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Background The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer. Methods Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline. Results Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) ( P  = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014–0.721; P  = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592–0.846). Conclusion Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer.

The incidence of local recurrence at 5 years was low among women with T1N0 grade 1 or 2 luminal A breast cancer who had undergone breast-conserving surgery and received endocrine therapy, but not radiotherapy.

Regulatory T cells help to keep adaptive immunity in check. Rudensky and colleagues show that these cells continuously require TCR signaling to maintain their cellular identity and homeostasis and to exert their suppressive ability. Foxp3 + regulatory T cells (T reg cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen receptor (TCR) is critical for the differentiation of T reg cells, the role of TCR signaling in T reg cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in T reg cell dysfunction that could not be attributed to impaired expression of the transcription factor Foxp3, decreased expression of T reg cell signature genes or altered ability to sense and consume interleukin 2 (IL-2). Instead, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated T reg cell transcriptional signature. Our results reveal a critical role for the TCR in the suppressor capacity of T reg cells.

Background A number of studies have linked positive Ki-67 expression with the prognosis of osteosarcoma (OS) patients. However, the results have been conflicting. To address this controversy, we conducted an analysis using a meta-analysis and a TCGA dataset to estimate the value of Ki-67 expression in the prognosis of OS. Methods A comprehensive search for relevant papers was conducted using NCBI PubMed, Embase, Springer, ISI Web of Knowledge, the Cochrane Library, and CNKI regardless of the publication year. The associations between Ki-67 expression and the clinical features and main prognostic outcomes of OS were measured. The TCGA dataset was also analyzed. The pooled odds ratio (OR) and its 95% confidential intervals (CIs) were utilized for statistical analysis. Results Overall, a total of 12 studies with 500 cases were included, and the results indicated that the expression of Ki-67 was significantly associated with Enneking stage (OR = 6.88, 95% CI: 2.92–16.22, p  < 0.05), distant metastasis (OR = 3.04, 95% CI: 1.51–6.12, p  < 0.05) and overall survival (OR = 8.82, 95% CI: 4.68–16.65, p  < 0.05) in OS patients. Additionally, we observed no significant heterogeneity among all retrieved studies. Associations between Ki-67 expression and overall survival and disease-free survival of sarcoma were confirmed using the TCGA and Kaplan-Meier plotter datasets. Conclusion The present study strongly suggests that positive Ki-67 expression was associated with Enneking stage, distant metastasis, and overall survival of OS, and it may be used as a potential biomarker to predict prognosis and guide clinical therapy for OS.

Background Lung cancer ranks as the leading cause of cancer-related deaths worldwide and we performed this meta-analysis to investigate eligible studies and determine the prognostic effect of Ki-67. Methods In total, 108 studies in 95 articles with 14,732 patients were found to be eligible, of which 96 studies reported on overall survival (OS) and 19 studies reported on disease-free survival (DFS) with relation to Ki-67 expression in lung cancer patients. Results The pooled hazard ratio (HR) indicated that a high Ki-67 level could be a valuable prognostic factor for lung cancer (HR = 1.122 for OS, P  < 0.001 and HR = 1.894 for DFS, P < 0.001). Subsequently, the results revealed that a high Ki-67 level was significantly associated with clinical parameters of lung cancer including age (odd ratio, OR = 1.246 for older patients, P  = 0.018), gender (OR = 1.874 for males, P  < 0.001) and smoking status (OR = 3.087 for smokers, P < 0.001). Additionally, significant positive correlations were found between Ki-67 overexpression and poorer differentiation (OR = 1.993, P  = 0.003), larger tumor size (OR = 1.436, P = 0.003), and higher pathologic stages (OR = 1.867 for III-IV, P  < 0.001). Furthermore, high expression of Ki-67 was found to be a valuable predictive factor for lymph node metastasis positive (OR = 1.653, P < 0.001) and advanced TNM stages (OR = 1.497 for stage III-IV, P  = 0.024). Finally, no publication bias was detected in any of the analyses. Conclusions This study highlights that the high expression of Ki-67 is clinically relevant in terms of the prognostic and clinicopathological characteristics for lung cancer. Nevertheless, more prospective well-designed studies are warranted to validate these findings.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

Breast cancer is a heterogeneous disease comprising a diversity of tumor subtypes that manifest themselves in a wide variety of clinical, pathological, and molecular features. One important subset, luminal breast cancers, comprises two clinically distinct subtypes luminal A and B each of them endowed with its own genetic program of differentiation and proliferation. Luminal breast cancers were operationally defined as follows: Luminal A: ER+, PR+, HER2-, Ki-67<14% and Luminal B: ER+ and/or PR+, HER2-,Ki-67≥14% or, alternatively ER+ and/or PR+, HER2+, any Ki-67. There is currently a need for a clinically robust and validated immunohistochemical assay that can help distinguish between luminal A and B breast cancer. MCM2 is a family member of the minichromosome maintenance protein complex whose role in DNA replication and cell proliferation is firmly established. As MCM2 appears to be an attractive alternative to Ki-67, we sought to study the expression of MCM2 and Ki-67 in different histological grades and molecular subtypes of breast cancer focusing primarily on ER-positive tumors. MCM2 and Ki-67 mRNA expression were studied using in silico analysis of available DNA microarray and RNA-sequencing data of human breast cancer. We next used immunohistochemistry to evaluate protein expression of MCM2 and Ki-67 on tissue microarrays of invasive breast carcinoma. We found that MCM2 and Ki-67 are highly expressed in breast tumors of high histological grades, comprising clinically aggressive tumors such as triple-negative, HER2-positive and luminal B subtypes. MCM2 expression was detected at higher levels than that of Ki-67 in normal breast tissues and in breast cancers. The bimodal distribution of MCM2 scores in ER+/HER2- breast tumors led to the identification of two distinct subgroups with different relapse-free survival rates. In conclusion, MCM2 expression can help sorting out two clinically important subsets of luminal breast cancer whose treatment and clinical outcomes are likely to diverge.

Background The prognosis of ground glass opacity featured lung adenocarcinomas (GGO-LUAD) is significantly better than that of solid nodule featured lung adenocarcinomas (SN-LUAD), but the underlying reasons remain unclear. Ki-67 and cell cycle regulator proteins are highly expressed in many cancers and linked to prognosis. This study aims to investigate their differential expression in LUAD with different radiological subtypes. Methods Patients with resected pathological stage 0−III LUAD in our department between July 2019 and March 2022 were retrospectively reviewed. All included patients were divided into four groups based on different consolidation-to-tumour ratio (CTR), we focuses on evaluating the differential expression of Ki-67 and cell cycle regulatory proteins (CCNA2, CCNB1, CCND1, P16, P21, TOP2A, TP53, and pRb) in LUAD with different CTR. Results A total of 481 patients were included, 108 in the pure ground glass opacity (PGGO, CTR = 0) group, 103 in the GGO-dominant (GGO-D, 0 < CTR ≤ 0.5) group, 74 in the SN-dominant (SN-D, 0.5 < CTR < 1) group, and 196 in the pure solid nodule (SN, CTR = 1) group. The expression of Ki-67 was significantly higher in elderly patients ( P  <  0.05), former or current smokers ( P  <  0.0001), males ( P  <  0.05), poorly differentiated tumors ( P  <  0.0001), and tumors with spread through air spaces (STAS) ( P  <  0.0001), and advanced stage tumors ( P  <  0.0001). Regardless of age, gender, smoking status and epidermal growth factor receptor (EGFR) mutation status, GGO-LUAD demonstrated significantly lower expression of Ki-67 compared to SN-LUAD. The expression of Ki-67 and cell cycle regulatory proteins (except P21) were significantly lower in the PGGO, GGO-D, SN-D than in the SN group. However, there was no significant difference in the expression of Ki-67 and cell cycle regulatory proteins among the PGGO, GGO-D, and SN-D groups. Conclusions GGO-LUAD demonstrated significantly lower expression of Ki-67 and cell cycle regulatory proteins compared to SN-LUAD, which may explain the reasons behind the excellent prognosis of GGO-LUAD. Graphical Abstract

Recently we have established that the kidney tubular epithelium is repaired by surviving epithelial cells. It is not known, however, whether a population of intratubular adult progenitor cells are responsible for this epithelial repair after acute kidney injury. In this study, we used an unbiased DNA analog-based approach that does not rely on candidate markers to track multiple rounds of cell division in vivo. In the proximal tubule, robust thymidine analog incorporation was observed postinjury. Cell division was stochastic and enriched among cells that were injured and dedifferentiated. There was no evidence for the presence of a population of specialized progenitors that repeatedly divide in response to injury. Instead, these results indicate that after injury, new epithelial cells arise from self-duplication of surviving cells, most of which are injured. Because the renal papilla contains DNA label-retaining cells and has been proposed as a stem cell niche, we examined the proliferative behavior of these putative progenitors after ischemia-reperfusion injury. Although label-retaining cells in the renal papilla diminished with time after ischemia-reperfusion injury, they neither proliferated nor migrated to the outer medulla or cortex. Thus, nonlethally injured cells repopulate the kidney epithelium after injury in the absence of any specialized progenitor cell population.

Although most women with luminal breast cancer do well on endocrine therapy alone, some will develop fatal recurrence thereby necessitating the need to prospectively determine those for whom additional cytotoxic therapy will be beneficial. Categorical combinations of immunohistochemical measures of ER, PR, HER2, and KI67 are traditionally used to classify patients into luminal A-like and B-like subtypes for chemotherapeutic reasons, but this may lead to the loss of prognostically relevant information. Here, we compared the prognostic value of quantitative measures of these markers, combined in the IHC4-score, to categorical combinations in subtypes. Using image analysis-based scores for all four markers, we computed the IHC4-score for 2498 patients with luminal breast cancer from two European study populations. We defined subtypes (A-like (ER + and PR + : and HER2- and low KI67) and B-like (ER + and/or PR + : and HER2 + or high KI67)) by combining binary categories of these markers. Hazard ratios and 95% confidence intervals for associations with 10-year breast cancer-specific survival were estimated in Cox proportional-hazard models. We accounted for clinical prognostic factors, including grade, tumor size, lymph-nodal involvement, and age, by using the PREDICT-score. Overall, Subtypes [hazard ratio (95% confidence interval) B-like vs. A-like = 1.64 (1.25–2.14); P -value < 0.001] and IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.32 (1.20–1.44); P -value < 0.001] were prognostic in univariable models. However, IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.24 (1.11–1.37); P -value < 0.001; likelihood ratio chi-square (LR χ 2 ) = 12.5] provided more prognostic information than Subtype [hazard ratio (95% confidence interval) B-like vs. A-like = 1.38 (1.02–1.88); P -value = 0.04; LR χ 2  = 4.3] in multivariable models. Further, higher values of the IHC4-score were associated with worse prognosis, regardless of subtype ( P -heterogeneity = 0.97). These findings enhance the value of the IHC4-score as an adjunct to clinical prognostication tools for aiding chemotherapy decision-making in luminal breast cancer patients, irrespective of subtype.