tool for assessing risk of bias(RoB 2.0) in randomized trial was used to assess the methodological quality of the included stu-dies. Meta-analysis was performed in RevMan 5.3 and Stata 12.0, and the grades of recommendation, assessment, development and evaluation(GRADE) was employed to evaluate the quality of evidence. A total of 54 RCTs(35 with drug combinations and 19 with single drugs) comprising 7 511 patients(3 973 in the observation group and 3 538 in the control group) were included. Meta-analysis showed that Bidouyan Oral Liquid + conventional treatment was superior to conventional treatment alone in increasing the total response rate(RR=1.19, 95%CI[1.15, 1.24], P<0.000 01) and decreasing the Lund-Kennedy scores(MD=-1.94, 95%CI[-2.61,-1.26], P<0.000 01), Lund-Mackay scores(MD=-2.14, 95%CI[-2.98,-1.31], P<0.000 01), and visual analogue scale(VAS) scores(MD_(total VAS scores)=-1.28, 95%CI[-1.56,-1.01], P<0.000 01; MD_(nasal congestion VAS scores)=-0.58, 95%CI[-0.89,-0.27], P=0.000 2; MD_(runny nose VAS scores)=-0.61, 95%CI[-0.93,-0.29], P=0.000 2; MD_(olfactory dysfunction VAS scores)=-0.43, 95%CI[-0.52,-0.34], P<0.000 01; MD_(head and facial pain VAS scores)=-0.41, 95%CI[-0.57,-0.26], P<0.000 01). Furthermore, the combined treatment outperformed conventional treatment alone in improving the mucociliary transport rate(MTR)(MD=1.64, 95%CI[1.08, 2.20], P<0.000 01) and lowering the levels of inflammatory cytokines{tumor necrosis factor-α(TNF-α)(SMD=-1.95, 95%CI[-2.57,-1.33], P<0.000 01), interleukin-6(IL-6)(SMD=-2.64, 95%CI[-4.08,-1.21], P=0.000 3)} in RS patients. In addition, the combined treatment did not increase the incidence of adverse reactions(RR=0.83, 95%CI[0.44, 1.57], P=0.57). Bidouyan Oral Liquid was superior to conventional treatment in increasing total response rate(RR=1.25, 95%CI[1.18, 1.32], P<0.000 01), decreasing the Lund-Kennedy(P<0.01) and Lund-Mackay scores(P<0.05), alleviating major symptoms(P_(total VAS scores)<0.01; P_(nasal congestion VAS scores)<0.01; P_(runny nose VAS scores)<0.01; P_(olfactory dysfunction VAS scores)<0.05; P_(head and facial pain VAS scores)<0.01), and decreasing adverse reactions(P=0.03). The results showed that either Bidouyan Oral Liquid or Bidouyan Oral Liquid + conventional treatment can increase the total response rate, decrease the Lund-Kennedy and Lund-Mackay scores, and mitigate major symptoms. In addition, Bidouyan Oral Liquid + conventional treatment improved MTR and reduced the expression of TNF-α and IL-6 without causing serious adverse events. However, due to the limited methodological quality of the included studies, large-sample and high-quality RCTs are needed to provide evidence support.

Hydrolytic endonucleolytic ribozyme (HYER) is programmable for sequence-specific DNA cleavage.

Ribozymes are catalytic RNAs with diverse functions including self-splicing and polymerization. This work aims to discover natural ribozymes that behave as hydrolytic and sequence-specific DNA endonucleases, which could be repurposed as DNA manipulation tools. Focused on bacterial group II-C introns, we found that many systems without intron-encoded protein propagate multiple copies in their resident genomes. These introns, named HYdrolytic Endonucleolytic Ribozymes (HYERs), cleaved RNA, single-stranded DNA, bubbled double-stranded DNA (dsDNA), and plasmids in vitro. HYER1 generated dsDNA breaks in the mammalian genome. Cryo-electron microscopy analysis revealed a homodimer structure for HYER1, where each monomer contains a Mg2+-dependent hydrolysis pocket and captures DNA complementary to the target recognition site (TRS). Rational designs including TRS extension, recruiting sequence insertion, and heterodimerization yielded engineered HYERs showing improved specificity and flexibility for DNA manipulation.

Preoperative CT Radiomics Nomogram for Predicting Microvascular Invasion in Stage I Non-Small Cell Lung Cancer.

RATIONALE AND OBJECTIVES: This study aims to develop and validate a nomogram integrating clinical-CT and radiomic features for preoperative prediction of microvascular invasion (MVI) in patients with stage I non­small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective study analyzed 188 cases of stage I NSCLC (63 MVI positives and 125 negatives), which were randomly assigned to training (n = 133) and validation cohorts (n = 55) at a ratio of 7:3. Preoperative non-contrast and contrast-enhanced CT (CECT) images were used to analyze computed tomography (CT) features and extract radiomics features. The student's t-test, the Mann-Whitney-U test, the Pearson correlation, the least absolute shrinkage and selection operator, and multivariable logistic analysis were used to select the significant CT and radiomics features. Multivariable logistic regression analysis was performed to build the clinical-CT, radiomics, and integrated models. The predictive performances were evaluated through the receiver operating characteristic curve and compared with the DeLong test. The integrated nomogram was analyzed regarding discrimination, calibration, and clinical significance. RESULTS: The rad-score was developed with one shape and four textural features. The integrated nomogram incorporating radiomics score, spiculation, and the number of tumor-related vessels (TVN) demonstrated better predictive efficacy than the radiomics and clinical-CT models in the training cohort (area under the curve [AUC], 0.893 vs 0.853 and 0.828, and p = 0.043 and 0.027, respectively) and validation cohort (AUC, 0.887 vs 0.878 and 0.786, and p = 0.761 and 0.043, respectively). The nomogram also demonstrated good calibration and clinical usefulness. CONCLUSION: The radiomics nomogram integrating the radiomics with clinical-CT features demonstrated good performance in predicting MVI status in stage I NSCLC. The nomogram may be a useful tool for physicians in improving personalized management of stage I NSCLC.

Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model.

Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a +/- Dravet syndrome and wild-type mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal Day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal Days 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal Day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wild-type. GABAergic signalling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density and GABAergic signalling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of Nav1.1 as a successful strategy to treat Dravet syndrome.

Five new and noteworthy species of Epidendroideae (Orchidaceae) from southwestern China based on morphological and phylogenetic evidence.

Five new orchid species from southwestern China's Yunnan Province and the Tibetan Autonomous Region, Neottialihengiae, Neottiachawalongensis, Papilionanthemotuoensis, Gastrochiluslihengiae, and Gastrochilusbernhardtianus, are described and illustrated. To confirm their identities, and to resolve phylogenetic relationships, we sequenced the complete plastomes of these taxa with their congeneric species, adding new plastomes of three Neottia species, two Papilionanthe species and nine Gastrochilus species. Combined with published plastid sequences, our well-resolved phylogeny supported the alliance of N.lihengiae with the the N.grandiflora + N.pinetorum clade. Neottiachawalongensis is now sister to N.alternifolia, while P.motuoensis is closely related to P.subulata + P.teres. Conversely, phylogenetic analyses based on complete plastomes and plastid sequences showed inconsistent relationships among taxa in the genus Gastrochilus, but the two new species, G.lihengiae and G.bernhardtianus were supported by all datasets.

Structural RNA components supervise the sequential DNA cleavage in R2 retrotransposon.

Retroelements are the widespread jumping elements considered as major drivers for genome evolution, which can also be repurposed as gene-editing tools. Here, we determine the cryo-EM structures of eukaryotic R2 retrotransposon with ribosomal DNA target and regulatory RNAs. Combined with biochemical and sequencing analysis, we reveal two essential DNA regions, Drr and Dcr, required for recognition and cleavage. The association of 3' regulatory RNA with R2 protein accelerates the first-strand cleavage, blocks the second-strand cleavage, and initiates the reverse transcription starting from the 3'-tail. Removing 3' regulatory RNA by reverse transcription allows the association of 5' regulatory RNA and initiates the second-strand cleavage. Taken together, our work explains the DNA recognition and RNA supervised sequential retrotransposition mechanisms by R2 machinery, providing insights into the retrotransposon and application reprogramming.

Quercetin alleviates nanoparticle-induced osteolysis via deactivating pyroptosis.

As one of the most successful stories in modern medicine, total joint arthroplasty (TJA) is performed several million times worldwide every year. However, more than 20% of patients will suffer from aseptic loosening (AL) following periprosthetic osteolysis (PPO) in the next few years. Unfortunately, the only effective treatment for PPO, i.e., revision surgery, can cause great surgical trauma. It has been reported that the accumulation of reactive oxidative species (ROS) generated by exposure to wear particles could activate NLRP3 inflammasome in macrophages and accelerate the progress of osteolysis. Given that the conservative treatment is not effective and can be accompanied by apparent side effects, we, therefore, investigated the therapeutic effect of the natural compound quercetin (Que) on wear particle-induced osteolysis. Our results showed that Que could activate nuclear factor erythroid 2-related factor 2 (Nrf2) to remove ROS and deactivate inflammasome activation. Besides, the imbalance between osteoclastogenesis and osteogenesis induced by inflammatory cytokines was also rescued by Que. Collectively, our work demonstrates that Que may be a qualified candidate for the conservative treatment of wear particle-induced osteolysis.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

A Nomogram Incorporating Tumor-Related Vessels for Differentiating Adenocarcinoma In Situ from Minimally Invasive and Invasive Adenocarcinoma Appearing as Subsolid Nodules.

OBJECTIVES: To develop a nomogram incorporating the quantity of tumor-related vessels (TRVs) and conventional CT features (CCTFs) for the preoperative differentiation of adenocarcinoma in situ (AIS) from minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) appearing as subsolid nodules. METHODS: High-resolution CT target scans of 274 subsolid nodules from 268 patients were included in this study and randomly assigned to the training and validation groups at a ratio of 7:3. A nomogram incorporating CCTFs with the category of TRVs (CTRVs, using TRVs as categorical variables) and a final nomogram combining the number of TRVs (QTRVs) and CCTFs were constructed using multivariable logistic regression analysis. The performance levels of the two nomograms were evaluated and validated on the training and validation datasets and then compared. RESULTS: The CCTF-QTRV nomogram incorporating abnormal air bronchogram, density, number of dilated and distorted vessels and number of adherent vessels showed more favorable predictive efficacy than the CCTF-CTRV nomogram (training cohort: area under the curve (AUC) = 0.893 vs. 0.844, validation cohort: AUC = 0.871 vs. 0.807). The net reclassification index (training cohort: 0.188, validation cohort: 0.326) and the integrated discrimination improvement values (training cohort: 0.091, validation cohort: 0.125) indicated that the CCTF-QTRV nomogram performed significantly better discriminative ability than the CCTF-CTRV nomogram (all p-value < 0.05). CONCLUSIONS: The nomogram incorporating the QTRVs and CCTFs showed favorable predictive efficacy for differentiating AIS from MIA-IAC appearing as subsolid nodules and may serve as a potential tool to provide individual care for these patients.

Vacciniumusneoides (Ericaceae), a new species from Yunnan, China.

Vacciniumusneoides (Ericaceae), a new species from Fugong County of Yunnan Province, China is described and illustrated. This new species belongs to Vacciniumsect.Calcicolus and is most similar to V.brachyandrum, but differs in its branches hanging down, much smaller leaf blades, shorter inflorescences and pedicels, non-glandular tomentellate or densely pubescent inflorescence rachis and pedicels, densely white-pubescent hypanthium and pilose filaments.

Observations on the pollination and breeding systems of two Corybas species (Diurideae; Orchidaceae) by fungus gnats (Mycetophilidae) in southwestern Yunnan, China.

Modes of floral presentation in some angiosperms attract flies that eat and/or oviposit on seasonal fruiting bodies of fungi. Mushroom mimesis by orchid flowers has been speculated in the geoflorous, Indo-Malaysian-Australasian, genus Corybas s.l. for decades but most studies remain fragmentary and are often inconclusive. Here we report the roles of fungus gnats as pollinators of Corybas geminigibbus and C. shanlinshiensis in southwestern Yunnan, China, combining results of field observations, lab analyses, and manipulative experiments. Hand pollination experiments suggested both species were self-compatible but incapable of mechanical self-pollination, thereby requiring pollinators for fruit production. A female of a Phthinia sp. (Mycetophilidae) carried a pollinarium of C. geminigibbus dorsally on its thorax. Two females and one male of Exechia sp. (Mycetophilidae) visiting flowers of C. shanlinshiensis carried dorsal depositions of pollinaria on their thoraces. Mycetophilid eggs were not found in the flowers of either species. The comparative fragrance analyses of these flowers and three co-fruiting mushroom species did not suggest that either orchid species was a brood-site mimic. This is the first confirmation of the dispersal of pollinaria of Corybas species by fungus gnats in subtropical-temperate Asia.

Effect of pediatric- versus adult-type chemotherapy regimens on outcomes of allogeneic hematopoietic stem cell transplants for adult T-cell acute lymphoblastic leukemia in first complete remission.

The optimal chemotherapy regimen pre-transplantation for adult T-cell acute lymphoblastic leukemia (T-ALL) patients remains unknown. Here, we compared the transplant outcomes in 127 subjects receiving pediatric- (N = 57) or adult-type (N = 70) regimens pre-transplant. The corresponding 3-year cumulative incidences of relapse (CIR) was 7% (95% CI: 3-11%) and 29% (95% CI: 23-35%; P = 0.02), leukemia-free survivals (LFS) was 86% (95% CI: 81-91%) and 57% (95% CI: 51-63%; P = 0.003), overall survivals (OS) was 88% (95% CI: 84-92%) and 58% (95% CI: 52-64%; P = 0.002), the 1-year NRM was 4% (95% CI: 1-7%) and 9% (95% CI: 4-14%; P = 0.40). Multivariate analysis showed that pediatric-type regimen was associated with lower CIR (Hazard Ratio [HR] = 0.31 [95% CI: 0.09-1.00]; P = 0.05), better LFS (HR = 0.34 [95% CI: 0.15-0.78]; P = 0.01) and OS (HR = 0.30 [95% CI: 0.13-0.72]; P = 0.01). Our results suggested that adult T-ALL patients undergoing allo-HSCT might benefit from pediatric-type chemotherapy.

Cost-Effectiveness of Lenvatinib Plus Pembrolizumab or Everolimus as First-Line Treatment of Advanced Renal Cell Carcinoma.

Background: In this study, compared to sunitinib as one of the available treatment options, we aimed to evaluate the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus as first-line treatment for advanced renal cell carcinoma (RCC) patients in a Chinese health system setting. Methods: A partitioned survival model was developed to simulate patient disease and death. Transition probabilities and adverse reaction data were obtained from the CLEAR trial. The utility value was derived from literature. Costs were based on the Chinese drug database and local charges. Sensitivity analyses and were performed to assess the robustness of the model. Outcomes were measured as quality-adjusted life-years (QALYs), cumulative cost (COST), and incremental cost-effectiveness ratio (ICER). Results: The model predicted that the expected mean result in the lenvatinib plus pembrolizumab group (2.60 QALYs) was superior to that in the sunitinib group (2.13 QALYs) to obtain 0.47 QALYs, but the corresponding cost was 1,253,130 yuan greater, resulting in an ICER of 2,657,025 RMB/QALYs. Compared with the sunitinib group, the lenvatinib plus everolimus group (2.17 QALYs) gained 0.04 QALYs, with an additional cost of 32,851 yuan, resulting in an ICER of 77,6202 RMB/QALYs. Conclusions: Lenvatinib plus pembrolizumab or everolimus has no economic advantage over sunitinib in treating advanced RCC in the Chinese healthcare system.

Mechanical Study of Jian-Gan-Xiao-Zhi Decoction on Nonalcoholic Fatty Liver Disease Based on Integrated Network Pharmacology and Untargeted Metabolomics.

Jian-Gan-Xiao-Zhi decoction (JGXZ) has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms by which JGXZ improve NAFLD are still unclear. Methods. In this study, we first used a high-fat diet (HFD) to establish a NAFLD rat model to clarify the therapeutic effect of JGXZ on NAFLD. Secondly, we used network pharmacology to predict the potential targets of JGXZ on NAFLD, and then the key targets obtained from network pharmacology were verified. Finally, we used untargeted metabolomics to study the metabolic regulatory mechanism of JGXZ. Results. JGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and oil red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. In addition, network pharmacology research found that the potential targets of JGXZ on NAFLD pathway were mainly associated with improving oxidative stress, apoptosis, inflammation, lipid metabolism disorders, and insulin resistance. Further experimental verification confirmed that JGXZ could inhibit inflammation and improve oxidative stress, insulin resistance, and lipid metabolism disorders. Serum untargeted metabolomics analyses indicated that the JGXZ in the treatment of NAFLD may work through the linoleic acid metabolism, alpha-linolenic acid metabolism, tryptophan metabolism, and glycerophospholipid metabolism pathways. Conclusions. In conclusion, this study found that JGXZ has an ameliorative effect on NAFLD, and JGXZ alleviates the inflammatory response and oxidative stress and lipid metabolism disorders in NAFLD rats. The mechanism of action of JGXZ in the treatment of NAFLD may be related to the regulation of linoleic acid metabolism, tryptophan metabolism, alpha-linolenic acid metabolism, and glycerophospholipid metabolism.

Radiologic Imaging Modalities for Colorectal Cancer.

BACKGROUND: Studies reported various diagnostic value of radiologic imaging modalities for diagnosis and management of colorectal cancer (CRC). AIMS: To summary the diagnosis and management of CRC using computed tomography colonography (CTC), magnetic resonance colonography (MRC), and positron emission tomography (PET)/computed tomography (CT). METHODS: Comprehensive literature searches were conducted in PubMed, EmBase, and the Cochrane library for studies published before April 2021. The diagnostic performance of CTC, MRC, and PET/CT for CRC was summarized. RESULTS: A total of 54 studies (17 studies for CTC, 8 studies for MRC, and 29 studies for PET/CT) were selected for final analysis. The sensitivity and specificity for CTC ranged from 27 to 100%, 88 to 100%, respectively, and the pooled sensitivity and specificity for CTC were 0.97 (95% CI 0.88-0.99) and 0.99 (95% CI 0.99-1.00). The sensitivity and specificity for MRC ranged from 48 to 100%, 60 to 100%, respectively, and the pooled sensitivity and specificity for MRC were 0.98 (95% C: 0.77-1.00) and 0.94 (95% CI 0.84-0.98). The sensitivity and specificity for PET/CT ranged from 84 to 100%, 33 to 100%, respectively, and the pooled sensitivity and specificity for PET/CT were 0.94 (95% CI 0.92-0.96) and 0.94 (95% CI 0.90-0.97). The area under the receiver operating characteristic curve for CTC, MRC, and PET/CT was 1.00 (95% CI 0.99-1.00), 0.99 (95% CI 0.98-1.00), and 0.97 (0.95% CI 0.95-0.98), respectively. CONCLUSIONS: This study suggested both CTC and MRC with relative higher diagnostic value for diagnosing CRC, while PET/CT with higher diagnostic value in detecting local recurrence for patients with CRC.

New contributions to Goodyerinae and Dendrobiinae (Orchidaceae) in the flora of China.

Eight new species from China, Cheirostylis chuxiongensis, C. yei, Myrmechis lingulata, M. longii, Bulbophyllum ximaense, B. xizangense, B. retusum and B. pulcherissimum, are described and illustrated. Cheirostylis chuxiongensis differs from C. thailandica by having 5-9 irregular and papillae-like calli on each side in the sac of the lip, epichile with entire lobes, petals narrowly obliquely obovate and an apex that is not recurved. Cheirostylis yei is easily distinguished from its relatives similar by having a long stem, pubescent ovary and sepals, epichile lobes with irregular and undulate margins, a subquadrate callus without teeth in the saccate hypochile. Myrmechis lingulata differs from M. chinensis by having a simple and lanceolate to ligulate lip, glabrous bracts and ovary, oblique and narrowly ovate petals. Myrmechis longii differs from M. pumila by having white-veined leaves, oblong-lanceolate epichile lobes, and viscidium attached to the middle of the caudicle. Bulbophyllum ximaense is easily distinguished from its relatives similar by having distant pseudobulbs, shorter scape, an inflorescence with 9-16 orange-red flowers, shorter lateral sepals with a long acuminate apex, incurved and tubular apical margins, a papillate lip disk and triangular-subulate stelidia. Bulbophyllum xizangense is easily distinguished from its relatives similar by having narrow lanceolate leaves, shorter inflorescence with 1-3 greenish-yellow flowers, falcate-ovoid lateral sepals, a lip with small lateral lobes and 3 keels at the base. Bulbophyllum retusum differs from B. spathulatum by having shorter inflorescence, peduncles with 2 tubular sheaths, dorsal sepals with a retuse apex, lateral sepals with lower edges that are connate to each other and free and divergent toward the apex, obovate petals with an acute or slightly retuse apex. Bulbophyllum pulcherissimum differs from B. lopalanthum by its 5-veined dorsal sepal, ovate-lanceolate lateral sepals, obliquely ovate-oblong petal, erose-toothed margins and obovate lip with a large, oblong basal callus, and an obtuse base. In addition, three species (Bulbophyllum frostii, B. raskotii and B. nematocaulon) are reported for the first time in China.