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.

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.

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.

Tumor budding in gastric cancer

The tumor,nodes,metastasis(TNM)staging system has long been the gold standard for the classification and prognosis of solid tumors.However,the TNM staging system is not without limitations.Prognostic heterogeneity exists within patients at the same stage.Therefore,the pursuit of other biomarkers with the potential to classify patients with cancer has never stopped.One of them,tumor budding(TB),has gained much success in colorectal cancer.In recent years,TB in gastric cancer has attracted much attention from researchers,beginning to reveal the molecular and biological aspects of this phenomenon in gastric cancer,and has emerged as a promising prognostic biomarker in gastric cancer,predicting disease progression and unfavorable survival.Therefore,it is time and essential to provide a holistic overview of TB in gastric cancer,which has not been achieved and is the aim of this review.

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.

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 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.

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.

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.

Study on PEG6000 Treatment on Budding Percentage And Germination Rate of Allium Tuberosum Roxb.Seeds

Allium tuberosum Roxb is very popular for its function of stomach-strengthening,spirit-freshening,yang-warming and kidney essencereplenishing,however,its seeds appear to low bud,irregular sapling and other side effects,which result in low yield and poor quality.This paper analyzed effects of PEG6000 concentration on budding percentage in detail.It comes to conclusions that budding percentage of No.1 seed increases from 71% to 92% on the basis of 36 h treatment by 20% PEG6000 and 24 h water-drying,that of No.3 seed ranges from 30.4% to 53.4% on the basis of the same treatment by 10% PEG6000.

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.

Mismatch repair protein expression and intratumoral budding in rectal cancer are associated with an increased pathological complete response to preoperative chemoradiotherapy: A case-control study

AIM To determine whether the association of rectal adenocarcinoma with a defective-mismatch repair system(dMMR) was associated with a pathological complete response(pCR) to preoperative chemoradiotherapy.METHODS A case-control study was designed with the aim of determining if patients with rectal adenocarcinoma with dM MR had an associated high pCR rate in response to neoadjuvant chemoradiotherapy(nCRT).RESULTS Seventy-two cases with pCR were compared against 144 controls without pCR. Across 216 cases, the mean age was 56.8 years, 140(64.8%) were men, and 63(29.2%) demonstrated the dMMR system. The pCR was associated with G1 tumors, dMMR, the absence of vascular invasion, and low tumor budding in the pretreatment biopsy. In a multivariant analysis, the factors associated with pCR were dMMR(OR: 2.61; 95%CI: 1.355-5.040, P = 0.004) and a low degree of tumor budding(OR: 2.52; 95%CI: 1.366-4.894, P = 0.025).CONCLUSION We found an independent association between dMMR and a low rate of tumor budding, with a higher rate of pCR, in the basal biopsies of patients with rectal carcinoma subjected to nCRT.

Circulating cytokeratin-positive cells and tumor budding in colorectal cancer

AIM To investigate whether circulating cytokeratin-positive(CK^+) cells in the mesenteric blood of resected colorectal specimens are prognostic and correlate with tumor budding.METHODS Fifty-six colorectal specimens were collected between 9/2007 and 7/2008.Blood from the mesenteric vein was drawn immediately after receiving the fresh and unfixed specimens in the pathology department.After separation of the mononuclear cells by Ficoll-Hypaquedensity-gradient centrifugation,cytological smears were immunocytochemically stained for CK18.Tumor budding was evaluated on slides stained for pan-cytokeratin.The identification of ≥ 30 buds/1.3 mm2 was defined as high grade budding.RESULTS CK^+ cells and clusters were identified in 29(48%) and 14(25%) of the samples,respectively.Two cells were identified in one of three non-malignant cases.Clusters were found exclusively in malignant cases.The occurrence of CK^+ cells or clusters was not associated with any of the evaluated clinicopathological factors,including surgical technique and tumor budding.Moreover,the occurrence of CK^+ cells or clusters had no influence on the cancerspecific survival [75 mo(CI:61;88) vs 83 mo(CI:72;95) and 80 mo(CI:63;98) vs 79 mo(CI:69;89),respectively].CONCLUSION CK^+ cells and showed neither prognostic significance nor an association with tumor budding.It is very likely that CK18-staining is not specific enough to identify the relevant cells.

Role of Self-Loop in Cell-Cycle Network of Budding Yeast

Study of network dynamics is very active area in biological and social sciences. However, the relationship between the network structure and the attractors of the dynamics has not been fully understood yet. In this study, we numerically investigated the role of degenerate self-loops on the attractors and its basin size using the budding yeast cell-cycle network model. In the network, all self-loops negatively suppress the node (self-inhibition loops) and the attractors are only fixed points, i.e. point attractors. It is found that there is a simple division rule of the state space by removing the self-loops when the attractors consist only of point attractors. The point attractor with largest basin size is robust against the change of the self-inhibition loop. Furthermore, some limit cycles of period 2 appear as new attractor when a self-activation loop is added to the original network. It is also shown that even in that case, the point attractor with largest basin size is robust.

Mec1-Dependent Phosphorylation of the Scc3 Subunit of Cohesin during Mitosis in Budding Yeast

Cohesin is an evolutionary conserved complex that controls chromosome segregation during mitosis. Here we show that, in response to DNA damage, Saccharomyces cerevisiae Scc3, one of the major regulatory subunits of the Smc1-Smc3-Scc1 cohesin ring, is phosphorylated on S/T-Q residues. This event depended on the Mec1 checkpoint kinase as well as on cell cycle arrest triggered by the DNA damage checkpoint network. This phosphorylation event also took place during mitosis of an unperturbed cell cycle. The present finding that S. cerevisiae Scc3 is phosphorylated during mitosis represents a potentially important new regulatory step in cohesin’s mitotic functions.

Research Progress on Molecular Mechanisms of Tumor Budding in Colorectal Cancer

Tumor buds are usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the front of invasive tumors which play an important role in the clinical pathological study of colorectal cancer.The prognostic value of tumor budding in colorectal cancer has been supported by a large amount of evidence.However,its molecular mechanism remains unclear,and it is also a research hotspot now.This paper reviews the latest research progress on the molecular mechanisms of tumor budding in colorectal cancer.

Tumor budding is a meaningful prognostic marker in patients with hepatocellular carcinoma after curative hepatectomy

Aim:Tumor budding(TB)has excellent prognostic value in many solid tumors,but there is little research on it in hepatocellular carcinoma(HCC).This study assessed the prognostic value of TB in patients with HCC who received hepatectomy.Methods:This retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University,between 2016 and 2018.TB was evaluated on hematoxylin-and eosin-stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference.t-tests,Chi-squared tests,and rank-sum tests were used to correlate the extent of TB with clinicopathological parameters.Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method.Results:The positive detection rate of TB was 45.2%(95/210)in 210 patients with HCC.Patients positive for TB always exhibit lower tumor differentiation,higher hepatitis B virus DNA levels,and more severe liver fibrosis.Multivariate Cox analysis identified TB(hazard ratio[HR]:2.232,95%confidence interval[CI]:1.479–3.368,p<0.001)as an independent prognostic factor for patients'recurrence-free survival(RFS),similar to tumor size(HR:1.070,95%CI:1.070–1.142,p=0.042)and satellite nodule(HR:2.266,95%CI:1.298–3.956,p=0.004).Kaplan–Meier analysis also demonstrated that TB-positive patients had a significantly worse RFS.Interestingly,subgroup analysis revealed that among HCC patients with negative microvascular invasion(MVI),TB was also strongly associated with RFS(HR:3.206,95%CI:1.667–6.168,p<0.001).These findings suggest that TB may serve as a supplemental prognostic biomarker for HCC-negative MVI.Conclusions:TB is an adverse prognostic biomarker for HCC,particularly in patients negative for MVI.TB evaluation should be considered in the postoperative pathological examination of HCC in clinical practice.