Predicting Lewis Acidity: Machine Learning the Fluoride Ion Affinity of p-Block-Atom-Based Molecules.

"How strong is this Lewis acid?" is a question researchers often approach by calculating its fluoride ion affinity (FIA) with quantum chemistry. Here, we present FIA49k, an extensive FIA dataset with 48,986 data points calculated at the RI-DSD-BLYP-D3(BJ)/def2-QZVPP//PBEh-3c level of theory, including 13 different p-block atoms as the fluoride accepting site. The FIA49k dataset was used to train FIA-GNN, two message-passing graph neural networks, which predict gas and solution phase FIA values of molecules excluded from training with a mean absolute error of 14 kJ mol-1 (r2=0.93) from the SMILES string of the Lewis acid as the only input. The level of accuracy is notable, given the wide energetic range of 750 kJ mol-1 spanned by FIA49k. The model's value was demonstrated with four case studies, including predictions for molecules extracted from the Cambridge Structural Database and by reproducing results from catalysis research available in the literature. Weaknesses of the model are evaluated and interpreted chemically. FIA-GNN and the FIA49k dataset can be reached via a free web app (www.grebgroup.de/fia-gnn).

Integration and viral oncogene expression of human papillomavirus type 16 in oropharyngeal squamous cell carcinoma and gastric cancer.

Persistent high-risk human papillomavirus (HR-HPV) infections cause cervical cancer and a fraction of head and neck cancer. To investigate whether HR-HPV infection might be also involved in the development of gastric cancer (GC), we developed a platform utilizing a rolling circle amplification (RCA)-based nested L1 polymerase chain reaction with Sanger sequencing to genotype the HPV DNA in cancer tissues of 361 GC and 89 oropharyngeal squamous cell carcinomas (OPSCC). HPV transcriptional activity was determined by E6/E7 mRNA expression and a 3' rapid amplification of cDNA ends was performed to identify HPV integration and expression of virus-host fusion transcripts. Ten of 361 GC, 2 of 89 OPSCC, and 1 of 22 normal adjacent tissues were HPV L1 DNA-positive. Five of the 10 HPV-positive GC were genotyped as HPV16 by sequencing and 1 of 2 GC with RCA/nested HPV16 E6/E7 DNA detection exhibited HPV16 E6/E7 mRNA. Two OPSCC displayed HPV16 L1 DNA and E6/E7 mRNA, of which 1 OPSCC tissue showed virus-host RNA fusion transcripts from an intron region of KIAA0825 gene. Together, our data reveal viral oncogene expression and/or integration in GC and OPSCC and a possible etiology role of HPV infections in gastric carcinogenesis.

Advanced Nanomedicine for High-Risk HPV-Driven Head and Neck Cancer.

The incidence of high-risk Human Papillomavirus (HR-HPV)-driven head and neck squamous cell carcinoma (HNSCC) is on the rise globally. HR-HPV-driven HNSCC displays molecular and clinical characteristics distinct from HPV-uninvolved cases. Therapeutic strategies for HR-HPV-driven HNSCC are under investigation. HR-HPVs encode the oncogenes E6 and E7, which are essential in tumorigenesis. Meanwhile, involvement of E6 and E7 provides attractive targets for developing new therapeutic regimen. Here we will review some of the recent advancements observed in preclinical studies and clinical trials on HR-HPV-driven HNSCC, focusing on nanotechnology related methods. Materials science innovation leads to great improvement for cancer therapeutics including HNSCC. This article discusses HPV-E6 or -E7- based vaccines, based on plasmid, messenger RNA or peptide, at their current stage of development and testing as well as how nanoparticles can be designed to target and access cancer cells and activate certain immunology pathways besides serving as a delivery vehicle. Nanotechnology was also used for chemotherapy and photothermal treatment. Short interference RNA targeting E6/E7 showed some potential in animal models. Gene editing by CRISPR-CAS9 combined with other treatments has also been assessed. These advancements have the potential to improve the outcome in HR-HPV-driven HNSCC, however breakthroughs are still to be awaited with nanomedicine playing an important role.

Strategies for Advanced Oncolytic Virotherapy: Current Technology Innovations and Clinical Approaches.

Oncolytic virotherapy is a type of nanomedicine with a dual antitumor mechanism. Viruses are engineered to selectively infect and lyse cancer cells directly, leading to the release of soluble antigens which induce systemic antitumor immunity. Representative drug Talimogene laherparepvec has showed promising therapeutic effects in advanced melanoma, especially when combined with immune checkpoint inhibitors with moderate adverse effects. Diverse viruses like herpes simplex virus, adenovirus, vaccina virus, and so on could be engineered as vectors to express different transgenic payloads, vastly expanding the therapeutic potential of oncolytic virotherapy. A number of related clinical trials are under way which are mainly focusing on solid tumors. Studies about further optimizing the genome of oncolytic viruses or improving the delivering system are in the hotspot, indicating the future development of oncolytic virotherapy in the clinic. This review introduces the latest progress in clinical trials and pre-clinical studies as well as technology innovations directed at oncolytic viruses. The challenges and perspectives of oncolytic virotherapy towards clinical application are also discussed.

Current Status of Human Papillomavirus-Related Head and Neck Cancer: From Viral Genome to Patient Care.

Human papillomavirus (HPV) infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers. Up to 38%-80% of head and neck squamous cell carcinoma (HNSCC) in oropharyngeal location (OPSCC) and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7. Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors, clinical trials on de-escalation treatment strategies for these patients have been studied. It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible. Moreover, understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy. This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions. With the advent of various sequencing technologies, further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.

Disulfiram Acts as a Potent Radio-Chemo Sensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines and Transplanted Xenografts.

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu2+ inhibited the cell proliferation (inhibitory concentration 50 (IC50) of DSF and DSF/Cu2+ were 13.96 µM and 0.24 µM). DSF and cisplatin displayed a synergistic effect (CI values were < 1). DSF or DSF/Cu2+ abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu2+ reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu2+, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu2+ enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.

Impact of Smoking on the Survival of Patients With High-risk HPV-positive HNSCC: A Meta-analysis.

BACKGROUND/AIM: High risk Human papillomavirus (hr-HPV) and smoking are independant risk factors for head and neck squamous cell carcinomas (HNSCC). While hr-HPV+ HNSCC has a better prognosis than smoking-associated HNSCC no systematic data are yet available about the combined risk. PATIENTS AND METHODS: We performed a meta-analysis to assess the overall survival of HNSCC patients relative to the hr-HPV and smoking status. A literature review up to November 2019 was conducted in PubMed and Cochrane Library using the search terms 'HPV, Smoking and HNSCC'. RESULTS: Nine out of 748 articles were included, 1,436 out of 2,080 patients were hr-HPV+ The prevalence of hr-HPV+ smokers was 36%. The meta-analysis showed a significantly better 5-year overall survival for HPV+ non-smokers compared to smokers with risk ratio of 1.94 (95% confidence intervaI=1.46-2.58). CONCLUSION: Smoking is a negative prognostic factor for overall survival in patients with hr-HPV+ HNSCC and should thus be an important part of staging and treatment.

Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer.

Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck.

Immunotherapies such as immune checkpoint blockade benefit only a portion of patients with head and neck squamous cell carcinoma. The multidisciplinary field of nanomedicine is emerging as a promising strategy to achieve maximal anti-tumor effect in cancer immunotherapy and to turn non-responders into responders. Various methods have been developed to deliver therapeutic agents that can overcome bio-barriers, improve therapeutic delivery into the tumor and lymphoid tissues and reduce adverse effects in normal tissues. Additional modification strategies also have been employed to improve targeting and boost cytotoxic T cell-based immune responses. Here, we review the state-of-the-art use of nanotechnologies in the laboratory, in advanced preclinical phases as well as those running through clinical trials assessing their advantages and challenges.

Rare involvement of paranasal sinuses in sarcoidosis: case report and literature review.

Sarcoidosis is a non-caseating inflammatory chronic systemic disease of unknown etiology, which may affect one or more organs. Paranasal sinuses involvement occurs sporadic in sarcoidosis. We report a patient with a medical history of sarcoidosis involving her lungs, liver, and lymphatic system for four years who now presented with nasal and sinuses symptoms. The primary treatment with local cortisone showed no improvement. Computed tomography (CT) scan of the paranasal sinuses (PNS) revealed signs of chronic pansinusitis. She was successfully treated with endoscopic sinonasal surgery. Subsequent histological analysis confirmed the involvement of the PNS with sarcoidosis. Her follow-up during the last 6 months was without recurrence.

Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation.

BACKGROUND: Disulfiram (DSF) is a drug used for treatment of alcoholism that has also displayed promising anti-cancer activity. It unfolds its effects by inhibiting the enzyme activity of aldehyde dehydrogenase (ALDH) isoforms. METHODS: MTT assay, spheroid formation, clonogenicity assay, qRT-PCR, and ALDH enzyme activity analysis were performed using ovarian cancer cell lines IGROV1, SKOV3 and SKOV3IP1. Cell cycle analyses and measurement of intracellular reactive oxygen species (ROS) were carried out by flow cytometry. ALDH+ and ALDH- cells were isolated by FACS sorting. RESULTS: ALDH activity was inhibited in ovarian cancer stem cells (the proportion of ALDH+ cells was reduced from 21.7% to 0.391%, 8.4% to 0%, 6.88% to 0.05% in cell lines IGROV1, SKOV3, and SKOV3IP1, respectively). DSF with or without the cofactor copper (Cu2+) exhibited cytotoxicity dose- and time-dependent and enhanced cisplatin-induced apoptosis. DSF + Cu2+ increased intracellular ROS levels triggering apoptosis of ovarian cancer stem cells (CSC). Significantly more colony and spheroid formation was observed in ALDH+ compared with ALDH- cells (P < 0.01). Moreover, ALDH+ cells were more resistant to cisplatin treatment compared with ALDH-cells (P < 0.05) and also exhibited a lower basal level of ROS. However, no significant difference in ROS accumulation nor in cellular viability was observed in ALDH + cells in comparison to ALDH- cells after pre-treatment with DSF (0.08 µM). CONCLUSION: Our findings provide evidence that DSF might be employed as a novel adjuvant chemotherapeutic agent in combination with cisplatin for treatment of ovarian cancer.

Prognostic Score Predicts Survival in HPV-Negative Head and Neck Squamous Cell Cancer Patients.

Although patients having head and neck squamous cell carcinoma (HNSCC) have high mortality, standardized prognostic tools are unavailable. As such, having a validated simple prognostic scoring system to help predict mortality in these high-risk patients is urgently needed. The current study aimed to develop and internally validate a prognostic scoring system for overall mortality in human papillomavirus (HPV)-independent HNSCC patients. Data on 400 consecutive patients from the Cancer Genome Atlas database with a known HPV-RNA negative status were analyzed. A prognostic model to predict patient overall mortality was developed using the logistic regression beta coefficients and a simple risk score was created. The model was internally validated using bootstrap validation with 2000 replications. Five covariates (age, pT, pN, perineural invasion, and EAp53 score) were used in the development of the mortality risk score in the final model. Three risk groups were stratified based on the prognostic scores: low-risk (<96 points), medium-risk (96-121 points), and high-risk (≥122 points) with a survival of 76%, 62% and 35%, respectively. The proposed model presented good discrimination in both the development (AUC = 0.76; 95% CI 0.70, 0.81) and bootstrap validation (AUC = 0.76; 95% CI 0.70, 0.81) with a non-significant Hosmer-Lemeshow chi-square of 6.17 (p = 0.63). The proposed prognostic scoring system is easy to use to predict patient overall mortality and could also help in the appropriate allocation of medical resources while managing HNSCC patients. External validation (including re-calibration if needed) should be conducted to test the model's generalizability in different populations.

An Effective Primary Head and Neck Squamous Cell Carcinoma In Vitro Model.

Head and neck squamous cell carcinoma is a highly malignant disease and research is needed to find new therapeutic approaches. Faithful experimental models are required for this purpose. Here, we describe the specific cell culture conditions enabling the efficient establishment of primary cell culture models. Whereas a classical 10% serum-containing medium resulted in the growth of fibroblast-like cells that outcompeted epithelial cells, we found that the use of specific culture conditions enabled the growth of epithelial tumor cells from HPV+ and HPV- head and neck cancer tissue applicable for research. EpCAM and high Thy-1 positivity on the cell surface were mutually exclusive and distinguished epithelial and fibroblast-like subpopulations in all primary cultures examined and thus can be used to monitor stromal contamination and epithelial cell content. Interestingly, cells of an individual patient developed tumor spheroids in suspension without the use of ultra-low attachment plates, whereas all other samples exclusively formed adherent cell layers. Spheroid cells were highly positive for ALDH1A1 and hence displayed a phenotype reminiscent of tumor stem cells. Altogether, we present a system to establish valuable primary cell culture models from head and neck cancer tissue at high efficiency that might be applicable in other tumor entities as well.

An eight-year epidemiologic study of head and neck tuberculosis in Texas, USA.

BACKGROUND: Head and neck tuberculosis (HNTB) especially cervical lymphadenopathy are the most common extrapulmonary indications of TB, but remain a diagnostic challenge. In this study, we describe and analyze the epidemiologic characteristics of HNTB on a population-level. MATERIALS AND METHODS: We retrospectively assessed 547 HNTB cases reported to the Centers for Disease Control and Prevention's TB Genotyping Information Management System in Texas from 2009 to 2016 and compare and contrast differences between diagnosed exclusively HNTB and HNTB with concurrent pulmonary tuberculosis (PTB). RESULTS: The majority of patients with HNTB were diagnosed with cervical lymphadenopathy (96.9%), age 25-44 (47.3%) and female (52.7%). Co-infection with human immunodeficiency virus, being homeless, excessive alcohol use within the past 12 months and drug use were more frequently seen for HNTB with concurrent pulmonary involvement compared to reported patients with exclusively HNTB. The highest prevalence of Mycobacterium tuberculosis lineage in exclusively HNTB was Euro-American L4 (52.3%), followed by Indo-Oceanic L1 (21.5%) and East-Asian L2 (13.1%). One multidrug resistant TB case was identified. Seven deaths were reported during treatment. CONCLUSION: Our findings provide a better understanding of the epidemiology of HNTB and characteristics associated with the disease at the population-level, which is important in managing HNTB patients.

Head and neck tuberculosis: Literature review and meta-analysis.

BACKGROUND: Head and neck tuberculosis (HNTB), including cervical lymphadenopathy, is the most common extrapulmonary manifestation of TB. The proposed study investigated the epidemiologic and clinical characteristics of HNTB. MATERIALS AND METHODS: A literature search was conducted via PubMed, Embase, Cochrane Library and Wanfang for keywords (tuberculosis, head and neck, laryngeal, pharyngeal, tongue, oropharyngeal, nasopharyngeal, and oral cavity). Scientific articles published from January 1990 through July 2017 were selected and reviewed to assess the epidemiology, presentation, diagnosis and treatment of HNTB disease. RESULTS: Results from the included 57 studies revealed that the majority of HNTB cases were age<40 years and female. The most common HNTB sites were cervical lymph nodes (87.9%), followed by larynx (8.7%). Involvement of other HN-regions was rare (3.4%). Multidrug resistant TB was not common among the majority of studies. Given the paucibacillary nature of HNTB, sputum tests did not have a good performance on HNTB diagnosis. Most of HNTB cases were diagnosed by fine-needle aspiration, cytology and excision biopsies in combination with clinical presentations. CONCLUSION: HNTB disease is an important manifestation in the diagnostic process in an otolaryngologist practice. The developments of rapid, ultrasensitive, simple and cost-effective high-throughput methods for early diagnosis of HNTB are urgently needed.

Heterogeneity of Head and Neck Squamous Cell Carcinoma Stem Cells.

Current systemic cancer treatment in head and neck squamous cell carcinoma (HNSCC) is moving toward more personalized approaches such as de-escalation protocols human-papilloma-virus dependent HNSCC or application of checkpoint inhibitors. However, these treatments have been challenged by cancer stem cells (CSC), a small population within the bulk tumor, which are leading to treatment failure, tumor recurrence, or metastases. This review will give an overview of the characteristics of HNSCC-CSC. Specifically, the mechanisms by which HNSCC-CSC induce tumor initiation, progression, recurrence, or metastasis will be discussed. Although evidence-based treatment options targeting HNSCC-CSC specifically are still being sought for, they warrant a promise for additional and sustainable treatment options where for HNSCC patients where others have failed.

Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines.

The chemotherapeutic agent cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to increase the sensitivity of CSCs to cisplatin-based chemotherapy, or to specifically target CSCs to improve the therapeutic outcome in breast cancer. Disulfiram (DSF) is a drug used clinically for alcoholism treatment that has displayed promising anti-cancer activity in vitro and in cancer xenografts in breast cancer. Our study provides evidence that DSF inhibits Aldehyde dehydrogenase (ALDH) enzyme activity, inhibits the expression of stemness-related transcription factors (Sox, Nanog, Oct) in CSC derived from breast cancer cell lines, and modulates intracellular reactive oxygen species (ROS) generation. Importantly, our research proved that ALDH + stem-like cells play important roles in the resistance to the conventional chemotherapeutic agent cisplatin. DSF enhances the cytotoxic effect of cisplatin through inhibiting the stemness and by overcoming cisplatin resistance of ALDH + stem-like cells. A quantitative measurement showed the synergistic effect of DSF and cisplatin. Further, we show that ALDH + cancer stem-like cells and ALDH- bulk cancer cells have different intrinsic ROS levels, what may explain differences in susceptibility to cisplatin treatment. Importantly, this difference is eliminated by DSF treatment making both cell types similarly susceptible for cytotoxic effects by cisplatin. These findings may influence chemotherapeutic treatment approaches in the future.

Specific Targeting of Oncogenes Using CRISPR Technology.

In recent decades, tools of molecular biology have enabled researchers to genetically modify model organisms, including human cells. RNAi, zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats and CRISPR-associated protein 9), retro- or lentiviral gene transfer, and many other methods can be utilized to remove genes, add genes, or change their expression. Within the same timeframe, survival rates for many highly malignant tumor diseases have not improved substantially. If modern medicine could apply even a subset of research methods in clinical management, which are already well established and controllable in basic research laboratories, this could strongly impact patients' prognosis. CRISPR-Cas9 is a method to precisely target and manipulate genomic loci and recent studies have attempted to use this method as a genetic treatment for Duchenne muscular dystrophy, blood disorders, autosomal-dominant hearing loss, and cancer. Some of these approaches target mutant genomic sequences specifically and try to avoid affecting the respective normal loci. Considering obvious genetic risks opposing the objected benefits, data are needed to show whether CRISPR technology is suitable as a future cancer therapy approach or not. Here, we develop strategies for the specific targeting of viral cancer drivers and oncogenes activated by mutation, using the latest CRISPR technology. Cancer Res; 78(19); 5506-12. ©2018 AACR.

pN status predicts outcomes in surgically treated pT1-pT2 patients of various disease stages with squamous cell carcinoma of the head and neck: a 17-year retrospective single center cohort study.

OBJECTIVES: The optimal treatment for a substantial proportion of patients with pT1-pT2 squamous cell carcinomas of the head and neck (SCCHN) remains to be refined. The extent of surgery, role and potential benefit of adjuvant treatment are to be balanced against therapy-induced side effects. We compared the outcomes of surgery with or without adjuvant radiotherapy (RT) or chemotherapy (CRT) and investigated the prognostic value of established clinicopathological parameters. METHODS: Data were retrospectively collected for 227 patients who were treated by surgery alone (n = 31), RT (n = 87) and CRT (n = 109) in a single center. RESULTS: Patients with stage I/II disease who had received adjuvant RT showed a better disease-free survival (DFS) (P = 0.04) than those who had received adjuvant CRT treatment. Conversely, patients with stage III/IV disease who had received CRT showed a better overall survival (OS) (P = 0.003) and DFS (P = 0.03) than those who had received surgery alone or adjuvant RT without chemotherapy. Survival analysis demonstrated that patients with pN0 to pN1 had better OS (P = 0.02), disease-specific survival (DSS) (P = 0.003), DFS (P = 0.02) and metastases free survival (MFS) (P = 0.002) compared to patients with pN2 to pN3. Multivariate analysis showed that the pN status was an independent factor for OS (P = 0.03), DSS (P = 0.04), relapse-free survival (P = 0.03), DFS (P = 0.03). CONCLUSION: The pN status is the most important prognostic factor for pT1 to pT2 SCCHN. Adjuvant CRT was associated with significantly better survival outcomes in patients with pN1 and pN2-3 or more advanced stage, while adjuvant RT showed significantly better outcomes in patients with pN0.