Integrative Single-Cell Analysis: Dissecting CD8+ Memory Cell Roles in LUAD and COVID-19 via eQTLs and Mendelian Randomization (preprint)

Lung adenocarcinoma exhibits high incidence and mortality rates, presenting a significant health concern. Concurrently, the COVID-19 pandemic has emerged as a grave global public health challenge. Existing literature suggests that T cells, pivotal components of cellular immunity, are integral to both antiviral and antitumor responses. Yet, the nuanced alterations and consequent functions of T cells across diverse disease states have not been comprehensively elucidated.We gathered transcriptomic data of peripheral blood mononuclear cells from lung adenocarcinoma patients, COVID-19 patients, and healthy controls. We followed a standardized analytical approach for quality assurance, batch effect adjustments, and preliminary data processing. We discerned distinct T cell subsets and conducted differential gene expression analysis. Potential key genes and pathways were inferred from GO and Pathway enrichment analyses. Additionally, we implemented Mendelian randomization to probe the potential links between pivotal genes and lung adenocarcinoma susceptibility.Our findings underscored a notable reduction in mature CD8+ central memory T cells in both lung adenocarcinoma and COVID-19 cohorts relative to the control group. Notably, the downregulation of specific genes, such as TRGV9, could impede the immunological efficacy of CD8+ T cells. Comprehensive multi-omics assessment highlighted genetic aberrations in genes, including TRGV9, correlating with heightened lung adenocarcinoma risk.Through rigorous single-cell transcriptomic analyses, this investigation meticulously delineated variations in T cell subsets across different pathological states and extrapolated key regulatory genes via an integrated multi-omics approach, establishing a robust groundwork for future functional inquiries. This study furnishes valuable perspectives into the etiology of multifaceted diseases and augments the progression of precision medicine.

Clinical outcomes of obstructive colorectal cancer patients during the coronavirus disease 2019 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected all aspects of clinical care including diagnosis and treatment of colorectal cancers (CRCs) globally, including in Türkiye. During the initial peak of the pandemic, elective surgeries and outpatient clinics were restricted in addition to the government-imposed lockdown, resulting in a decrease in the number of colonoscopies being performed and patients admitted to inpatient wards for treatment of CRCs. In this study, we aimed to investigate whether the pandemic has affected presentation characteristics and outcomes of obstructive colorectal cancer in this period. METHODS: This is a single-center, retrospective cohort study based on all CRC adenocarcinoma patients that underwent surgical resection in a high-volume tertiary referral center in Istanbul, Türkiye. Patients were divided into two groups before and after 15 months of identification of 'patient-zero' in Türkiye (March 18, 2020). Patient demographics, initial presentation characteristics, clin-ical outcomes, and pathological cancer stages were compared. RESULTS: Overall, 215 patients underwent resection for CRC adenocarcinoma during 30 months (COVID era: 107, pre-COVID era: 108). Patient characteristics, tumor location, and clinical staging were comparable between two groups. During the COVID period, the number of obstructive CRCs (P<0.01) and emergency presentations (P<0.01) increased significantly compared to the respective pre-COVID period. However, there were no differences between 30-day morbidity, mortality, and pathological outcomes (P>0.05). CONCLUSION: Although the results of our study indicate a significant increase in emergency presentation and a decrease in elective admissions of CRCs during the pandemic, patients treated during the COVID period were not at a significant disadvantage in terms of post-operative outcomes. Further efforts should be made to decrease risks related to an emergency presentation of CRCs for future adverse events.

Risk factors and actionable molecular signatures in COVID-19-associated lung adenocarcinoma and lung squamous cell carcinoma patients.

The molecular mechanism of the pathological impact of COVID-19 in lung cancer patients remains poorly understood to date. In this study, we used differential gene expression pattern analysis to try to figure out the possible disease mechanism of COVID-19 and its associated risk factors in patients with the two most common types of non-small-cell lung cancer, namely, lung adenocarcinoma and lung squamous cell carcinoma. We also used network-based approaches to identify potential diagnostic and molecular targets for COVID-19-infected lung cancer patients. Our study showed that lung cancer and COVID-19 patients share 36 genes that are expressed differently and in common. Most of these genes are expressed in lung tissues and are mostly involved in the pathogenesis of different respiratory tract diseases. Additionally, we also found that COVID-19 may affect the expression of several cancer-associated genes in lung cancer patients, such as the oncogenes JUN, TNC, and POU2AF1. Moreover, our findings suggest that COVID-19 may predispose lung cancer patients to other diseases like acute liver failure and respiratory distress syndrome. Additionally, our findings, in concert with published literature, suggest that molecular signatures, such as hsa-mir-93-5p, CCNB2, IRF1, CD163, and different immune cell-based approaches could help both diagnose and treat this group of patients. Altogether, the scientific findings of this study will help formulate appropriate management measures and guide the development of diagnostic and therapeutic measures for COVID-19-infected lung cancer patients.

Pan-cancer landscape of CENPO and its underlying mechanism in LUAD.

BACKGROUND: Centromere protein O (CENPO) is a newly discovered constitutive centromeric protein, associated with cell death. However, little is known about how CENPO expression is associated with human cancers or immune infiltration. Here, we assessed the function of CENPO in pan-cancer and further verified the results in lung adenocarcinoma (LUAD) through in vitro and in vivo experiments. METHODS: Sangerbox and TCGA databases were used to evaluate the CENPO expression level in different human cancer types. A subsequent evaluation of the potential role of CENPO as a diagnostic and prognostic biomarker in pancancer was conducted. The CENPO mutations were analyzed using the cBioPortal database and its function was analyzed using the LinkedOmics and CancerSEA databases. The TIMER2 and TISIDB websites were used to find out how CENPO affects immune infiltration. The expression level of CENPO in LUAD was revealed by TCGA database and immunohistochemical (IHC) staining. Targetscan, miRWalk, miRDB, miRabel, LncBase databases, and Cytoscape tool were used to identify microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that regulate expression and construct ceRNA network. Subsequently, loss-of-function assays were performed to identify the functions of CENPO on the malignant behavior and tumor growth of LUAD in vitro and in vivo experiments. RESULTS: In most cancers, CENPO was upregulated and mutated, which predicted a poorer prognosis. Furthermore, infiltration of CENPO and myeloid-derived suppressor cells (MDSC) showed a significant positive correlation, while T-cell NK infiltration showed a significant negative correlation in most cancers. CENPO was expressed at high levels in LUAD and was correlated with p-TNM stage. Furthermore, CENPO knockdown suppressed the malignant phenotypes of LUAD cells, manifested by slower proliferation, cycle in G2, increased apoptosis, decreased migration, and attenuated tumorigenesis. Furthermore, CENPO knockdown decreased CDK1/6, PIK3CA, and inhibited mTOR phosphorylation, suggesting that the mTOR signaling pathway may be involved in CENPO-mediated regulation of LUAD development. CONCLUSIONS: In pan-cancer, especially LUAD, CENPO may be a potential biomarker and oncogene. Furthermore, CENPO has been implicated in immune cell infiltration in pan-cancer and represents a potential immunotherapeutic target for tumor therapy.

Cribriform adenocarcinoma of the minor salivary glands: a case report.

BACKGROUND: Polymorphous adenocarcinoma is the third most common malignant salivary gland tumor. Within polymorphous adenocarcinoma, cribriform adenocarcinoma of salivary glands is a rare subtype and resembles papillary thyroid carcinoma histopathologically. Diagnostically, cribriform adenocarcinoma of salivary glands is challenging for pathologists and surgeons alike as initial presentation and cytologic nuclear features can be easily confused with papillary thyroid carcinoma arising from a thyroglossal duct remnant or lingual thyroid. CASE PRESENTATION: A healthy 64-year-old Caucasian woman presented to a community otolaryngologist with a 4-year history of progressive postnasal drip, globus sensation, and eventual dysphonia. Flexible fiberoptic laryngoscopy showed a large, smooth, vallecular lesion filling the oropharynx. Computed tomography imaging of the neck showed a rounded heterogeneous mass centered within the right aspect of the oropharynx measuring 4.2 × 4.4 × 4.5 cm. Fine needle aspiration biopsy was suspicious for papillary carcinoma due to microscopic findings of malignant cells, nuclear grooves, and a powdery chromatin pattern. In the operating room, the tumor was resected en bloc using a lateral pharyngotomy approach with partial resection of the right lateral hyoid. A limited cervical lymphadenectomy was performed to facilitate the lateral pharyngotomy approach and two out of three lymph nodes demonstrated regional metastatic disease. Nuclear grooves, nuclear membrane notching, and occasional intranuclear pseudoinclusions were identified, which are overlapping histopathological characteristics of papillary thyroid carcinoma and cribriform adenocarcinoma of salivary glands. It was negative for thyroglobulin and thyroid transcription factor-1, which was in keeping with cribriform adenocarcinoma of salivary glands rather than papillary thyroid carcinoma. CONCLUSION: It is difficult to distinguish cribriform adenocarcinoma of salivary glands from papillary thyroid carcinoma solely by cytology, and the distinct characteristics of regional lymph node metastasis coupled with nuanced histologic differences should be emphasized in the evaluation of patients presenting with neck lymphadenopathy and an unknown primary or tongue mass. If sufficient fine needle aspiration biopsy material is available, thyroid transcription factor-1, thyroglobulin, or molecular testing may prove useful in differentiating cribriform adenocarcinoma of salivary glands from papillary thyroid carcinoma. A misdiagnosis of papillary thyroid carcinoma may lead to inappropriate treatment including unnecessary thyroidectomy. Therefore, it is critical for both pathologists and surgeons to be aware of this uncommon entity to avoid misdiagnosis and subsequent mismanagement.

Seven bacterial response-related genes are biomarkers for colon cancer.

BACKGROUND: Colon cancer (CC) is a common tumor that causes significant harm to human health. Bacteria play a vital role in cancer biology, particularly the biology of CC. Genes related to bacterial response were seldom used to construct prognosis models. We constructed a bacterial response-related risk model based on three Molecular Signatures Database gene sets to explore new markers for predicting CC prognosis. METHODS: The Cancer Genome Atlas (TCGA) colon adenocarcinoma samples were used as the training set, and Gene Expression Omnibus (GEO) databases were used as the test set. Differentially expressed bacterial response-related genes were identified for prognostic gene selection. Univariate Cox regression analysis, least absolute shrinkage and selection operator-penalized Cox regression analysis, and multivariate Cox regression analysis were performed to construct a prognostic risk model. The individual diagnostic effects of genes in the prognostic model were also evaluated. Moreover, differentially expressed long noncoding RNAs (lncRNAs) were identified. Finally, the expression of these genes was validated using quantitative polymerase chain reaction (qPCR) in cell lines and tissues. RESULTS: A prognostic signature was constructed based on seven bacterial response genes: LGALS4, RORC, DDIT3, NSUN5, RBCK1, RGL2, and SERPINE1. Patients were assigned a risk score based on the prognostic model, and patients in the TCGA cohort with a high risk score had a poorer prognosis than those with a low risk score; a similar finding was observed in the GEO cohort. These seven prognostic model genes were also independent diagnostic factors. Finally, qPCR validated the differential expression of the seven model genes and two coexpressed lncRNAs (C6orf223 and SLC12A9-AS1) in 27 pairs of CC and normal tissues. Differential expression of LGALS4 and NSUN5 was also verified in cell lines (FHC, COLO320DM, SW480). CONCLUSIONS: We created a seven-gene bacterial response-related gene signature that can accurately predict the outcomes of patients with CC. This model can provide valuable insights for personalized treatment.

Gain-of-glycosylation in breast multi-drug-resistant MCF-7 adenocarcinoma cells and cancer stem cells characterized by site- and structure-specific N-glycoproteomics.

N-linked glycosylation (N-glycosylation) is a common protein post-translational modification, occurring on more than half of mammalian proteins; in striking contract with small molecule modifications (such as methylation, phosphorylation) with only single structures, N-glycosylation has multiple dimensional structural features (monosaccharide composition, sequence, linkage, anomer), which generates enormous N-glycan structures; and these structures widely regulate protein structure and functions. For the modification site, N-glycosylation occurs on the Asn residue among the consensus N-X-S/T/C (X≠P) motif; mutation-originated amino acid change may lead to loss of such an original motif and thus loss-of-glycosylation (LoG) or gain of such a new motif and thus gain-of-glycosylation (GoG). Both LoG and GoG generates new structures and functions of glycoproteins, which has been observed in the S protein of SARS-Cov-2 as well as malignant diseases. Here we report our glycoproteome-wide qualitative N-glycoproteomics characterization of GoGs in breast cancer Adriamycin drug resistance (ADR) cells (MCF-7/ADR) and cancer stem cells (MCF-7/ADR CSCs); comprehensive N-glycosite and N-glycan structure information at the intact N-glycopeptide level were reported.

Effect of DPP4/CD26 expression on SARS­CoV­2 susceptibility, immune response, adenosine (derivatives m62A and CD) regulations on patients with cancer and healthy individuals.

The worldwide COVID­19 pandemic was brought on by a new coronavirus (SARS Cov­2). A marker/receptor called Dipeptidyl peptidase 4/CD26(DPP4/CD26) may be crucial in determining susceptibility to tumors and coronaviruses. However, the regulation of DPP4 in COVID­invaded cancer patients and its role on small molecule compounds remain unclear. The present study used the Human Protein Atlas, Monaco, and Schmiedel databases to analyze the expression of DPP4 in human tissues and immune cells. The association between DPP4 expression and survival in various tumor tissues was compared using GEPIA 2. The DNMIVD database was used to analyze the correlation between DPP4 expression and promoter methylation in various tumors. On the cBioPortal network, the frequency of DPP4 DNA mutations in various cancers was analyzed. The correlation between DPP4 expression and immunomodulators was analyzed by TISIDB database. The inhibitory effects of cordycepin (CD), N6, N6­dimethyladenosine (m62A) and adenosine (AD) on DPP4 in cancer cells were evaluated. DPP4 was mainly expressed in endocrine tissue, followed by gastrointestinal tract, female tissue (mainly in placenta), male tissue (mainly in prostate and seminal vesicle), proximal digestive tract, kidney, bladder, liver, gallbladder and respiratory system. In immune cells, DPP4 mRNA was mainly expressed in T cells, and its expression was upregulated in esophageal carcinoma, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma and thymoma. However, it was downregulated in breast invasive carcinoma, kidney chromophobe, lung squamous cell carcinoma and skin cutaneous melanoma. Thus, DPP4 is involved in viral invasion in most types of cancer. The expression of DPP4 could be inhibited by CD, m62A and AD in different tumor cells. Moreover, CD significantly inhibited the formation of GFP­positive syncytial cells. In vivo experiments with AD injection further showed that AD significantly inhibited lymphocyte activating factor 3 expression. These drugs may have potential to treat COVID­19 by targeting DPP4. Thus, DPP4 may be medically significant for SARS­CoV­2­infected cancer patients, providing prospective novel targets and concepts for the creation of drugs against COVID­19.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial.

BACKGROUND: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS: We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS: Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING: Janssen Research and Development.

Malignant polyps in the COVID-19 era: a population-based analysis.

BACKGROUND: Malignant polyps represent the early development of colorectal adenocarcinoma. During 2020, there was widescale rationing of health-care resources in response to the COVID-19 pandemic. In particular there was deferral of some colonoscopy procedures required for timely malignant polyp detection. This study sought to assess how these deferrals affected the diagnosis of malignant polyps. METHODS: A population wide analysis was performed of 2079 malignant polyps, diagnosed in Queensland, Australia from 2011 to 2020. A regression analysis, with 95% prediction intervals, was produced to determine whether there was a significant impact on the number of malignant polyps diagnosed in 2020 compared to previous years. Univariate statistical analysis of patient, procedural, and pathological variables was also performed. RESULTS: In 2020 there were 211 malignant polyps diagnosed, which was significantly lower than was predicted by the univariate regression analysis (r2  = 0.85, 95% prediction interval: 255.07-323.91, P < 0.001). These malignant polyps were less likely to be diagnosed in a private setting (P < 0.001), and exhibited significantly less depth of submucosal invasion (P = 0.017). There was no significant difference in the management strategy (polypectomy, resection or trans-anal resection) between 2011 and 2019 and 2020. CONCLUSION: Because of the significant decrease in the number of malignant polyps, and the natural history of the disease, it is expected that there will be an increase in more advanced colorectal adenocarcinomas presenting in 2021 and beyond. This has implications for healthcare resources, particularly in light of the ongoing strain on health departments as a result of the COVID-19 pandemic.

Survival outcomes following treatment delays among patients with early-stage female cancers: a nationwide study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) severely hindered the timely receipt of health care for patients with cancer, especially female patients. Depression and anxiety were more pronounced in female patients than their male counterparts with cancer during treatment wait-time intervals. Herein, investigating the impact of treatment delays on the survival outcomes of female patients with early-stage cancers can enhance the rational and precise clinical decisions of physicians. METHODS: We analyzed five types of cancers in women from the Surveillance, Epidemiology, and End Results (SEER) program between Jan 2010 and Dec 2015. Univariate and multivariate Cox regression analyses were used to determine the impacts of treatment delays on the overall survival (OS) and cancer-specific survival (CSS) of the patients. RESULTS: A total of 241,661 females with early-stage cancer were analyzed (12,617 cases of non-small cell lung cancer (NSCLC), 166,051 cases of infiltrating breast cancer, 31,096 cases of differentiated thyroid cancer, 23,550 cases of colorectal cancer, and 8347 cases of cervical cancer). Worse OS rates were observed in patients with treatment delays ≥ 3 months in stage I NSCLC (adjustedHazard ratio (HR) = 1.11, 95% Confidence Interval (CI): 1.01-1.23, p = 0.044) and stage I infiltrating breast cancer (adjustedHR = 1.23, 95% CI 1.11-1.37, p < 0.001). When the treatment delay intervals were analyzed as continuous variables, similar results were observed in patients with stage I NSCLC (adjustedHR = 1.04, 95% CI 1.01-1.06, p = 0.010) and in those with stage I breast cancer (adjustedHR = 1.03, 95% CI 1.00-1.06, p = 0.029). However, treatment delays did not reduce the OS of patients with differentiated thyroid cancer, cervical cancer, or colorectal cancer in the early-stage. Only intermediate treatment delays impaired the CSS of patients with cervical cancer in stage I (adjustedHR = 1.31, 95% CI 1.02-1.68, p = 0.032). CONCLUSION: After adjusting for confounders, the prolonged time from diagnosis to the initiation of treatment (< 6 months) showed limited negative effects on the survival of most of the patients with early-stage female cancers. Whether our findings serve as evidence supporting the treatment deferral decisions of clinicians for patients with different cancers in resource-limited situations needs further validation.

Use of a Cytosponge biomarker panel to prioritise endoscopic Barrett's oesophagus surveillance: a cross-sectional study followed by a real-world prospective pilot.

BACKGROUND: Endoscopic surveillance is recommended for patients with Barrett's oesophagus because, although the progression risk is low, endoscopic intervention is highly effective for high-grade dysplasia and cancer. However, repeated endoscopy has associated harms and access has been limited during the COVID-19 pandemic. We aimed to evaluate the role of a non-endoscopic device (Cytosponge) coupled with laboratory biomarkers and clinical factors to prioritise endoscopy for Barrett's oesophagus. METHODS: We first conducted a retrospective, multicentre, cross-sectional study in patients older than 18 years who were having endoscopic surveillance for Barrett's oesophagus (with intestinal metaplasia confirmed by TFF3 and a minimum Barrett's segment length of 1 cm [circumferential or tongues by the Prague C and M criteria]). All patients had received the Cytosponge and confirmatory endoscopy during the BEST2 (ISRCTN12730505) and BEST3 (ISRCTN68382401) clinical trials, from July 7, 2011, to April 1, 2019 (UK Clinical Research Network Study Portfolio 9461). Participants were divided into training (n=557) and validation (n=334) cohorts to identify optimal risk groups. The biomarkers evaluated were overexpression of p53, cellular atypia, and 17 clinical demographic variables. Endoscopic biopsy diagnosis of high-grade dysplasia or cancer was the primary endpoint. Clinical feasibility of a decision tree for Cytosponge triage was evaluated in a real-world prospective cohort from Aug 27, 2020 (DELTA; ISRCTN91655550; n=223), in response to COVID-19 and the need to provide an alternative to endoscopic surveillance. FINDINGS: The prevalence of high-grade dysplasia or cancer determined by the current gold standard of endoscopic biopsy was 17% (92 of 557 patients) in the training cohort and 10% (35 of 344) in the validation cohort. From the new biomarker analysis, three risk groups were identified: high risk, defined as atypia or p53 overexpression or both on Cytosponge; moderate risk, defined by the presence of a clinical risk factor (age, sex, and segment length); and low risk, defined as Cytosponge-negative and no clinical risk factors. The risk of high-grade dysplasia or intramucosal cancer in the high-risk group was 52% (68 of 132 patients) in the training cohort and 41% (31 of 75) in the validation cohort, compared with 2% (five of 210) and 1% (two of 185) in the low-risk group, respectively. In the real-world setting, Cytosponge results prospectively identified 39 (17%) of 223 patients as high risk (atypia or p53 overexpression, or both) requiring endoscopy, among whom the positive predictive value was 31% (12 of 39 patients) for high-grade dysplasia or intramucosal cancer and 44% (17 of 39) for any grade of dysplasia. INTERPRETATION: Cytosponge atypia, p53 overexpression, and clinical risk factors (age, sex, and segment length) could be used to prioritise patients for endoscopy. Further investigation could validate their use in clinical practice and lead to a substantial reduction in endoscopy procedures compared with current surveillance pathways. FUNDING: Medical Research Council, Cancer Research UK, Innovate UK.

Anxiety and depression status prior to radioactive iodine therapy among differentiated thyroid cancer patients during the COVID­19 pandemic.

OBJECTION: The psychological health of thyroid cancer patients cannot be ignored; however, few studies have been conducted on the psychological status and influencing factors of thyroid cancer patients before radioactive iodine (RAI) therapy. The aim of this study was to investigate the incidence and risk factors for anxiety and depression in thyroid cancer patients prior to RAI therapy. METHODS: Clinical data were collected from patients with differentiated thyroid cancer (DTC) patients preparing for RAI therapy. Anxiety and depression were measured before RAI therapy using the Generalized Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-9). We used the chi-square test and logistic regression analysis to identify independent risk factors for anxiety and depression. RESULTS: A total of 112 patients with thyroid cancer were included. Of these, 72.32% (n = 81) were female, with a mean age of 41.50 years. Anxiety and depression were reported by 46 (41.08%) and 38 (33.93%) patients, respectively. Based on the chi-square test and univariate logistic regression analysis, being female and having ever-experienced RAI therapy were significant risk factors for anxiety and depression among DTCs prior to RAI therapy. On multivariable analysis, the results of model 2 which included age, sex, education level, and ever suffering radioactive iodine therapy showed that being female was markedly associated with anxiety and depression in these patients, while having ever undergone RAI therapy was significantly related to anxiety but not depression. CONCLUSIONS: The incidence of anxiety and depression among patients with DTC prior to RAI therapy were 41.08% and 33.93%, respectively. Being female and having ever experienced RAI therapy significantly influenced anxiety and depression. Based on these findings, anxiety and depression assessment should be an important part of pre-RAI therapy in patients with DTC, and appropriate psychological nursing intervention can be carried out for key patients.

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

Sleep Problems Prior to Radio-chemotherapy in Patients With Locally Advanced Cancer of the Esophagus or the Esophagogastric Junction.

BACKGROUND/AIM: Many patients with locally advanced cancer of the esophagus or esophagogastric junction receive definitive or neoadjuvant radiochemotherapy. Patient anticipation of this treatment can cause or aggravate distress and sleep disorders. This study aimed to identify the prevalence of sleep disorders and risk factors. PATIENTS AND METHODS: Thirty-eight patients assigned to radio-chemotherapy were retrospectively evaluated for pre-treatment sleep disorders. Investigated characteristics included age; sex; performance score; comorbidity index; previous malignancies; family history; distress score; emotional, physical or practical problems; tumor site; histology and grading; tumor stage; planned treatment; and relation to 2019 Coronavirus pandemic. RESULTS: Sleep problems were reported by 15 patients (39.5%). Significant associations were found for higher distress scores (p=0.016) and greater numbers of emotional problems (p<0.0001). A trend was observed for greater numbers of physical problems (p=0.176). CONCLUSION: The prevalence of sleep problems was high. Risk factors were found that can help identify patients requiring psychological support already prior to radio-chemotherapy.

Genetic alterations, RNA expression profiling and DNA methylation of HMGB1 in malignancies.

The high mobility group box 1 (HMGB1) is a potential biomarker and therapeutic target in various human diseases. However, a systematic, comprehensive pan-cancer analysis of HMGB1 in human cancers remains to be reported. This study analysed the genetic alteration, RNA expression profiling and DNA methylation of HMGB1 in more than 30 types of tumours. It is worth noting that HMGB1 is overexpressed in malignant tissues, including lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). Interestingly, there is a positive correlation between the high expression of HMGB1 and the high survival prognosis of THYM. Finally, this study comprehensively evaluates the genetic variation of HMGB1 in human malignant tumours. As a prospective biomarker of COVID-19, the role that HMGB1 plays in THYM is highlighted.

Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: Natural Fungal Compounds and Synthetic Derivatives with In Vitro Anthelmintic Activities and Antiproliferative Effects against Two Human Cancer Cell Lines.

Neglected tropical diseases affect the world's poorest populations with soil-transmitted helminthiasis and schistosomiasis being among the most prevalent ones. Mass drug administration is currently the most important control measure, but the use of the few available drugs is giving rise to increased resistance of the parasites to the drugs. Different approaches are needed to come up with new therapeutic agents against these helminths. Fungi are a source of secondary metabolites, but most fungi remain largely uninvestigated as anthelmintics. In this report, the anthelmintic activity of Albatrellus confluens against Caenorhabditis elegans was investigated using bio-assay guided isolation. Grifolin (1) and neogrifolin (2) were identified as responsible for the anthelmintic activity. Derivatives 4-6 were synthesized to investigate the effect of varying the prenyl chain length on anthelmintic activity. The isolated compounds 1 and 2 and synthetic derivatives 4-6, as well as their educts 7-10, were tested against Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum. Prenyl-2-orcinol (4) and geranylgeranyl-2-orcinol (6) showed promising activity against newly transformed schistosomula. The compounds 1, 2, 4, 5, and 6 were also screened for antiproliferative or cytotoxic activity against two human cancer lines, viz. prostate adenocarcinoma cells (PC-3) and colorectal adenocarcinoma cells (HT-29). Compound 6 was determined to be the most effective against both cell lines with IC50 values of 16.1 µM in PC-3 prostate cells and 33.7 µM in HT-29 colorectal cells.

Native size exclusion chromatography-based mass spectrometry (SEC-MS) identifies novel components of the Heat Shock Protein 90-dependent proteome (preprint)

The molecular chaperone heat shock protein 90 (HSP90) works in concert with co-chaperones to stabilize its client proteins, which include multiple drivers of oncogenesis and malignant progression. Pharmacologic inhibitors of HSP90 have been observed to exert a wide range of effects on the proteome, including depletion of client proteins, induction of heat shock proteins, dissociation of co-chaperones from HSP90, disruption of client protein signaling networks, and recruitment of the protein ubiquitylation and degradation machinery—suggesting widespread remodeling of cellular protein complexes. However, proteomics studies to date have focused on inhibitor-induced changes in total protein levels, often overlooking protein complex alterations. Here, we use size-exclusion chromatography in combination with mass spectrometry (SEC-MS) to characterize the changes in native protein complexes following treatment with the HSP90 inhibitor tanespimycin (17-AAG) in the HT29 colon adenocarcinoma cell line. After confirming the signature cellular response to HSP90 inhibition (e.g., induction of heat shock proteins, decreased total levels of client proteins), we were surprised to find only modest perturbations to the global distribution of protein elution profiles in inhibitor-treated cells. Similarly, co-chaperones that co-eluted with HSP90 displayed no clear difference between control and treated conditions. However, two distinct analysis strategies identified multiple inhibitor-induced changes, including several known components of the HSP90 proteome, as well as numerous proteins and protein complexes with no previous links to HSP90. We present this dataset as a resource for the HSP90, proteostasis, and cancer communities ( https://www.bioinformatics.babraham.ac.uk/shiny/HSP90/SEC-MS/ ), laying the groundwork for future mechanistic and therapeutic studies related to HSP90 pharmacology. Data are available via ProteomeXchange with identifier PXD033459 .

Extended Delay to Treatment for Stage III-IV Non-Small-Cell Lung Cancer and Survival: Balancing Risks During the COVID-19 Pandemic.

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, patients may encounter lung cancer care delays. Here, we sought to examine the impact of extended treatment delay for stage III-IV non-small-cell lung cancer on patient survival. MATERIALS AND METHODS: Using National Lung Screening Trial (NLST) and National Cancer Data Base (NCDB) data, Cox regression analysis with penalized smoothing splines was performed to examine the association between treatment delay and all-cause mortality for stage III-IV lung adenocarcinoma and squamous cell carcinoma. In the NCDB, propensity score-matched analysis was used to compare cumulative survival in patients who received "early" versus "delayed" treatment (ie, 0-30 vs. 90-120 days following diagnosis). RESULTS: Cox regression analysis of the NLST (n = 392) and NCDB (n = 275,198) cohorts showed a decrease in hazard ratio the longer treatment was delayed. In propensity score-matched analysis, no significant differences in survival were found between early and delayed treatment for patients with stage IIIA, IIIB (T3-4,N2,M0), IIIC, and IV (M1B-C) adenocarcinoma and patients with IIIA, IIIB, IIIC, and IV squamous cell carcinoma (all log-rank P > .05). For patients with stage IIIB (T1-2,N3,M0) and stage IV (M1A) adenocarcinoma, delayed treatment was associated with improved survival (log-rank P = .03, P = .02). The findings were consistent in sensitivity analysis accounting for wait time bias. CONCLUSION: In this national analysis, for patients with stage III-IV adenocarcinoma and squamous cell carcinoma, an extended treatment delay by 3 to 4 months was not associated with significantly decreased overall survival compared to prompt treatment. These findings can be used to guide decision-making during the ongoing COVID-19 pandemic.

Uterine cervix metastasis from primary colon adenocarcinoma: a case report and review of the literature.

INTRODUCTION: Metastases to the female genital tract from extragenital primary tumors are unusual. We report a rare case of uterine cervix metastasis from colon adenocarcinoma and discuss diagnostic and therapeutic issues. CASE REPORT: We report a case of a 38-year-old North African Caucasian woman treated for a non-metastatic colon adenocarcinoma. She had a sigmoidectomy and incomplete adjuvant chemotherapy. Six months later, she consulted with vaginal bleeding caused by a cervical tumor, which was confirmed to be metastatic disease, and the patient underwent decompressive and hemostatic radiotherapy. CONCLUSION: Uterine cervix metastasis from primary colon adenocarcinoma is rare. The resection remains the standard protocol for the local treatment of resectable metastatic disease. Otherwise, systemic therapy is the preferable option.