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Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1 – 4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5 – 8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9 , 10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3 , 4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2 , CBFA2T3 , PRDM6 , UTX and OTX2 . CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens , and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB. Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Expression of Ki-67 and P16 proteins in cervical cancer and precancerous lesions of young women and the diagnostic value for cervical cancer and precancerous lesions were investigated. A total of 64 paraffin-embedded specimens of uterus tissue from young female patients who were admitted to Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health Sciences from January 2015 to December 2017 were selected. According to pathological examination, the specimens were divided into chronic cervicitis group (control group, 10 cases), low-grade squamous intraepithelial lesion (LSIL) group (12 cases), high-grade squamous intraepithelial lesion (HSIL) group (20 cases) and squamous carcinoma of the cervix (SCC) group (22 cases). Expression of Ki-67 and P16 protein was detected by immunohistochemistry and the diagnostic values were analyzed. Positive rates of Ki-67 and P16 expression in HSIL and SCC groups were significantly higher than those in LSIL and control groups (P<0.05), but there was no significant difference between LSIL and control groups (P>0.05). Spearman's analysis showed that the expression levels of Ki-67 and P16 were positively correlated with the degree of cervical lesions (rs=0.725; rs=0.829), and their expression levels were also positively correlated (rs=0.772). Sensitivity and specificity analysis showed that the Ki-67 diagnosis has higher sensitivity (95.2%), but the specificity is poor (86.7%). Diagnosis using P16 has high specificity (94.6%), but the sensitivity is poor (85.4%). When the two were combined for diagnosis, sensitivity (94.8%) and specificity (93.2%) were both at a high level. The combined detection of Ki-67 and P16 protein has a high application prospect as an auxiliary diagnosis of SCC.

Mutations of telomerase reverse transcriptase (TERT) and the α thalassemia/mental retardation syndrome X-linked (ATRX) genes have been the subject of numerous studies on the classification and prognosis of glioma. However, the association between TERT and ATRX in World Health Organization (WHO) grade II to IV glioma remains unclear. The present study utilized Sanger sequencing and immunohistochemical methods to detect the expression of the TERT promoter region, ATRX mutations and proliferation marker protein Ki-67 (Ki-67) protein expression in 179 cases of glioma. The current study analyzed these variables and their association with clinicopathological characteristics to further basic research and provide a theoretical basis for the clinical diagnosis and treatment of this type of tumor (1). The results demonstrated that TERT promoter mutations were negatively associated with ATRX. Additionally, Ki-67 protein expression in TERT wild-type samples was higher compared with samples with ATRX deletion. Overall, the results demonstrated, for the first time to the best of the authors' knowledge, that TERT promoter mutations are negatively associated with ATRX expression in WHO grade II to IV gliomas. These findings provide a theoretical basis for further basic research and may improve clinical diagnosis and treatment of glioma in the future.

As a nuclear and nucleolar protein, proliferation marker protein Ki-67 (Ki-67) serves a vital role in tumorigenesis due to its positive correlation with tumor proliferation. High expression of Ki-67 in the cell cycle from the G1 to M phase makes it a potential biomarker for certain tumors and useful for selecting medical treatment. However, the diagnostic value of Ki-67 in oral squamous cell carcinoma (OSCC) has not been fully evaluated. In the present study, the objective was the elucidation of the prognostic value of Ki-67 in a large number of OSCC patients. Ki-67 expression was detected by immunohistochemical staining methods in 298 OSCC specimens and 98 tumor-free oral mucosa specimens (62 dysplasia mucosa and 36 normal mucosa), acquired from Nanjing Stomatological Hospital, Medical School of Nanjing University (Nanjing, China). Expression of Ki-67 in normal tissues, dysplasia tissues and OSCC tissues was compared. Associations between Ki-67 expression and clinicopathological parameters were analyzed by χ2 test. Kaplan-Meier survival curves and Cox progression analysis were used to assess the diagnostic value of Ki-67 for OSCC. The results showed that Ki-67 expression was higher in OSCC tissues than in tumor-free tissues and that it increased with the progression of dysplasia in oral mucosa tissues. In addition, patients with high Ki-67 expression had a worse clinical outcome, including poor tumor differentiation (P=0.001), increased positive lymph node metastasis (P=0.006) and increased worst pattern of invasion type (P<0.0001). Kaplan-Meier survival analysis demonstrated that higher Ki-67 expression was associated with poorer overall survival (OS) (P=0.035), recurrence-free survival (RFS) (P=0.017), metastasis-free survival (MFS) (P=0.032) and disease-free survival (DFS) (P=0.018) times. Additional multivariate analysis demonstrated that Ki-67 expression was negatively associated with OS, DFS, RFS and MFS. In conclusion, Ki-67 overexpression is associated with the progression of OSCC and serves as an independent prognostic factor for OSCC patients.

Evaluating intratumor heterogeneity with image texture analysis offers a more sophisticated understanding of sarcoma response to treatment. We examined the effects of inductive moderate hyperthermia (IMH) on sarcoma-45 growth and intratumor heterogeneity across tissue, cellular and molecular levels using magnetic resonance imaging (MRI), ultrasound and histology image analysis. IMH (42 MHz, 20 W) inhibited sarcoma-45 growth kinetics by 34% compared to the untreated control group. T2-weighted MRI brightness was increased by 42%, reflecting more extensive tumor necrosis, while Young’s modulus increased by 37% due to more pronounced connective tissue replacement in response to IMH. Whereas calculations of Moran’s spatial autocorrelation index revealed distinctions in heterogeneity between tumor core, periphery and capsule regions of interest (ROIs) on MRI, ultrasound and histological examination in the untreated tumor-bearing animals, there was no significant difference between core and periphery after IMH. Exposure to IMH increased overall tumor ROI heterogeneity by 22% on MRI but reduced heterogeneity in the core and periphery on ultrasound and histology images. Ki-67 protein distribution was 25% less heterogeneous on the tumor periphery after IMH. Therefore, this study provides a quantitative characterization of IMH effects on different manifestations of intratumor sarcoma-45 heterogeneity using experimental imaging data.

Due to development of magnetic resonance-based functional imaging, it is easier to detect micro-structural alterations of tumor tissues. The aim of this study was to conduct a preliminary evaluation of the correlation of non-Gaussian diffusion kurtosis imaging (DKI) parameters with expression of molecular markers (epidermal growth factor receptor [EGFR]; anaplastic lymphoma kinase [ALK]; Ki-67 protein) in patients with advanced lung adenocarcinoma, using routine diffusion-weighted imaging as the reference standard. Data from patients with primary lung adenocarcinoma diagnosed at Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) from 2016 to 2019 were collected for retrospective analysis. The pathologic and magnetic resonance imaging data of 96 patients who met the inclusion criteria were included in this study. Specifically, the Kapp and Dapp parameters measured from the DKI model; apparent diffusion coefficient (ADC) value from the diffusion-weighted imaging model; and the EGFR, ALK, and Ki-67 biomarkers detected by immunohistochemistry and/or molecular biology techniques after biopsy or surgery were evaluated. The relations between quantitative parameters (ADC, Kapp, Dapp) and pathologic outcomes (EGFR, ALK, and Ki-67 expression) were analyzed by Spearman correlation test. Of the 96 lung adenocarcinoma lesions (from 96 patients), the number of EGFR- and ALK-positive and high Ki-67 expressing lesions were 53, 12, and 83, respectively. The Kapp values were significantly higher among patients with EGFR-positive mutations (0.81 ± 0.12 vs. 0.66 ± 0.10, t = 6.41, P < 0.001), ALK rearrangement-negative (0.76 ± 0.12 vs. 0.60 ± 0.15, t = 4.09, P < 0.001), and high Ki-67 proliferative index (PI) (0.76 ± 0.12 vs. 0.58 ± 0.13, t = 4.88, P < 0.001). The Dapp values were significantly lower among patients with high Ki-67 PI (3.19 ± 0.69 μm/ms vs. 4.20 ± 0.83 μm/ms, t = 4.80, P < 0.001) and EGFR-positive mutations (3.11 ± 0.73 μm/ms vs. 3.59 ± 0.77 μm/ms, t = 3.12, P = 0.002). The differences in mean Dapp (3.73 ± 1.26 μm/ms vs. 3.26 ± 0.68 μm/ms, t = 1.96, P = 0.053) or ADC values ([1.34 ± 0.81] × 10 mm/s vs. [1.33 ± 0.41] × 10 mm/s, t = 0.07, P = 0.941) between the groups with or without ALK rearrangements were not statistically significant. The ADC values were significantly lower among patients with EGFR-positive mutation ([1.19 ± 0.37] × 10 mm/s vs. [1.50 ± 0.53] × 10 mm/s, t = 3.38, P = 0.001) and high Ki-67 PI ([1.28 ± 0.39] × 10 mm/s vs. [1.67 ± 0.77] × 10 mm/s, t = 2.88, P = 0.005). Kapp was strongly positively correlated with EGFR mutations (r = 0.844, P = 0.008), strongly positively correlated with Ki-67 PI (r = 0.882, P = 0.001), and strongly negatively correlated with ALK rearrangements (r = -0.772, P = 0.001). Dapp was moderately correlated with EGFR mutations (r = -0.650, P = 0.024) or Ki-67 PI (r = -0.734, P = 0.012). ADC was moderately correlated with Ki-67 PI (r = -0.679, P = 0.033). The Kapp value of DKI parameters was strongly correlated with different expression of EGFR, ALK, and Ki-67 in advanced lung adenocarcinoma. The results potentially indicate a surrogate measure of the status of different molecular markers assessed by non-invasive imaging tools.

We analyzed the changes in mitochondrial DNA (mtDNA) copy numbers and the shifting of mtDNA D310 sequence variations (D310 mutation) with their relationships to pathological status and the expression levels of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2/neu), tumor-suppressor protein p53 and cellular proliferation protein Ki-67 in breast invasive ductal carcinoma (BIDC), respectively. Fifty-one paraffin-embedded BIDCs and their paired non-cancerous breast tissues were dissected for DNA extraction. The mtDNA copy number and mtDNA D310 sequence variations were determined by quantitative real-time polymerase chain reaction (q-PCR) and PCR-based direct sequencing, respectively. The expression levels of ER, PR, HER-2/neu, p53 and Ki-67 were determined by immunohistochemical (IHC) staining. Compared to the paired non-cancerous breast tissues, 24 (47.1%) BIDCs had elevated mtDNA copy numbers and 29 (56.9%) harbored mtDNA D310 mutations. Advanced T-status (p=0.056), negative-ER (p=0.005), negative-PR (p=0.007), positive-p53 (p=0.050) and higher Ki-67 (p=0.004) expressions were related to a higher mtDNA copy ratio. In addition, advanced T-status (p=0.019) and negative-HER-2/neu expression (p=0.061) were associated with mtDNA D310 mutations. In conclusion, higher mtDNA copy ratio and D310 mutations may be relevant biomarkers correlated with pathological T-status and the expression levels of ER, PR, HER-2/neu, p53 and Ki-67 in BIDCs.

To study the inhibitory effect of Hedyotis diffusa on cervical cancer and its underlining biomolecular mechanism. Human cervical carcinoma nude mice xenograft was established and the mice were treated by intra-gastric administration of boiled and concentrated Hedyotis diffusa . When the tumor grew to 10 mm in diameter, the mice were randomly divided into Hedyotis diffusa Willd. (HDW) group and control group. The tumor inhibitory rate, survival time, and the expression rate of Ki-67 protein in Hela cells as well as tumor cell apoptosis were compared between these two groups. Hedyotis diffusa had inhibitory effect on cervical cancer cells and induced apoptosis of Hela cells. The expression of Ki-67 protein significantly decreased ( P  < 0.05) in HDW group, and the mean survival time of the mice was significantly extended ( P  < 0.05). Hedyotis diffusa directly inhibited the proliferation of cervical cancer cells and induced apoptosis of the tumor cells. It has a positive effect for the treatment of cervical cancer to achieve the goal of clearing the heat, removing the toxins, eliminating the stasis, and dissolving the masses.

We examined postoperative material from 28 patients aged 39-61 years with gliomas of different degrees of anaplasia (the diagnosis was histologically verified according to the WHO classification of CNS tumors) who had not previously received antitumor treatment. In glioma tissue, the glucose concentration was significantly higher than in the brain tissue of subjects dead from traumas (control), while lactate concentration did not differ from that in the control group or was lower. Hexokinase activity demonstrated a tendency to an increase in grade I and significant elevation in grades II and III, while in grade IV gliomas, this parameter did not differ from the control. Activities of the pentose-phosphate pathway enzymes glucose-6-phosphate dehydrogenase and transketolase increased with increasing of tumor anaplasia. Activity of glycogen synthase 3β kinase was significantly higher than in the control group. IDH1 mutation was discovered in 40% cases, the MGMT promoter methylation was detected in more than 50%, the Ki-67 level increased with increasing tumor anaplasia. The most significant correlations with glioma markers were detected for glucose-6-phosphate dehydrogenase and glycogen synthase 3β kinase. Activities of the studied enzymes of carbohydrate metabolism significantly correlated with Ki-67 marker.

The clinical and histopathological distinction between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is essential, but frequently difficult to make. The utility of CK17 and Ki-67 expression in distinguishing between KA and SCC was investigated. Immunohistochemical staining patterns for CK17 and Ki-67 were evaluated in 24 KA and 27 SCC cases. The pattern of staining was evaluated as central, peripheral or diffuse, according to the basal/peripheral and suprabasal/central cell staining of tumor lobules. The sensitivity and specificity of the central CK17 staining pattern in the identification of KA were 92 and 70%, respectively. Additionally, the sensitivity and specificity of the diffuse Ki-67 staining pattern in the identification of SCC were 81 and 100%, respectively. The results of the present study suggest that a diffuse Ki-67 staining pattern may be used to diagnose SCC, while a central CK17 staining pattern indicates KA. However, the KA-like SCC cases exhibited mixed patterns, which limits the effectiveness of these markers.