Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer

BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Mathematical Modeling of Cell Polarity Establishment of Budding Yeast

The budding yeast Saccharomyces cerevisiae is a powerful model system for studying the cell polarity establishment.The cell polarization process is regulated by signaling molecules,which are initially distributed in the cytoplasm and then recruited to a proper location on the cell membrane in response to spatial cues or spontaneously.Polarization of these signaling molecules involves complex regulation,so the mathematical models become a useful tool to investigate the mechanism behind the process.In this review,we discuss how mathematical modeling has shed light on different regulations in the cell polarization.We also propose future applications for the mathematical modeling of cell polarization and morphogenesis.

Prognostic significance of tumor budding,desmoplastic reaction,and lymphocytic infiltration in patients with gastric adenocarcinoma

BACKGROUND Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors.In this context,Accumulated data suggests that pathological evaluation of tumor budding(TB),desmoplastic reaction(DR),and tumor-infiltrating lymphocytes(TILs)may be crucial in determining tumor behavior in the gastrointestinal tract.Regarding gastric adenocarcinoma(GAC),although some results suggest that TB and TILs may be effective in determining the course of the disease,the data do not agree.Moreover,very few studies have investigated the relationship between DR and survival.At present,the associations between tumor TB,DR and TILs in GAC patients have not been determined.AIM To establish the relationships between TB,DR,and TILs in patients with GAC and to assess their influence on prognosis.METHODS Our study group comprised 130 patients diagnosed with GAC.The definition of TB was established based on the International TB Consensus Conference.The DR was categorized into three groups according to the level of tumor stroma maturation.The assessment of TILs was conducted using a semiquantitative approach,employing a cutoff value of 5%.The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27.RESULTS A significant correlation between peritumoral budding(PTB)and intratumoral budding(ITB)was noted(r=0.943).Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs(P<0.01).PTB and ITB were associated with histological subtype,lymph node metastasis(LNM),and stage(P<0.01).ITB,PTB,LNM,DR,and stage were significant risk factors associated with poor prognosis.The multivariate Cox regression analysis identified ITB,PTB,and LNM as independent prognostic variables(P<0.05).In intestinal-type adenocarcinomas,a positive correlation between PTB and ITB was noted(r=0.972).While univariate analysis revealed that LNM,stage,PTB,ITB,and DR were strong parameters for predicting survival(P<0.05),only PTB and ITB were found to be independent prognostic factors(P<0.001).CONCLUSION TB may be a potential prognostic marker in GAC.However,further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.

Identification of potential metabolites responsible for cold tolerance in buds of Vitis amurensis

Cold tolerance is one of the important traits for grapevine,especially in regions with extremely low temperatures in winter.Vitis amurensis is wild species in the Vitis genus with excellent cold hardiness compared with Vitis vinifera.However,metabolites that contribute to the cold tolerance of V.amurensis remain unknown.Here,the metabolomics of buds from V.amurensis‘Zuoshan-1'during cold acclimation(CA)were identified,and cold-sensitive cultivar(V.vinifera‘Jingzaojing')was used as the control.The buds were collected in October,November,and December in 2016 and 2018.The cold hardiness of the buds increased during CA in the two grapevines.However,browning was observed only in V.vinifera buds at temperature below-10℃.Among detected metabolites from buds,443 metabolites were overlapped between two years.Forty-four and thirty differentially accumulated metabolites(DAMs)were identified in V.amurensis and V.vinifera,respectively.Ten DAMs including monoacylglycerol(MAG,18:2)isomer 1,trehalose 6-phosphate,and D-glucose showed identical variations in the two grapevines,indicating conserved CA responses within the Vitis genus.Eighteen DAMs exhibited higher accumulation in V.amurensis than in V.vinifera.Maltotetraose,D-glucoronic acid,L-aspartic acid,azelaic acid,and 4-hydroxybenzoic acid were reported to accumulate during CA in other plants.Enhanced cold tolerance was detected in grapevine leaves with exogenous 5 mmol L^(-1)L-aspartic acid and 1%proanthocyanidins.Potential contributions of other DAMs found in V.amurensis such as Cyanidin 3-O-glucoside need to be further elucidated.Thus,eighteen metabolites accumulated in V.amurensis can be used for practical application in improvement of cold resistance in grapevine.Our findings provide new insights into understanding the cold hardiness of V.amurensis.

Pilot Study of Drought Resistance for Maize at Budding Stage

The drought resistances of 44 maize germplasms at budding stage were studied with 19.2% polyethylene glycol(PEG-6000)in order to provide new germplasm resource for drought resistance breeding of maize.The results showed there were five extremely high drought resistance germplasms,20 germplasms with high drought resistance,and 19 germplasms with medium drought resistance.The significance testing was also used to demonstrate that the germination index(GI)and germination of drought resistance index(GDRI)of N4,N54-1 and Wuming No.1 were dramatically remarkable than others.The conclusion was that the 44 maize germplasm had good drought resistance and could be used as germplasm resource of the drought resistance breeding of maize,which had a great value of development and utilization.

Influences of fillet radius and draft angle on local loading process of titanium alloy T-shaped components

In order to study influences of geometric parameters on the T-shaped components local loading process, a new mathematical model considering the fillet radius and draft angle was established by using the slab method. The results obtained by the mathematical model agree with the data form experiment and numerical simulation, and the results are closer to the experimental and simulation results. The influence of draft angle may be neglected under the forming conditions used. The influence of fillet radius is notable, especially in the case that the ratio of fillet radius to rib width is less than 0.75.

Research on Budding "Villages in Cities" during Urbanization Process in Lanzhou City of China——A Case Study of Chaijiahe Village,China

By introducing the theory of suburb urbanization,it was considered that budding villages in cities emerged with the close relation between city and suburb during rapid urbanization process.The paper had briefly analyzed development of villages in cities in China.By taking villages in Lanzhou City for example,it had studied geological location,appearance,spatial structure,economy and demographic feature of budding villages in cities.Furthermore,with Chaijiahe Village of Xiguoyuan Town as case study,empirical study had been conducted and development thought of Chaijiahe Village as budding village in city had been discussed.It emphasized that it should control the development scale of villages,economically and intensively utilize lands;develop industrialized high-efficiency agriculture and leisure agriculture,develop lily economy and explore the potential of characteristic industries;realize integration of urban and rural development;strive to develop education,improve villages' quality and cultivate villagers of new generation who possessed pioneering spirit and modern agriculture technology.On this basis,it summarized approaches to realize sustainable development of budding villages in cities.

Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma

Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter （VAChT）, as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields （5×0.785 mm2）. Cut-offvalues were calculated by receiver operating characteristic curve analysis. Results： VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/（5×0.785） mm2, with a median of 18 fibers/（5×0.785） mm2. Patients with parasympathetic neurogenesis 〉 15 fibers/（5×0.785） mm2 were defined as the high-density group （39 patients, 66.1%）, and those with parasympathetic neurogenesis 〈15 fibers/（5×0.785） mm2 as the low-density group （20 patients, 33.9%）. The high-density group had a higher occurrence of tumor budding （P=0.001） and a higher rate of early recurrence （P=0.035）. Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio （HR）=2.45, 95% confidence interval （95% CI）： 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer （AJCC） stage （P=0.010） and tumor budding （P=0.009）. Conclusions： Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.

Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ield.RESULTS: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

Performance of a Self-Aligned InP/GaInAs SHBT with a Novel T-Shaped Emitter

A self-aligned InP/GalnAs single heterojunction bipolar transistor（HBT） is investigated using a novel T-shaped emitter. A U-shaped emitter layout,selective wet etching,laterally etched undercut, and an air-bridge are applied in this process. The device, which has a 2μm×12μm U-shaped emitter area,demonstrates a common-emitter DC current gain of 170,an offset voltage of 0.2V,a knee voltage of 0.5V, and an open-base breakdown voltage of over 2V. The HBT exhibits good microwave performance with a current gain cutoff frequency of 85GHz and a maximum oscillation frequency of 72GHz, These results indicate that these InP/InGaAs SHBTs are suitable for low-voltage,low-power,and high-frequency applications.

Tumor budding as a potential histopathological biomarker in colorectal cancer:Hype or hope?

Colorectal cancer （CRC）, the third most commonly di- agnosed type of cancer in men and women worldwide is recognized as a complex multi-pathway disease, an observation sustained by the fact that histologically identical tumors may have different outcome, including various response to therapy. Therefore, particularly in early and intermediate stage （stages Ⅱ and Ⅲ, respec- tively） CRC, there is a compelling need for biomarkers helpful of selecting patients with aggressive disease that might benefit from adjuvant and targeted therapy. Histopathological examination shows that likely other solid tumors the development and progression of hu- man CRC is not only determined by genetically abnor- mal cells, but also by intricate interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumor mi- croenvironment as potential predictive and prognostic biomarkers. Among the histopathological biomarkers, tumor budding （i.e., the presence of individual cells and small clusters of tumor cells at the tumor invasive front）has received much recent attention, particularly in the setting of CRC. Although its acceptance as a reportable factor has been held back by a lack of uniformity with respect to qualitative and quantitative aspects, tumor budding is now considered as an independent adverse prognostic factor in CRC that may allow for stratifica- tion of patients into risk categories more meaningful than those defined by tumor-node-metastasis staging alone, and also potentially guide treatment decisions, especially in T2-T3 NO （stage Ⅱ） CRCs.

Improved design of special boundary elements for T-shaped reinforced concrete walls

This study examines the design provisions of the Chinese GB 50011-2010 code for seismic design of buildings for the special boundary elements of T-shaped reinforced concrete walls and proposes an improved design method. Comparison of the design provisions of the GB 50011-2010 code and those of the American code ACI 318-14 indicates a possible deficiency in the T-shaped wall design provisions in GB 50011-2010. A case study of a typical T-shaped wall designed in accordance with GB 50011-2010 also indicates the insufficient extent of the boundary element at the non-flange end and overly conservative design of the flange end boundary element. Improved designs for special boundary elements ofT-shaped walls are developed using a displacement-based method. The proposed design formulas produce a longer boundary element at the non-flange end and a shorter boundary element at the flange end, relative to those of the GB 50011-2010 provisions. Extensive numerical analysis indicates that T-shaped walls designed using the proposed formulas develop inelastic drift of 0.01 for both cases of the flange in compression and in tension.

Prognostic and pathological impact of tumor budding in gastric cancer: A systematic review and meta-analysis

BACKGROUND Tumor budding,is a promising prognostic hallmark in many cancers,and can help us better assess the degree of malignancy in gastric cancer(GC)and in colorectal cancer.In the past few years,several articles on the relationship between tumor budding and GC have been published,but different results have been observed.As the relationship between tumor budding and GC remains controversial,we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis.AIM To systematically evaluate the prognostic and pathological impact of tumor budding in GC.METHODS Literature searches were conducted in the PubMed,Cochrane Library,EMBASE and Web of Science databases,and 7 cohort studies involving 2178 patients met our criteria and included in the analysis.The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding,and the cut-off values for tumor budding varied across the included studies.The hazard ratios(HRs)with 95%confidence intervals(CIs)were calculated to estimate the impact of tumor budding on overall survival(OS)in GC patients.The odds ratios(ORs)with 95%CIs were used to determine the correlation between tumor budding and pathological parameters(tumor stage,tumor differentiation,lymphovascular invasion,lymph node metastasis)of GC.RESULTS Seven studies involving 2178 patients were included in the meta-analysis.The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage(OR=6.63,95%CI:4.01-10.98,P<0.01),tumor differentiation(OR=3.74,95%CI:2.68-5.22,P<0.01),lymphovascular invasion(OR=7.85,95%CI:5.04-12.21,P<0.01),and lymph node metastasis(OR=5.75,95%CI:3.20-10.32,P<0.01).Moreover,high-grade tumor budding predicted a poor 5-year OS(HR=1.79,95%CI:1.53-2.05,P<0.01)in patients with GC and an adverse 5-year OS(HR=1.93,95%CI:1.45-2.42,P<0.01)in patients with intestinal-type GC.CONCLUSION High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.

Artificial intelligence-based comprehensive analysis of immune-stemness-tumor budding profile to predict survival of patients with pancreatic adenocarcinoma

Objective:Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignancy.CD8^(+)T cells,cancer stem cells(CSCs),and tumor budding(TB)have been significantly correlated with the outcome of patients with PDAC,but the correlations have been independently reported.In addition,no integrated immune-CSC-TB profile for predicting survival in patients with PDAC has been established.Methods:Multiplexed immunofluorescence and artificial intelligence(AI)-based comprehensive analyses were used for quantification and spatial distribution analysis of CD8^(+)T cells,CD133^(+)CSCs,and TB.In vivo humanized patient-derived xenograft(PDX)models were established.Nomogram analysis,calibration curve,time-dependent receiver operating characteristic curve,and decision curve analyses were performed using R software.Results:The established‘anti-/pro-tumor’models showed that the CD8^(+)T cell/TB,CD8^(+)T cell/CD133^(+)CSC,TB-adjacent CD8^(+)T cell,and CD133^(+)CSC-adjacent CD8^(+)T cell indices were positively associated with survival of patients with PDAC.These findings were validated using PDX-transplanted humanized mouse models.An integrated nomogram-based immune-CSC-TB profile that included the CD8^(+)T cell/TB and CD8^(+)T cell/CD133^(+)CSC indices was established and shown to be superior to the tumor-nodemetastasis stage model in predicting survival of patients with PDAC.Conclusions:‘Anti-/pro-tumor’models and the spatial relationship among CD8^(+)T cells,CSCs,and TB within the tumor microenvironment were investigated.Novel strategies to predict the prognosis of patients with PDAC were established using AI-based comprehensive analysis and machine learning workflow.The nomogram-based immune-CSC-TB profile can provide accurate prognosis prediction for patients with PDAC.

Numerical investigation of flow pattern and components of three-dimensional velocity around a submerged T-shaped spur dike in a 90° bend

Spur dike is one of the river training structures. This work presented a numerical simulation of flow field and three-dimensional velocity around a T-shaped spur dike located in bend using SSIIM model. The main objective of this work is to investigate the three-dimensional velocities and streamlines at transverse and longitudinal sections and plan views around the T-shaped spur dike in different submergence ratios(0, 5%, 15%, 25% and 50%). It is concluded that by increasing the submergence ratio from 5% to 50%, the maximum of scour is reduced; the maximum of longitudinal velocity increases by 7.7% and occurs at the water surface in spur dike axis. Near the bed, the maximum of vertical velocity occurs at the end of spur wing. By analyzing the streamlines at transverse sections, the followings were deduced for different submergence ratios: different dimensions and different positions of vortices around the spur dike.

Analytical Modeling of Fluid Sloshing in A 2D Rectangular Container with A Bottom-Mounted T-Shaped Baffle

An analytical procedure is presented to evaluate the fluid sloshing characteristics in a two-dimensional(2D)rectangular container with a bottom-mounted T-shaped baffle.The fluid region is divided into several sub-domains with hypothetical interfaces and the velocities and pressures of the fluid on adjacent interfaces should be identical.The separation of variables in conjunction with the superposition principle is employed to formulate the velocity potential of each sub-domain.The Fourier series expansion is used to derive the eigenvalue equation by substituting the velocity potential solutions into the free surface conditions and the continuity conditions on adjacent interfaces.Under the horizontal base excitation,the total velocity potential of fluid is decomposed of the impulsive and perturbed velocity potentials.The orthogonality of the sloshing modes is demonstrated by implementing Gauss formula.The dynamic response equation is established by incorporating the total velocity potential solution into the surface wave equation.Excellent agreements are achieved between the present results and those from the reported literature and finite element code.Numerical results are exhibited to reveal the effect of the baffle parameters and excitation frequency on sloshing characteristics and responses of liquid.

Static and dynamic responses of a microcantilever with a T-shaped tip mass to an electrostatic actuation

In this study, nonlinear static and dynamic responses of a microcantilever with a T-shaped tip mass excited by electrostatic actuations are investigated. The electrostatic force is generated by applying an electric voltage between the horizontal part of T-shaped tip mass and an opposite electrode plate. The cantilever microbeam is modeled as an Euler-Bernoulli beam. The T-shaped tip mass is assumed to be a rigid body and the nonlinear effect of electrostatic force is considered. An equation of motion and its associated boundary conditions are derived by the aid of combining the Hamilton principle and Newton’s method. An exact solution is obtained for static deflection and mode shape of vibration around the static position. The differential equation of nonlinear vibration around the static position is discretized using the Galerkin method. The system mode shapes are used as its related comparison functions. The discretized equations are solved by the perturbation theory in the neighborhood of primary and subharmonic resonances. In addition, effects of mass inertia, mass moment of inertia as well as rotation of the T-shaped mass, which were ignored in previous works, are considered in the analysis. It is shown that by increasing the length of the horizontal part of the T-shaped mass, the amount of static deflection increases, natural frequency decreases and nonlinear shift of the resonance frequency increases. It is concluded that attaching an electrode plate with a T-shaped configuration to the end of the cantilever microbeam results in a configuration with larger pull-in voltage and smaller nonlinear shift of the resonance frequency compared to the configuration in which the electrode plate is directly attached to it.

Prognostic role of tumor budding in breast cancer

Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.

Vertical polarization-induced doping InN/InGaN heterojunction tunnel FET with hetero T-shaped gate

A novel vertical InN/InGaN heterojunction tunnel FET with hetero T-shaped gate as well as polarization-doped source and drain region(InN-Hetero-TG-TFET)is proposed and investigated by Silvaco-Atlas simulations for the first time.Compared with the conventional physical doping TFET devices,the proposed device can realize the P-type source and N-type drain region by means of the polarization effect near the top InN/InGaN and bottom InGaN/InN heterojunctions respectively,which could provide an effective solution of random dopant fluctuation(RDF)and the related problems about the high thermal budget and expensive annealing techniques due to ion-implantation physical doping.Besides,due to the hetero T-shaped gate,the improvement of the on-state performance can be achieved in the proposed device.The simulations of the device proposed here in this work show ION of 4.45×10^(-5)A/μm,ION/IOFF ratio of 10^(13),and SS_(avg)of 7.5 mV/dec in InN-Hetero-TG-TFET,which are better than the counterparts of the device with a homo T-shaped gate(InN-Homo-TG-TFET)and our reported lateral polarization-induced InN-based TFET(PI-InN-TFET).These results can provide useful reference for further developing the TFETs without physical doping process in low power electronics applications.

Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers

Hepatocellular(HCC)and intrahepatic cholangiocarcinoma(ICC),the most common primary tumors of the liver,are among the most important causes of cancer deaths worldwide.Because patients with primary liver tumors are frequently diagnosed at an advanced stage and have high mortality,many efforts have been made to identify new markers to determine their behavior and treatment,similar to those in other solid organ tumors.Recently,morphological assessment of tumor budding(TB)has been revealed as a promising prognostic finding to predict tumor behavior and survival across several different tumor types.Currently,the TB score in colorectal cancer has been revealed as an important parameter in pathology report protocols to determine the course of the disease.Regarding the liver,despite enormous data showing that many mechanisms involved in TB are associated with tumor behavior in both HCC and ICC,studies focusing on the role of TB in predicting the behavior and prognosis of these tumors have started to be investigated very recently.The purpose of this review is to present data about TB in primary tumors of the liver,pointing out the potential role of this parameter in determining the course of the disease,and emphasize the need to increase the number of further studies focusing on the evaluation of this parameter with an overview of the mechanisms involved in TB.