High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas.

Background: HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) are sensitive to chemo-radiation therapy and have favorable survival outcomes compared with HPV-negative cancers. These tumors are usually not related to tobacco and alcohol exposure. Therefore, diagnosing HPV-positive OPSCCs for the appropriate disease management is crucial, and no suitable markers are available for detecting early malignancies in HPV-infected tissues.

Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers.

Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)-a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation-represent a pool of therapeutically resistant cells.

Effect of COVID-19 on Lungs: Focusing on Prospective Malignant Phenotypes.

Currently, the healthcare management systems are shattered throughout the world, even in the developed nations due to the COVID-19 viral outbreak. A substantial number of patients infected with SARS-CoV2 develop acute respiratory distress syndrome (ARDS) and need advanced healthcare facilities, including invasive mechanical ventilation. Intracellular infiltration of the SARS-CoV2 virus particles into the epithelial cells in lungs are facilitated by the spike glycoprotein (S Protein) on the outer side of the virus envelope, a membrane protein ACE2 (angiotensin-converting enzyme 2) and two proteases (TMPRSS2 and Furin) in the host cell.

Urothelial Carcinoma In Situ of the Bladder: Correlation of CK20 Expression With Adaptive Immune Resistance, Response to BCG Therapy, and Clinical Outcome.

Immunohistochemical stains have been suggested to aid in diagnostically challenging cases of urothelial carcinoma in-situ (CIS). Although full thickness immunostaining for CK20 is supportive of CIS, a subset of CIS cases is CK20(-), the clinical significance of which was unknown. This study included 43 patients with primary diagnosis of bladder CIS including 32 with only CIS, 5 with CIS and separate noninvasive high-grade papillary urothelial carcinoma, and 6 with CIS and separate high-grade urothelial carcinoma with lamina propria invasion.

Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy.

Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma.

GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.

Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin.

Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma.

Mutations in mitochondrial DNA (mtDNA) have been linked to risk, progression, and treatment response of head and neck squamous cell carcinoma (HNSCC). Due to their clonal nature and high copy number, mitochondrial mutations could serve as powerful molecular markers for detection of cancer cells in bodily fluids, surgical margins, biopsies and lymph node (LN) metastasis, especially at sites where tumor involvement is not histologically apparent. Despite a pressing need for high-throughput, cost-effective mtDNA mutation profiling system, current methods for library preparation are still imperfect for detection of low prevalence heteroplasmic mutations.

Immune profiles in primary squamous cell carcinoma of the head and neck.

Objectives: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.

Materials And Methods: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively).

Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer.

Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of non-CSC tumor cells, CSCs are often drug-resistant, leading to tumor recurrence and metastasis. The heterogeneity of CSCs is the main challenge in developing CSC-targeting therapy; therefore, we and other investigators have focused on developing novel therapeutic strategies that combine conventional chemotherapy with inhibitors of CSC-regulating pathways.

Expression of programmed cell death ligand 1 in non-small cell lung cancer: Comparison between cytologic smears, core biopsies, and whole sections using the SP263 assay.

Background: Evaluation of programmed cell death ligand 1 (PD-L1) expression can be made on both resection specimens and diagnostic biopsies; however, more than 30% of patients with advanced non-small cell lung cancer (NSCLC) do not have adequate histologic material to perform PD-L1 assays and require additional biopsies. In addition, in our practice, more than 16% of cases have cytological smears as the only available material. Our aim was to validate the PD-L1 immunocytochemistry assay on cytological smears and compare its accuracy with the results obtained from tissue cores and whole tumor sections using the clinically relevant cutoff of 50%.

CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer.

Background: CD24 is a cornerstone of tumour progression in urothelial carcinoma of the bladder (UCB). However, its contribution to cancer stem cell (CSC)-like traits and the clinical utility of CD24 as a urinary biomarker for cancer detection have not been determined.

Methods: The functional relevance of CD24 was evaluated using in vitro and in vivo approaches.

PD-L1 expression comparison between primary and relapsed non-small cell lung carcinoma using whole sections and clone SP263.

We assessed the concordance, in terms of PD-L1 expression, between primary and metastatic non-small cell lung carcinoma (NSCLC) of different histotypes using validated SP263 clone. A few samples of local recurrences have also been analyzed. Whole sections of consecutive cases of primary NSCLC and paired relapses undergone surgical resection have been stained with PD-L1 clone SP263; for scoring purposes, a three-tiered system was applied using the following thresholds: <1%, 1-49% and ≥50%.

Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma.

It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene.

Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.

Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFβ2), we performed extended studies of GULP1.

PD-L1 Assays 22C3 and SP263 are Not Interchangeable in Non-Small Cell Lung Cancer When Considering Clinically Relevant Cutoffs: An Interclone Evaluation by Differently Trained Pathologists.

Pembrolizumab is the only programmed cell death 1/programmed death-ligand 1 inhibitor for treatment of patients with non-small cell lung cancer, with a companion diagnostic assay, the 22C3 PharmDx. Although in many studies 22C3 and Ventana's SP263 appear to yield overlapping results, they show discrepancies at clinically relevant cutoffs (1% and 50%). We provide a solid comparison between 22C3 and SP263 assays in a large cohort of non-small cell lung cancer cases taking into account interobserver variability between trained pathologists who are used to either clone in their clinical practice.

PD-L1 Expression Heterogeneity in Non-Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections.

Introduction: Determination of programmed death ligand 1 (PD-L1) expression defines eligibility for treatment with pembrolizumab in patients with advanced NSCLC. This study was designed to better define which value across core biopsy specimens from the same case more closely reflects the PD-L1 expression status on whole sections and how many core biopsy specimens are needed for confident classification of tumors in terms of PD-L1 expression.

Methods: We built tissue microarrays as surrogates of biopsies collecting five cores per case from 268 cases and compared PD-L1 staining results obtained by using the validated clone SP263 with the results obtained by using whole tumor sections.

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy.

YAP1 is one of the most important effectors of the Hippo pathway and has crosstalk with other cancer promoting pathways. YAP1 contributes to cancer development in various ways that include promoting malignant phenotypes, expansion of cancer stem cells and drug resistance of cancer cells. Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers.

Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells.

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance.

YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells.

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs.

A Panel of Novel Detection and Prognostic Methylated DNA Markers in Primary Non-Small Cell Lung Cancer and Serum DNA.

To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non-small cell lung cancer (NSCLC). Identification of differentially methylated regions (DMR) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples. A methylation panel of 6 genes (, and ) was selected from TCGA dataset.