High Expression of CLDN 18.2 is Associated with Poor Disease-Free Survival of HER-2 Positive Gastric Cancer.

Background: Anti-claudin (CLDN) 18.2 therapy has been proven to be effective in treating advanced gastric cancer with negative human epidermal growth factor receptor 2 (HER-2). This study purposed to investigate the relationship of CLDN 18.2 expression with prognosis of HER-2-positive gastric cancer patients. Objective: To investigate the expression of claudin (CLDN) 18.2 in Human epidermal growth factor receptor 2 (HER-2) positive gastric cancer patients after radical resection and its relationship with gastric cancer prognosis. Methods: A total of 55 postoperative HER-2-positive gastric cancer patients were included in this study. CLDN 18.2 protein was detected by immunohistochemistry, and detailed clinical and pathological information was collected. Factors considered potentially important in the univariate analysis were included in the multivariate analysis, which involved COX regression to find the independent prognostic factors affecting disease-free survival (DFS). Results: Immunohistochemistry showed that different levels of CLDN 18.2 protein were expressed in HER-2 positive gastric cancer tissues, and the Chi-square analysis showed that the expression level of CLDN 18.2 was significantly correlated with the lymph node stage. Higher expression levels of CLDN 18.2 were found in patients with lymph node positivity and were associated with poor prognosis in HER-2-positive gastric cancer patients. Gastric cancer patients with low and high expressions of CLDN 18.2 had postoperative median DFS of 38.5 months (95% confidence interval (CI) 28.8-48.2 months) and 12.1 months (95% CI, 11.7-41.0 months), respectively. Conclusion: High expression of CLDN 18.2 in HER-2 positive gastric cancer is associated with poor prognosis, and the optimal treatment mode for this population is worth exploring after the approval of anti-CLDN 18.2 drugs.

5-Fluorouracil resistant CRC cells derived exosomes promote cancer-associated fibroblasts secreting more CXCL12.

Background: Chemoresistance is a key reason for treatment failure in colorectal cancer (CRC) patients. The tumor microenvironment of chemoresistant CRC is distinctly immunosuppressive, although the underlying mechanisms are unclear. Methods: The CRC data sets GSE69657 and GSE62080 were downloaded from the GEO database, and the correlation between TRPC5 and FAP expression was analyzed by Pearson method. The in-situ expression of transient receptor potential channel 5 (TRPC5) and fibroblast activation protein (FAP) in the CRC tissues was examined by immunohistochemistry. TRPC5 expression levels in the HCT8 and HCT116 cell lines and the corresponding 5-fluorouracil (5-FU)-resistant cell lines (HCT8R and HCT116R) were analyzed by western blotting and RT-PCR. Exosomes were isolated from the HCT8R and HCT116R cells and incubated with colorectal normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs)markers were detected. NFs were also incubated with exosomes isolated from TRPC5-knockdown HCT8R cells, and the changes in intracellular Ca2+ levels and C-X-C motif chemokine ligand 12 (CXCL12) secretion were analyzed. Results: TRPC5 and FAP expression showed positive correlation in the datasets. Immunostaining of CRC tissue specimens further revealed that high TRPC5 and FAP expressions were significantly associated with worse tumor regression. Furthermore, chemoresistant CRC cells expressed higher levels of TRPC5 compared to the chemosensitive cells, and knocking down TRPC5 reversed chemoresistance. Exosomes derived from CRC cells induced the transformation of NFs to CAFs. However, TRPC5-exosomes derived from chemoresistant CRC cells can promote CAFs to secrete more CXCL12. Conclusion: Chemoresistant CRC cells can induce CAFs activation and promote CXCL12 secretion through exosomal TRPC5.

The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study.

PURPOSE: Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. METHODS: We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. RESULTS: The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: ß = 0.063, P = 0.034), the genus Butyrivibrio (IVW: ß = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: ß=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: ß=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: ß=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: ß = 0.235, P = 0.03) and the order Clostridiales (IVW: ß = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: ß = 0.953, P = 0.022) and the order Lactobacillales (IVW: ß=-0.806, P = 0.042) were suggestive of an association with PAI-1. CONCLUSION: This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases.

Combining regularization and logistic regression model to validate the Q-matrix for cognitive diagnosis model.

Q-matrix is an important component of most cognitive diagnosis models (CDMs); however, it mainly relies on subject matter experts' judgements in empirical studies, which introduces the possibility of misspecified q-entries. To address this, statistical Q-matrix validation methods have been proposed to aid experts' judgement. A few of these methods, including the multiple logistic regression-based (MLR-B) method and the Hull method, can be applied to general CDMs, but they are either time-consuming or lack accuracy under certain conditions. In this study, we combine the L1 regularization and MLR model to validate the Q-matrix. Specifically, an L1 penalty term is imposed on the log-likelihood of the MLR model to select the necessary attributes for each item. A simulation study with various factors was conducted to examine the performance of the new method against the two existing methods. The results show that the regularized MLR-B method (a) produces the highest Q-matrix recovery rate (QRR) and true positive rate (TPR) for most conditions, especially with a small sample size; (b) yields a slightly higher true negative rate (TNR) than either the MLR-B or the Hull method for most conditions; and (c) requires less computation time than the MLR-B method and similar computation time as the Hull method. A real data set is analysed for illustration purposes.

Causal effect between gut microbiota and gastroesophageal reflux disease: a bidirectional two-sample Mendelian randomization study.

Previous observational studies have found that the gut microbiota is closely related to the pathogenesis of gastroesophageal reflux disease (GERD), while their causal relationship is unclear. A two-sample multivariate Mendelian randomization analysis was implemented to estimate the causal effect of gut microbiota on GERD. The gut microbiota aggregated statistics were derived from a meta-analysis of the largest available genome-wide association studies (GWAS) conducted by the MiBioGen alliance ( n  = 13 266). GERD aggregated statistics were derived from published GWAS (129 080 cases and 473 524 controls). A bidirectional two-sample Mendelian randomization study was conducted to explore the causal relationship between gut microbiota and GERD using the inverse variance weighted (IVW), Mendelian randomization Egger, single model, weighted median, and weighted model. To verify the stability of the main results of Mendelian randomization analysis, we performed sensitivity analysis. Based on the results of IVW, we found that Anaerostipes was causally associated with an increased risk of GERD [odds ratio (OR): 1.09, P  = 0.018]. Eight gut microbiota taxa ( Actinobacteria, Bifidobacteriales, Bifidobacteriaceae, Clostridiales vadin BB60 group, Rikenellaceae, Lachnospiraceae UCG004, Methanobrevibacter , and unknown genus id.1000000073 ) are predicted to act causally in suppressing the risk of GERD ( P  < 0.05). In addition, reverse Mendelian randomization analyses revealed that the abundance of 15 gut microbiota taxon was found to be affected by GERD. No significant estimation of heterogeneity or pleiotropy is detected. Our study presents a complicated causal relationship between gut microbiota and GERD that offers guidance on the selection of appropriate probiotics as clinical interventions for GERD.

The effect of reading engagement on scientific literacy - an analysis based on the XGBoost method.

Scientific literacy is a key factor of personal competitiveness, and reading is the most common activity in daily learning life, and playing the influence of reading on individuals day by day is the most convenient way to improve the level of scientific literacy of all people. Reading engagement is one of the important student characteristics related to reading literacy, which is highly malleable and is jointly reflected by behavioral, cognitive, and affective engagement, and it is of theoretical and practical significance to explore the relationship between reading engagement and scientific literacy using reading engagement as an entry point. In this study, we used PISA2018 data from China to explore the relationship between reading engagement and scientific literacy with a sample of 15-year-old students in mainland China. 36 variables related to reading engagement and background variables (gender, grade, and socioeconomic and cultural status of the family) were selected from the questionnaire as the independent variables, and the score of the Scientific Literacy Assessment (SLA) was taken as the outcome variable, and supervised machine learning method, the XGBoost algorithm, to construct the model. The dataset is randomly divided into training set and test set to optimize the model, which can verify that the obtained model has good fitting degree and generalization ability. Meanwhile, global and local personalized interpretation is done by introducing the SHAP value, a cutting-edge machine model interpretation method. It is found that among the three major components of reading engagement, cognitive engagement is the more influential factor, and students with high reading cognitive engagement level are more likely to get high scores in scientific literacy assessment, which is relatively dominant in the model of this study. On the other hand, this study verifies the feasibility of the current popular machine learning model, i.e., XGBoost, in a large-scale international education assessment program, with a better model adaptability and conditions for global and local interpretation.

Complex relationship between gut microbiota and thyroid dysfunction: a bidirectional two-sample Mendelian randomization study.

Background: Many studies have reported the link between gut microbiota and thyroid dysfunction. However, the causal effect of gut microbiota on thyroid dysfunction and the changes in gut microbiota after the onset of thyroid dysfunction are not clear. Methods: A two-sample Mendelian randomization (MR) study was used to explore the complex relationship between gut microbiota and thyroid dysfunction. Data on 211 bacterial taxa were obtained from the MiBioGen consortium, and data on thyroid dysfunction, including hypothyroidism, thyroid-stimulating hormone alteration, thyroxine deficiency, and thyroid peroxidase antibodies positivity, were derived from several databases. Inverse variance weighting (IVW), weighted median, MR-Egger, weighted mode, and simple mode were applied to assess the causal effects of gut microbiota on thyroid dysfunction. Comprehensive sensitivity analyses were followed to validate the robustness of the results. Finally, a reverse MR study was conducted to explore the alteration of gut microbiota after hypothyroidism onset. Results: Our bidirectional two-sample MR study revealed that the genera Intestinimonas, Eubacterium brachy group, Ruminiclostridium5, and Ruminococcaceae UCG004 were the risk factors for decreased thyroid function, whereas the genera Bifidobacterium and Lachnospiraceae UCG008 and phyla Actinobacteria and Verrucomicrobia were protective. The abundance of eight bacterial taxa varied after the onset of hypothyroidism. Sensitivity analysis showed that no heterogeneity or pleiotropy existed in the results of this study. Conclusion: This novel MR study systematically demonstrated the complex relationship between gut microbiota and thyroid dysfunction, which supports the selection of more targeted probiotics to maintain thyroid-gut axis homeostasis and thus to prevent, control, and reverse the development of thyroid dysfunction.

A ratiometric fluorescent dye for detection of Lys and Arg and its bioimaging in live cells and zebrafish larvae.

A ratiometric and pH-sensitive fluorescent dye named IDE was applied to the detection of argine and lysine from common amino acids and exploited to monitor the Lys and Arg levels in living cells and zebrafish larvae successfully. IDE will be a useful fluorescence indicator of pH changes by Lys and Arg.

Prognosis stratification and response to treatment in breast cancer based on one-carbon metabolism-related signature.

Introduction: Breast cancer (BC) is the most common malignant tumor in the female population. Despite staging and treatment consensus guidelines, significant heterogeneity exists in BC patients' prognosis and treatment efficacy. Alterations in one-carbon (1C) metabolism are critical for tumor growth, but the value of the role of 1C metabolism in BC has not been fully investigated. Methods: To investigate the prognostic value of 1C metabolism-related genes in BC, 72 1C metabolism-related genes from GSE20685 dataset were used to construct a risk-score model via univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm, which was validated on three external datasets. Based on the risk score, all BC patients were categorized into high-risk and low-risk groups. The predictive ability of the model in the four datasets was verified by plotting Kaplan-Meier curve and receiver operating characteristic (ROC) curve. The candidate genes were then analyzed in relation to gene mutations, gene enrichment pathways, immune infiltration, immunotherapy, and drug sensitivity. Results: We identified a 7-gene 1C metabolism-related signature for prognosis and structured a prognostic model. ROC analysis demonstrated that the model accurately predicted the 2-, 3-, and 5-year overall survival rate of BC patients in the four cohorts. Kaplan-Meier analysis revealed that survival time of high-risk patients was markedly shorter than that of low-risk patients (p < 0.05). Meanwhile, high-risk patients had a higher tumor mutational burden (TMB), enrichment of tumor-associated pathways such as the IL-17 signaling pathway, lower levels of T follicular helper (Tfh) and B cells naive infiltration, and poorer response to immunotherapy. Furthermore, a strong correlation was found between MAT2B and CHKB and immune checkpoints. Discussion: These findings offer new insights into the effect of 1C metabolism in the onset, progression, and therapy of BC and can be used to assess BC patients' prognosis, study immune infiltration, and develop potentially more effective clinical treatment options.

In-situ comparison of interface instability of basal and edge planes during unidirectional growth of sea ice.

The evolutions of water/ice interface with distinct ice orientations are one of the central problems in sea ice growth. Some misunderstandings prevailed in previous hypothesis on morphological evolution of sea ice, which need the validation with carefully designed experiments. Up to now, there is no in-situ comparison of unidirectional freezing behavior between distinct ice orientations, which makes the previous hypothesis on sea ice growth skeptical about its physical basis. The aim of this paper is to provide an in-situ comparison of unidirectional growth behavior of lamellar sea ice between basal and edge planes. Our experiment is realized by a delicate design of parallel freezing samples with two specified ice orientations in a modeled sea water under an imposed thermal gradient. The planar instability as well as the unidirectional cellular/dendritic growth patterns of water/ice interfaces of basal and edge plane ice are compared. It is found that the instability grows faster for edge plane ice, which is addressed by an incubation time coupled with the surface tension anisotropy. In addition, two types of tilted growth patterns of sea ice after planar instability are observed simultaneously, which are suggested to stem from distinct physical origins and provide a new insight into the tilted growth of cellular/dendritic ice. Collectively, these experimental results are suggested to promote our understanding of morphological evolution of unidirectional growth of sea ice, as well as its diverse relevance to many other areas involving ice growth.

Ubiquitination and SUMOylation: protein homeostasis control over cancer.

Ubiquitination and SUMOylation are two essential components of the ubiquitination proteasome system playing fundamental roles in protein homeostasis maintenance and signal transduction, perturbation of which is associated with tumorigenesis. By comparing the mechanisms of ubiquitination and SUMOylation, assessing their crosstalk, reviewing their differential associations with cancer and identifying unaddressed yet important questions that may lead the field trend, this review sheds light on the similarities and differences of ubiquitination and SUMOylation toward the improved harnessing of both post-translational modification machineries, as well as forecasts novel onco-therapeutic opportunities through cell homeostasis control.

Lay abstract Ubiquitination and SUMOylation are two key components of the ubiquitination-proteasome system, playing central roles in cancer initiation and development. Despite knowledge of these mechanisms and clinical efforts in developing proteasome inhibitors into onco-therapeutics, researchers are still questioning how the ubiquitination-proteasome system could be precisely harnessed in cancer control. Besides, the seemingly redundant roles played by ubiquitination and SUMOylation complicate the understanding of the roles of the ubiquitination-proteasome system in carcinogenesis. By comparing the mechanisms of ubiquitination and SUMOylation, reviewing their differential associations with cancer and identifying unaddressed yet important questions, this review sheds light on the similarities and differences of ubiquitination and SUMOylation and forecasts novel onco-therapeutic opportunities taking advantages of both machineries.

Tilting Behavior of Lamellar Ice Tip during Unidirectional Freezing of Aqueous Solutions.

Freezing of ice has been largely reported from many aspects, especially its complex pattern formation. Ice grown from liquid phase is usually characteristic of lamellar morphology that plays a significant role in various domains. However, tilted growth of ice via transition from coplanar to noncoplanar in directional solidification has been paid little attention in previous studies and there was a misleading explanation of the formation of tilted lamellar ice. Here, we in situ investigated the variations of tilting behavior of lamellar ice tips under different conditions within a single ice crystal of manipulated orientation via unidirectional freezing of aqueous solutions. It is found that tilted growth of ice tips is sensitive to pulling velocity and solute type. These experimental results reveal intrinsic tilted growth behavior of lamellar ice, which is suggested to enrich our understanding of pattern formation of ice in relevant physical processes.

Quantitative determination of tip undercooling of faceted sea ice within situexperiments.

Sea ice growth with lamellar microstructure containing brine channels has been extensively investigated. However, the quantitative growth information of sea ice remains lack due to the uncontrolled crystalline orientation in previous investigations. For the first time, wein situobserved the unidirectional growth of lamellar sea ice with well-manipulated ice crystal orientation and visualized tip undercooling of lamellar sea ice. With the real-time observation, interesting phenomena of doublon tip in cellular ice growth and growth direction shift of unidirectionally grown ice tip are discovered for the first time, which are attributed to the complex solutal diffusion and anisotropic interface kinetics in ice growth. The quantitative experiments provide a clear micro scenario of sea ice growth, and are suggested to promote relevant investigations of sea ice.

Single Ice Crystal Growth with Controlled Orientation during Directional Freezing.

Ice growth has attracted great attention for its capability of fabricating hierarchically porous microstructure. However, the formation of tilted lamellar microstructure during freezing needs to be reconsidered due to the limited control of ice orientation with respect to the thermal gradient during in situ observations, which can greatly enrich our insight into architectural control of porous biomaterials. This paper provides an in situ study of the solid/liquid interface morphology evolution of directionally solidified single crystal ice with its C-axis (optical axis) perpendicular to directions of both the thermal gradient and the incident light in poly(vinyl alcohol, PVA) solutions. Multifaceted morphology and V-shaped lamellar morphology were clearly observed in situ for the first time. Quantitative characterizations on lamellar spacing, tilt angle, and tip undercooling of lamellar ice platelets provide a clearer insight into the inherent ice growth habit in polymeric aqueous systems and are suggested to exert significant impact on future design and optimization in porous biomaterials.

Development of a five-stage solid-state linear transformer driver.

In this paper, the development of a five-stage solid-state linear transformer driver (LTD) is described. Each stage consists of eight compact pulse generating modules and a magnetic core. The pulse generating modules contain a multilayer-ceramic-capacitor-based pulse-forming network (PFN) and an insulated-gate bipolar transistor (IGBT) switch array, as well as magnetic switches, which are used to speed up the pulse front. To prevent damage from the reverse voltage to the IGBT switch, a reverse voltage absorption circuit was added to the PFN. For this study, a larger cross-sectional core with improved output characteristics was adopted. The developed five-stage LTD has the advantages of long life, low jitter, fast rising edge, and so on. The device can provide a 35 kV, 119 ns, 4.3 kA square pulse train with a maximum frequency of 50 Hz. On this basis, a 50-stage LTD of output 500 kV, which would serve as a high-power microwave driver source, is under development.

A solid-state pulse generator based on multilayer ceramic capacitors and insulated gate bipolar transistors.

A solid-state pulse-forming network (PFN) module was designed using multilayer ceramic capacitors (MLCCs). In addition, an all-solid-state pulse generator was fabricated with a Blumlein line that consisted of two PFN single lines and an insulated gate bipolar transistor (IGBT) switch array. This generator was integrated on printed circuit boards (PCBs). The stage capacitors of the PFN were composed of MLCCs connected in series and parallel. To obtain a compact structure, folded, copper-clad wires were used as interstage inductors. The copper-clad wires were structurally optimized to reduce coupling between adjacent interstage inductors. A relatively fast rising waveform edge was obtained using an IGBT gate-boosting circuit and magnetic switch technology. A square-wave pulse with a rise time of 27 ns, a voltage of 5 kV, a width of 120 ns, a maximum repetition rate of 100 Hz, and an evaluated lifetime of 109 pulses was obtained on a load of 6.6 Ω. With its compact size, fast rise time, and long lifetime, the fabricated pulse generator can be used as a component in linear transformer drivers or Marx generators.

Phase-field simulation of microstructure evolution in electron beam additive manufacturing.

Electron beam additive manufacturing (EBAM) is an emerging additive manufacturing technology with extremely high energy beam. The rapid solidification in the molten pool is of interest but not fully understood. In EBAM, with both large thermal gradient and cooling rate, the microstructure evolution during solidification is difficult to be described. The quantitative multi-phase-field model provides an effective way to reveal the dynamic evolution of dendrites in the molten pool of EBAM. In this study, the thermal profile is interpolated from the macroscale simulation at each time-step, to couple the realistic thermal evolution in the molten pool. The microstructure evolution and competitive growth have been investigated in details. Simulations of dendrite arrays with the same orientation showed how the growth velocity and the primary spacing of columnar dendrites depend on thermal gradient and cooling rate. The results are in agreement with theoretical models qualitatively. Moreover, the Gaussian nucleation model was introduced so as to give a better prediction of the microstructure in EBAM.

The ratiometric fluorescent probe with high quantum yield for quantitative imaging of intracellular pH.

Intracellular pH, especially cytoplasmic pH (~7.2) plays a crucial role in cell functions and metabolism. A ratiometric fluorescent probe namely, 6-(2-(benzothiazol-2-yl)vinyl)naphthalen-2-ol (BTNO) was facilely synthesized by the condensation of 6-hydroxy-2-naphthaldehyde and 2-methylbenzothiazole. BTNO exhibited a remarkable ratiometric emission (F456/F526) enhancement in response to a pH change with a linear range of pH = 9.50-7.00 and a pKa value of 7.91 ±â€¯0.03, which is desirable for measuring and monitoring the cytoplasmic pH fluctuations. In addition, because of the high fluorescence quantum yield of BTNO (Φ = 0.88 in DMSO and 0.61 in water relative to quinine sulfate solution in 0.1 M H2SO4), the interferences of the probe on the physiological functions could be greatly reduced. This could also provide enhanced measurement sensitivity. The successful demonstration of BTNO in detecting and monitoring the intracellular pH changes in live HeLa cells via a ratiometric approach confirmed that BTNO held a practical potential in biomedical research.

Tuning the pKa of two-photon bis-chromophoric probes for ratiometric fluorescence imaging of acidic pH in lysosomes.

Lysosomes are organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Abnormal lysosomal pH changes are known to associate with dysfunction of cells linking to various diseases such as cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions. We report herein two novel, highly sensitive and fast responsive bis-chromophoric ratiometric two-photon fluorescent probes with different emission wavelengths, namely VP and VL for acidic pH sensing in live cells. Importantly, by adopting bis-chromophoric approach, the VP and VL probes bearing pyridyl and quinolyl as acid sensing sites exhibit pKa values of 4.62 and 5.26, respectively, which are ideal for quantitative analysis of lysosomal pH changes in live cells. These two biocompatible probes are not only highly lysosomal targeting, sensitive towards pH change with distinct emission color shifting but also highly two-photon active in cells with excellent photostability and reversibility. These probes were successfully applied to ratiometrically track and image pH fluctuation in lysosomes of HeLa cells by one- and two-photon excited fluorescence microscopy. For the first time, we have demonstrated here that the bis-chromophoric strategy is a useful tool to effectively modify and tune the pKa of a fluorescent probe.

Efficient Semisynthesis of (-)-Pseudoirroratin A from (-)-Flexicaulin A and Assessment of Their Antitumor Activities.

Accumulating evidence indicates that natural ent-kaurane diterpenoids show great potential for medical treatment of different pathological conditions including cytotoxicity, antibacterial, and anti-inflammatory activity. Among a variety of diterpenoids tested, (-)-pseudoirroratin A displayed a promising antitumor property in vitro and in vivo. However, this diterpenoid could merely be isolated in a limited amount from a rare source of Isodon pseudoirrorata. To overcome such scanty source, we developed a novel, facile, and efficient semisynthetic strategy to prepare (-)-pseudoirroratin A from natural (-)-flexicaulin A, which can be expediently obtained from I. flexicaulis in a great quantity. The three-dimensional structure and the absolute configuration of our synthetic diterpenoid have been determined and confirmed with the X-ray crystallographic analysis. More importantly, we demonstrated for the first time that pseudoirroratin A exerted significant cytotoxicity against human colorectal carcinoma cells via an induction of apoptosis, as well as a remarkable suppression on tumor growth in a colon cancer xenograft mouse model.