Master Role of Hypoxia in Cancer Progression: Major Insights During ISOTT's Half-Century.

On the occasion of ISOTT's half-century, in this chapter, tumour hypoxia (i.e. critically reduced oxygen levels on macro- and microscopic scales), recently classified as an additional hallmark of cancer, its various aetiology-related classifications (diffusion- or perfusion-limitations, hypoxaemic), time-frames of exposure (acute, chronic, cyclic), and different levels (moderate, mild, severe) within and across tumours, and its Janus-face-like role ("dichotomy") in tumour regression (e.g. apoptosis, necrosis) versus "adaptive" tumour progression have been updated and summarised. This latter knowledge is, to a great extent, based on (a) direct, reliable assessments and mapping of the heterogeneous tumour oxygenation status using minimally invasive polarographic pO2 microsensors in clinical settings since the late 1980s, and (b) the discovery of the hypoxia-inducible factors (HIFs) in the early 1990s. These data have clarified the role of hypoxia in stimulating a variety of biologic responses that mediate cancer progression through changes (a) in the genome (associated with clonal selection and expansion), (b) in the transcriptome, and (c) in the proteome, as well as its role as a barrier to the effectiveness of anti-cancer therapies.

Baseline SUVmax is correlated with tumor hypoxia and patient outcomes in nasopharyngeal carcinoma.

To evaluate the prognostic significance of the maximum standardized uptake value (SUVmax) in nasopharyngeal carcinoma (NPC), establish a gene signature that correlates with SUVmax, and explore the underlying biological behaviors associated with these correlations for the prediction of clinical outcomes. A cohort of 726 patients with NPC was examined to identify correlations between SUVmax and various clinical variables. RNA sequencing was performed to identify genes related to SUVmax, and these genes were used to develop an SUV signature. Additionally, transcriptome enrichment analysis was conducted to investigate the potential biological behaviors underlying the observed correlations. Higher SUVmax was associated with an increased tumor burden and worse prognosis. The SUV signature, which consisted of 10 genes, was positively correlated with SUVmax, and it predicted worse survival outcomes. This signature was highly expressed in malignant epithelial cells and associated with hypoxia and resistance to radiotherapy. Additionally, the signature was negatively correlated with immune function. SUVmax is a valuable prognostic indicator in NPC, with higher values predicting worse outcomes. The SUV signature offers further prognostic insights, linking glucose metabolism to tumor aggressiveness, treatment resistance, and immune function, and it could represent a potential biomarker for NPC.

DDR2 expression in breast cancer is associated with blood vessel invasion, basal-like tumors, tumor associated macrophages, regulatory T cells, detection mode and prognosis.

Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase for collagen, stimulating epithelial-mesenchymal transition and stiffness in breast cancer. Here, we investigated levels of DDR2 in breast tumor cells in relation to vascular invasion, TIL subsets, macrophages, molecular tumor subtypes, modes of detection and prognosis. This retrospective, population-based series of invasive breast carcinomas from the Norwegian Screening Program in Vestfold County (Norway), period 2004-2009, included 200 screening patients and 82 cases detected in screening intervals. DDR2 was examined on core needle biopsies using a semi-quantitative, immunohistochemical staining index and dichotomized as low or high DDR2 expression. Counts of macrophages and TIL subsets were dichotomized based on immunohistochemistry using TMA. We also recorded blood or lymphatic vessel invasion (BVI or LVI) as present or absent by immunohistochemistry. High expression of DDR2 in tumor cells showed significant relation with high counts of CD163+ macrophages (p < 0.001) and FOXP3 TILs (p = 0.011), presence of BVI (p = 0.028), high tumor cell proliferation by Ki67 (p = 0.033), ER negativity (p = 0.001), triple-negative cases (p = 0.038), basal-like features (p < 0.001) as well as interval detection (p < 0.001). By multivariate analysis, high DDR2 expression was related to reduced recurrence-free survival (HR, 2.3, p = 0.017), when examined together with histologic grading, lymph node assessment, tumor diameter, BVI, and molecular tumor subtype. This study supports a link between high DDR2 expression, high counts of macrophages by CD163 (tumor associated) and regulatory T cells by FOXP3 together with the presence of BVI, possibly indicating increased tumor motility and intravasation in aggressive breast tumors.

Clinical significances of several fibrotic markers for prognosis in hepatocellular carcinoma patients who underwent hepatectomy.

Background: Progression of chronic liver fibrosis and related increased fibrotic markers are associated with functional liver reserves or patient prognosis as well as tumor factors in hepatocellular carcinoma (HCC) patients. The aim of this study was to newly clarify the relationship between fibrotic markers and HCC malignant behaviors or its long-term postoperative prognosis by the retrospective cohort study. Methods: We examined the relationship between tumor-related factors or six liver fibrosis-associated parameters, including platelet count, hyaluronic acid (HA), Mac-2 binding protein glycosylation isomer (M2BPGi), type IV collagen 7S (T4C7), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (Fib-4) index, and clinicopathological parameters, surgical records, and postoperative prognosis in 130 HCC who underwent curative hepatectomy. Results: Histological fibrosis stage 4 as cirrhosis was in 31%. The platelet count significantly decreased in stage 4 fibrosis and correlated with grade B liver damage (P<0.01). HA levels were significantly increased in multiple HCC, stage 4 fibrosis, and grade B liver damage (P<0.01). T4C7 was significantly increased in patients with post-hepatectomy tumor recurrence compared to those without (P<0.01). Additionally, M2BPGi was significantly higher in stage 4 fibrosis and liver damage grade B, and was significantly associated with poor prognosis (P<0.05). Fib-4 index was significantly higher in patients with liver damage B (P<0.05), and T4C7 alone did not correlate with other five fibrosis markers. Stage 4 fibrosis, higher T4C7, higher M2BPGi, and increased tumor size were significantly associated with shorter cancer-free, overall, and cancer-specific survivals. Higher T4C7, non-met Milan criteria, liver damage B, blood transfusion, and curability C were independently associated with cancer-specific survivals (P<0.05). Conclusions: Type IV collagen 7S (T4C7) may reflect not only impaired liver function but also HCC malignant behaviors and patient survivals.

Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

Nomograms Predict PFS and OS for SCLC Patients After Standardized Treatment: A Real-World Study.

Purpose: This study aims to investigate the process of small cell lung cancer (SCLC) patients from achieving optimal efficacy to experiencing disease progression until death. It examines the predictive value of the treatment response on progression free survival (PFS) and overall survival (OS) of SCLC patients. Patients and Methods: We conducted a retrospective analysis on 136 SCLC patients diagnosed from 1992 to 2018. Important prognostic factors were identified to construct nomogram models. The predictive performance of the models was evaluated using the receiver operating characteristic curves and calibration curves. Survival differences between groups were compared using Kaplan-Meier survival curves. Subsequently, an independent cohort consisting of 106 SCLC patients diagnosed from 2014 to 2021 was used for validation. Results: We constructed two nomograms to predict first-line PFS (PFS1) and OS of SCLC. The area under the receiver operating characteristic curves for the PFS1 nomogram predicting PFS at 3-, 6-, and 12-months were 0.919 (95% CI: 0.867-0.970), 0.908 (95% CI: 0.860-0.956) and 0.878 (95% CI: 0.798-0.958), and for the OS nomogram predicting OS at 6-, 12-, and 24-months were 0.814 (95% CI: 0.736-0.892), 0.819 (95% CI: 0.749-0.889) and 0.809 (95% CI: 0.678-0.941), indicating those two models with a high discriminative ability. The calibration curves demonstrated the models had a high degree of consistency between predicted and observed values. According to the risk scores, patients were divided into high-risk and low-risk groups, showing a significant difference in survival rate. And these findings were validated in another independent validation cohort. Conclusion: Based on the patients' treatment response after standardized treatment, we developed and validated two nomogram models to predict PFS1 and OS of SCLC. The models demonstrated good accuracy, reliability and clinical applicability by validating in an independent cohort.

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Primary Negative Prognostic Factors in Pediatric and Adult Patients Undergoing Trigger Finger Surgery.

Objectives This study aims to investigate the negative prognostic indicators of pediatric and adult trigger finger surgery patients concerning complications, recurrence, and satisfaction. Methods A retrospective study was conducted on 61 patients with a total of 91 trigger fingers, including 31 in children and 30 in adult patients, all of whom were treated using a standardized surgical technique. The study considered several demographic and clinical factors, including age, gender, dominant hand, body mass index, occupation, history of trauma, single or multiple finger involvement, staging according to Green classification, diabetes mellitus, comorbidities, recurrence, revision surgery, utilization of non-surgical treatment methods, need for rehabilitation after surgery, time to return to work, the time interval from clinic initiation to the surgery, satisfaction and the duration of the follow-up period. In addition, the quick version of the disabilities of the arm, shoulder, and hand (QDASH); and the visual analog scale (VAS) were used to assess patients' data. Results In adult patients, a statistically significant relationship was observed between the increasing grade of the Green stage and complication rate (p<0.001), recurrence (p<0.001), and lower satisfaction (p<0.001). No statistically significant relationship was identified between Green's classification and complications (p=0.129), recurrence (p=0.854), or satisfaction (p=0.143) in pediatric patients. While a statistically significant relationship existed between the time interval from clinic initiation to surgery and complications (p=0.033) in adult patients, no significant relationships were observed for recurrence or satisfaction. Conversely, there was no statistically significant relationship between the time interval from clinic initiation to surgery and complications, recurrence, or satisfaction in pediatric patients. Conclusion This study demonstrates that increasing the grade of the Green stage and duration of symptoms before surgery were the substantial factors contributing to prognosis in adult patients but not in pediatric patients. These findings can assist physicians during patients' treatment management. We suggest that physicians consider these factors for patients' satisfaction.

Lactate in breast cancer cells is associated with evasion of hypoxia-induced cell cycle arrest and adverse patient outcome.

Tumor hypoxia is a common microenvironmental factor in breast cancers, resulting in stabilization of Hypoxia-Inducible Factor 1 (HIF-1), the master regulator of hypoxic response in cells. Metabolic adaptation by HIF-1 results in inhibition of citric acid cycle, causing accumulation of lactate in large concentrations in hypoxic cancers. Lactate can therefore serve as a secondary microenvironmental factor influencing cellular response to hypoxia. Presence of lactate can alter the hypoxic response of breast cancers in many ways, sometimes in opposite manners. Lactate stabilizes HIF-1 in oxidative condition, as well as destabilizes HIF-1 in hypoxia, increases cellular acidification, and mitigates HIF-1-driven inhibition of cellular respiration. We therefore tested the effect of lactate in MDA-MB-231 under hypoxia, finding that lactate can activate pathways associated with DNA replication, and cell cycling, as well as tissue morphogenesis associated with invasive processes. Using a bioengineered nano-patterned stromal invasion assay, we also confirmed that high lactate and induced HIF-1α gene overexpression can synergistically promote MDA-MB-231 dissemination and stromal trespass. Furthermore, using The Cancer Genome Atlas, we also surprisingly found that lactate in hypoxia promotes gene expression signatures prognosticating low survival in breast cancer patients. Our work documents that lactate accumulation contributes to increased heterogeneity in breast cancer gene expression promoting cancer growth and reducing patient survival.

QSOX2 Upregulated in triple-negative breast cancer exacerbates patient prognosis by stabilizing integrin ß1.

Breast cancer (BC) remains a significant global health threat, with triple-negative breast cancer (TNBC) standing out as a particularly aggressive subtype lacking targeted therapies. Addressing this gap, we propose Quiescin Q6 sulfhydryl oxidase 2 (QSOX2) as a potential therapeutic target, a disulfide bond-forming enzyme implicated in cancer progression. Using publicly available datasets, we conducted a comprehensive analysis of QSOX2 expression in BC tumor and non-tumor tissues, assessing its specificity across different molecular subtypes. We further explored correlations between QSOX2 expression and patient outcomes, utilizing datasets like TCGA and METABRIC. In addition, we performed in vitro experiments to evaluate QSOX2 expression in BC cell lines and investigate the effects of QSOX2 knockdown on various TNBC cellular processes, including cell proliferation, apoptosis resistance, migration, and the epithelial-to-mesenchymal transition (EMT). Our results reveal significantly elevated QSOX2 expression in BC tumor tissues, particularly in TNBC, and establish an association between high QSOX2 expression and increased patient mortality, cancer progression, and recurrence across various BC subtypes. Notably, QSOX2 knockdown in TNBC cell lines reduces cell proliferation, enhances apoptosis, and suppresses migration, potentially mediated through its influence on the EMT process. Furthermore, we identify a significant link between QSOX2 and integrin ß1 (ITGB1), suggesting that QSOX2 enhances ITGB1 stability, subsequently exacerbating the malignancy of TNBC. In conclusion, elevated QSOX2 expression emerges as a key factor associated with adverse patient outcomes in BC, particularly in TNBC, contributing to disease progression through various mechanisms, including the modulation of ITGB1 stability. Our findings underscore the potential of targeting QSOX2 as a therapeutic strategy for improving patient prognoses not only in TNBC but also in other BC subtypes.

VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma.

VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV-) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles' heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.

Loss of the epithelial marker CDX1 predicts poor prognosis in early-stage CRC patients.

BACKGROUND: We have previously shown that non-curative chemotherapy imposes fetal conversion and high metastatic capacity to cancer cells. From the set of genes differentially expressed in Chemotherapy Resistant Cells, we obtained a characteristic fetal intestinal cell signature that is present in a group of untreated tumors and is sufficient to predict patient prognosis. A feature of this fetal signature is the loss of CDX1. METHODS: We have analyzed transcriptomic data in public datasets and performed immunohistochemistry analysis of paraffin embedded tumor samples from two cohorts of colorectal cancer patients. RESULTS: We demonstrated that low levels of CDX1 are sufficient to identify patients with poorest outcome at the early tumor stages II and III. Presence tumor areas that are negative for CDX1 staining in stage I cancers is associated with tumor relapse. CONCLUSIONS: Our results reveal the actual possibility of incorporating CDX1 immunostaining as a valuable biomarker for CRC patients.

Comparing the clinical value of baseline [68 Ga]Ga-FAPI-04 PET/CT and [18F]F-FDG PET/CT in pancreatic ductal adenocarcinoma: additional prognostic value of the distal pancreatitis.

PURPOSE: Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the performance of [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT on the disease staging and prognostic value of patients with localized PDAC on contrast-enhanced (CE)-CT images. METHODS: Patients with suspected localized PDAC on CE-CT were recruited for static [68 Ga]Ga-FAPI-04 and 18[F]F-FDG and PET/CT, and select patients underwent simultaneous 60-min dynamic 68 Ga-FAPI-04 PET/CT. The diagnostic and staging performances of the static PET/CT results were evaluated by delineating regions of interest in the primary tumor, whole pancreas, and distal pancreas in both types of scans and then evaluating correlations between the PET/CT findings and clinicopathological characteristics. Furthermore, Kaplan-Meier and hazard ratio (log-rank) methods were used to evaluate the prognostic value of the combined dynamic [68 Ga]Ga-FAPI-04 and static [18F]F-FDG PET/CT method. RESULTS: We included 49 patients with histologically confirmed PDAC adenocarcinomas; 32 underwent 60-min dynamic [68 Ga]Ga-FAPI-04 PET/CT imaging simultaneously. The static [68 Ga]Ga-FAPI-04 method had significantly higher accuracy and uptake values than the static [18F]F-FDG method for primary PDAC lesions, metastatic lymph nodes, and distal metastases. Furthermore, 18.4% and 10.2% of the patients' stages changed after using the [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT methodologies, respectively, compared to the CE-CT-designated stage. The Ki values obtained from dynamic [68 Ga]Ga-FAPI-04 PET/CT did not differ between PDAC and distal obstructive pancreatitis lesions. Pathologically enlarged tumor size, poor differentiation, and perineural invasion were associated with increased [68 Ga]Ga-FAPI-04 uptake but not with [18F]F-FDG uptake. The preoperative prognostic performance of [68 Ga]Ga-FAPI-04 was better than that of [18F]F-FDG. Interestingly, combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG uptake results in the whole pancreas could further stratify patients based on their postoperative prognosis. CONCLUSION: 6[68 Ga]Ga-FAPI-04 PET/CT was more sensitive and accurate than [18F]F-FDG PET/CT for tumor, node, and metastasis staging of PDAC identified on CE-CT. Additionally, [68 Ga]Ga-FAPI-04 uptake was significantly associated with pathologically aggressive tumor features. Combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT findings improved the prognostic value, potentially providing a non-invasive guide for clinical management. Finally, increased fibroblast activity in PDAC-induced obstructive pancreatitis may be associated with poor patient survival rates.

COL7A1 Expression Improves Prognosis Prediction for Patients with Clear Cell Renal Cell Carcinoma Atop of Stage.

Clear-cell renal cell carcinoma (ccRCC) accounts for 75% of kidney cancers. Due to the high recurrence rate and treatment options that come with high costs and potential side effects, a correct prognosis of patient survival is essential for the successful and effective treatment of patients. Novel biomarkers could play an important role in the assessment of the overall survival of patients. COL7A1 encodes for collagen type VII, a constituent of the basal membrane. COL7A1 is associated with survival in many cancers; however, the prognostic value of COL7A1 expression as a standalone biomarker in ccRCC has not been investigated. With five publicly available independent cohorts, we used Kaplan-Meier curves and the Cox proportional hazards model to investigate the prognostic value of COL7A1, as well as gene set enrichment analysis to investigate genes co-expressed with COL7A1. COL7A1 expression stratifies patients in terms of aggressiveness, where the 5-year survival probability of each of the four groups was 72.4%, 59.1%, 34.15%, and 8.6% in order of increasing expression. Additionally, COL7A1 expression was successfully used to further divide patients of each stage and histological grade into groups of high and low risk. Similar results were obtained in independent cohorts. In vitro knockdown of COL7A1 expression significantly affected ccRCC cells' ability to migrate, leading to the hypothesis that COL7A1 may have a role in cancer aggressiveness. To conclude, we identified COL7A1 as a new prognosis marker that can stratify ccRCC patients.

Influence of time between surgery and adjuvant radiotherapy on prognosis for patients with head and neck squamous cell carcinoma: A systematic review.

The timing of postoperative radiotherapy following surgical intervention in patients with head and neck cancer remains a controversial issue. This review aims to summarize findings from available studies to investigate the influence of time delays between surgery and postoperative radiotherapy on clinical outcomes. Articles between 1 January 1995 and 1 February 2022 were sourced from PubMed, Web of Science, and ScienceDirect. Twenty-three articles met the study criteria and were included; ten studies showed that delaying postoperative radiotherapy might negatively impact patients and lead to a poorer prognosis. Delaying the start time of radiotherapy, 4 weeks after surgery did not result in poorer prognoses for patients with head and neck cancer, although delays beyond 6 weeks might worsen patients' overall survival, recurrence-free survival, and locoregional control. Prioritization of treatment plans to optimize the timing of postoperative radiotherapy regimes is recommended.

Association of Membranous WNT-1 and Nuclear mTOR with Endometrial Cancer Grade.

Endometrial cancer remains a common cancer affecting the female reproductive system. There is still a need for more efficient ways of determining the degree of malignancy and optimizing treatment. WNT and mTOR are components of signaling pathways within tumor cells, and dysfunction of either protein is associated with the pathogenesis of neoplasms. Therefore, the aim of our study was to assess the impact of subcellular WNT-1 and mTOR levels on the clinical course of endometrial cancer. WNT-1 and mTOR levels in the plasma membrane, nucleus, and cytoplasm were evaluated using immunohistochemical staining in a group of 64 patients with endometrial cancer of grades 1-3 and FIGO stages I-IV. We discovered that the levels of WNT-1 and mTOR expression in the cellular compartments were associated with tumor grade and staging. Membranous WNT-1 was negatively associated, whereas cytoplasmic WNT-1 and nuclear mTOR were positively associated with higher grading of endometrial cancer. Furthermore, nuclear mTOR was positively associated with FIGO stages IB-IV. To conclude, we found that the assessment of WNT-1 in the cell membrane may be useful for exclusion of grade 3 neoplasms, whereas cytoplasmic WNT-1 and nuclear mTOR may be used as indicators for confirmation of grade 3 neoplasms.

Stress-Inducible SCAND Factors Suppress the Stress Response and Are Biomarkers for Enhanced Prognosis in Cancers.

The cell stress response is an essential system present in every cell for responding and adapting to environmental stimulations. A major program for stress response is the heat shock factor (HSF)-heat shock protein (HSP) system that maintains proteostasis in cells and promotes cancer progression. However, less is known about how the cell stress response is regulated by alternative transcription factors. Here, we show that the SCAN domain (SCAND)-containing transcription factors (SCAN-TFs) are involved in repressing the stress response in cancer. SCAND1 and SCAND2 are SCAND-only proteins that can hetero-oligomerize with SCAN-zinc finger transcription factors, such as MZF1(ZSCAN6), for accessing DNA and transcriptionally co-repressing target genes. We found that heat stress induced the expression of SCAND1, SCAND2, and MZF1 bound to HSP90 gene promoter regions in prostate cancer cells. Moreover, heat stress switched the transcript variants' expression from long noncoding RNA (lncRNA-SCAND2P) to protein-coding mRNA of SCAND2, potentially by regulating alternative splicing. High expression of HSP90AA1 correlated with poorer prognoses in several cancer types, although SCAND1 and MZF1 blocked the heat shock responsiveness of HSP90AA1 in prostate cancer cells. Consistent with this, gene expression of SCAND2, SCAND1, and MZF1 was negatively correlated with HSP90 gene expression in prostate adenocarcinoma. By searching databases of patient-derived tumor samples, we found that MZF1 and SCAND2 RNA were more highly expressed in normal tissues than in tumor tissues in several cancer types. Of note, high RNA expression of SCAND2, SCAND1, and MZF1 correlated with enhanced prognoses of pancreatic cancer and head and neck cancers. Additionally, high expression of SCAND2 RNA was correlated with better prognoses of lung adenocarcinoma and sarcoma. These data suggest that the stress-inducible SCAN-TFs can function as a feedback system, suppressing excessive stress response and inhibiting cancers.

Deep learning-based pathology image analysis predicts cancer progression risk in patients with oral leukoplakia.

BACKGROUND: Oral leukoplakia (OL) is associated with an increased risk for oral cancer (OC) development. Prediction of OL cancer progression may contribute to decreased OC morbidity and mortality by favoring early intervention. Current OL progression risk assessment approaches face large interobserver variability and is weakly prognostic. We hypothesized that convolutional neural networks (CNN)-based histology image analyses could accelerate the discovery of better OC progression risk models. METHODS: Our CNN-based oral mucosa risk stratification model (OMRS) was trained to classify a set of nondysplastic oral mucosa (OM) and a set of OC H&E slides. As a result, the OMRS model could identify abnormal morphological features of the oral epithelium. By applying this model to OL slides, we hypothesized that the extent of OC-like features identified in the OL epithelium would correlate with its progression risk. The OMRS model scored and categorized the OL cohort (n = 62) into high- and low-risk groups. RESULTS: OL patients classified as high-risk (n = 31) were 3.98 (95% CI 1.36-11.7) times more likely to develop OC than low-risk ones (n = 31). Time-to-progression significantly differed between high- and low-risk groups (p = 0.003). The 5-year OC development probability was 21.3% for low-risk and 52.5% for high-risk patients. The predictive power of the OMRS model was sustained even after adjustment for age, OL site, and OL dysplasia grading (HR = 4.52, 1.5-13.7). CONCLUSION: The ORMS model successfully identified OL patients with a high risk of OC development and can potentially benefit OC early diagnosis and prevention policies.

Identification and validation of a glycolysis-related gene signature for depicting clinical characteristics and its relationship with tumor immunity in patients with colon cancer.

Colon cancer (CC) is one of the most common gastrointestinal malignant tumors with a high mortality rate. Glycolysis is an important pathway for tumors to obtain energy. However, its role in CC remains largely unknown. In present study, we analyzed glycolysis-related gene expression to depict clinical characteristics and its relationship with tumor immunity in CC to find potential target treatments. A prognostic model based on 13 glycolysis-related genes was established by univariate and multivariate Cox regression analyses. The efficacy of the gene model was tested via survival analysis, receiver operating characteristic analysis, and principal component analysis. Furthermore, our findings revealed and validated 13 glycolysis-related genes (NUP107, SEC13, ALDH7A1, ALG1, CHPF, FAM162A, FBP2, GALK1, IDH1, TGFA, VLDLR, XYLT2, and OGDHL), which constituted a prognostic prediction model. The model exhibited clinical implication potential, had a relatively high accuracy, and was closely associated with the patients' clinical features. In particular, the tumor stage could be clearly distinguished by glycolysis-related gene signatures. Finally, a significant difference between glycolysis-related gene colon cancer immunity and sensitive immune drugs was observed. Our glycolysis-related gene model could provide the basis for potential early individualized treatment. The 13 glycolysis-related gene signature was a reliable predictive tool for the prognosis of colon cancer. Our findings could help patients select targets for individualized treatment and immunotherapy strategies. The study findings advance our understanding of the potential mechanism of glycolysis in colon cancer.

Integrated analysis of the clinical consequence and associated gene expression of ALK in ALK-positive human cancers.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is genetically altered in several cancers, including NSCLC, melanoma, lymphoma, and other tumors. Although ALK is associated with various cancers, the relationship between ALK expression and patient prognosis in different cancers is poorly understood. Here, using multidimensional approaches, we revealed the correlation between ALK expression and the clinical outcomes of patients with LUAD, melanoma, OV, DLBC, AML, and BC. We analyzed ALK transcriptional expression, patient survival rate, genetic alteration, protein network, and gene and microRNA (miRNA) co-expression. Compared to that in normal tissues, higher ALK expression was found in LUAD, melanoma, and OV, which are associated with poor patient survival rates. In contrast, lower transcriptional expression was found to decrease the survival rate of patients with DLBC, AML, and BC. A total of 202 missense mutations, 17 truncating mutations, 7 fusions, and 3 in-frame mutations were identified. Further, 17 genes and 19 miRNAs were found to be exclusively co-expressed and echinoderm microtubule-associated protein-like 4 (EML4) was identified as the most positively correlated gene (log odds ratio >3). The gene ontology and signaling pathways of the genes co-expressed with ALK in these six cancers were also identified. Our findings offer a basis for ALK as a prognostic biomarker and therapeutic target in cancers, which will potentially contribute to precision oncology and assist clinicians in identifying suitable treatment options.