Colorectal cancer is one of the leading causes of cancer-related death worldwide. The early diagnosis of colon cancer not only reduces mortality but also reduces the burden related to the treatment strategies such as chemotherapy and/or radiotherapy. However, when the microscopic examination of the suspected colon tissue sample is carried out, it becomes a tedious and time-consuming job for the pathologists to find the abnormality in the tissue. In addition, there may be interobserver variability that might lead to conflict in the final diagnosis. As a result, there is a crucial need of developing an intelligent automated method that can learn from the patterns themselves and assist the pathologist in making a faster, accurate, and consistent decision for determining the normal and abnormal region in the colorectal tissues. Moreover, the intelligent method should be able to localize the abnormal region in the whole slide image (WSI), which will make it easier for the pathologists to focus on only the region of interest making the task of tissue examination faster and lesser time-consuming. As a result, artificial intelligence (AI)-based classification and localization models are proposed for determining and localizing the abnormal regions in WSI. The proposed models achieved F-score of 0.97, area under curve (AUC) 0.97 with pretrained Inception-v3 model, and F-score of 0.99 and AUC 0.99 with customized Inception-ResNet-v2 Type 5 (IR-v2 Type 5) model.

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one-third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n = 137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n = 50, IHC). In contrast, high RRAS expression (cohort 4, n = 252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3A-high-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n = 49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

A newly introduced pan-immune-inflammation value (PIV) was not evaluated for its role in oral cavity squamous cell carcinoma (OSCC). In this study, the PIV was calculated with the following equation (neutrophil count × platelet count × monocyte count)/lymphocyte count from the results of the automated hematology analyzers in 853 OSCC patients from 2005 to 2017. The optimal cutoff for the preoperative PIV was 268, as determined by a receiver operating characteristic curve. Significant differences were observed for alcohol consumption, smoking, pT status, pN status, overall pathological status, extranodal extension, cell differentiation, depth of invasion, and perineural invasion between higher and lower PIV patients (all p values < 0.05). Kaplan-Meier and univariate regression analyses indicated that higher PIV was associated with worse overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival (all p values < 0.001). Multivariate analyses adjusted by various factors further demonstrated that PIV was an independent prognostic factor for overall and distant metastasis-free survival (p = 0.027, HR: 1.281 and p = 0.031, HR: 1.274, respectively). In conclusion, a higher PIV level was associated with poor clinicopathological factors in OSCC patients and could be used to predict poor posttreatment outcomes, especially for overall and distant metastasis-free survival.

The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.

Oral cavity squamous cell carcinomas (OSCCs) are aggressive tumors, and their recurrence leads to poor prognosis and reduced survival rates. This study aimed to identify therapeutic targets and to evaluate the efficacy of targeted inhibitors in OSCC patient-derived xenograft (PDX) models. Herein, we reported that OSCC PDXs recapitulated the genomic signatures of their paired primary tumors and the expression of CHEK1, PIK3CA, and PIK3CD was significantly upregulated in OSCC. The antitumor efficacy of CHK1 inhibitors (PF477736, AZD7762, LY2606368) and PI3K inhibitors (BYL719, GDC0941, GSK1059615) was investigated in OSCC cell lines and PDX models. Targeting either CHK1 or PI3K effectively inhibited cell proliferation and colony formation by inducing cell cycle arrest and apoptosis in in vitro cell-based assays. Cisplatin-based chemotherapy combined with CHK1 inhibitor treatment synergistically inhibited cell proliferation by suppressing CHK1 phosphorylation and inducing PARP cleavage. Furthermore, compared with monotherapy, cotreatment with CHK1 and PI3K inhibitors exerted synergistic anticancer effects by suppressing CHK1, AKT, and 4E-BP1 phosphorylation. In summary, our study identified CHK1 and PI3K as promising targets, especially in a dual treatment strategy combining a CHK1 inhibitor with cisplatin or a PI3K inhibitor as a novel therapeutic approach for OSCC patients with aberrant cell cycle regulation and PI3K signaling activation.