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Coarse-grained (CG) simulations are an important computational tool in chemistry and materials science. Recently, systematic ``bottom-up" CG models have been introduced to capture electronic structure variations of molecules and polymers at the CG resolution. However, the performance of these models is limited by the ability to select reduced representations that preserve electronic structure information, which remains a challenge. We propose two methods for (i) identifying important electronically coupled atomic degrees of freedom and (ii) scoring the efficacy of CG representations used in conjunction with CG electronic predictions. The first method is a physically-motivated approach that incorporates nuclear vibrations and electronic structure derived from simple quantum chemical calculations. We complement this physically-motivated approach with a machine learning technique based on the marginal contribution of nuclear degrees of freedom to electronic prediction accuracy using an equivariant graph neural network. By integrating these two approaches, we can both identify critical electronically coupled atomic coordinates and score the efficacy of arbitrary CG representations for making electronic predictions. We leverage this capability to make a connection between optimized CG representations and the future potential for ``bottom-up" development of simplified model Hamiltonians incorporating non-linear vibrational modes.

Oral squamous cell carcinoma (OSCC) is the predominant histological type of the head and neck squamous cell carcinoma (HNSCC). By comparing the differentially expressed genes (DEGs) in OSCC-TCGA patients with copy number variations (CNVs) that we identify in OSCC-OncoScan dataset, we herein identified 37 dysregulated candidate genes. Among these potential candidate genes, 26 have been previously reported as dysregulated proteins or genes in HNSCC. Among 11 novel candidates, the overall survival analysis revealed that melanotransferrin (MFI2) is the most significant prognostic molecular in OSCC-TCGA patients. Another independent Taiwanese cohort confirmed that higher MFI2 transcript levels were significantly associated with poor prognosis. Mechanistically, we found that knockdown of MFI2 reduced cell viability, migration and invasion via modulating EGF/FAK signaling in OSCC cells. Collectively, our results support a mechanistic understanding of a novel role for MFI2 in promoting cell invasiveness in OSCC.

Hepatocellular carcinoma (HCC) accounts for almost 80% of all liver cancers and is the sixth most common cancer and the second most common cause of cancer-related death worldwide. The survival rate of sorafenib-treated advanced HCC patients is still unsatisfactory. Unfortunately, no useful biomarkers have been verified to predict sorafenib efficacy in HCC. We assessed a sorafenib resistance-related microarray dataset and found that anterior gradient 2 (AGR2) is highly associated with overall and recurrence-free survival and several clinical parameters in HCC. However, the mechanisms underlying the role of AGR2 in sorafenib resistance and HCC progression remain unknown. We found that sorafenib induces AGR2 secretion via posttranslational modification, and AGR2 plays a critical role in sorafenib-regulated cell viability and endoplasmic reticulum (ER) stress and induces apoptosis in sorafenib-sensitive cells. Sorafenib downregulated intracellular AGR2 and conversely induces AGR2 secretion, which suppresses its regulation of ER stress and cell survival in sorafenib-sensitive cells. In addition, AGR2 is highly intracellularly expressed in sorafenib-resistant cells, which supports ER homeostasis and cell survival. We suggest that AGR2 regulates ER stress to influence HCC progression and sorafenib resistance. This is the first report that AGR2 can modulate ER homeostasis via the IRE1α-XBP1 cascade to regulate HCC progression and sorafenib resistance. Elucidation of the predictive value of AGR2 and its molecular and cellular mechanisms in sorafenib resistance could provide additional opportunities for HCC treatment.

Simple Summary Radioresistance is one of the major factors contributing to radiotherapy failure in OSCC. By systematically comparing the prognostic values of all genes in TCGA-OSCC patients with and without radiotherapy, radioresistance-associated genes were identified. Higher RPL36A transcript levels were found to be associated with a poor prognosis only in OSCC patients with radiotherapy in the cohort of TCGA and another independent Taiwanese cohort. RPL36A was then shown to be involved in the regulation of DNA damage, cell cycle and apoptosis, leading to radioresistance. Thus, such integrated studies are expected to be greatly beneficial for the development of new therapeutic interventions for radioresistant OSCC in the future. Abstract Radioresistance is one of the major factors that contributes to radiotherapy failure in oral cavity squamous cell carcinoma (OSCC). By comparing the prognostic values of 20,502 genes expressed in patients in The Cancer Genome Atlas (TCGA)-OSCC cohort with (n = 162) and without radiotherapy (n = 118), herein identified 297 genes positively correlated with poor disease-free survival in OSCC patients with radiotherapy as the potential radioresistance-associated genes. Among the potential radioresistance-associated genes, 36 genes were upregulated in cancerous tissues relative to normal tissues. The bioinformatics analysis revealed that 60S ribosomal protein L36a (RPL36A) was the most frequently detected gene involved in radioresistance-associated gene-mediated biological pathways. Then, two independent cohorts (n = 162 and n = 136) were assessed to confirm that higher RPL36A transcript levels were significantly associated with a poor prognosis only in OSCC patients with radiotherapy. Mechanistically, we found that knockdown of RPL36A increased radiosensitivity via sensitizing cells to DNA damage and promoted G2/M cell cycle arrest followed by augmenting the irradiation-induced apoptosis pathway in OSCC cells. Taken together, our study supports the use of large-scale genomic data for identifying specific radioresistance-associated genes and suggests a regulatory role for RPL36A in the development of radioresistance in OSCC.

Tumor cells express immune checkpoints to exhaust CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical applications. However, the radiotherapy-mediated molecular mechanism affecting CD8+ T cell activity remains elusive. We aimed to uncover the mechanism of radiotherapy augmenting cytotoxic CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive NSCLC cell lines were co-cultured with CD8+ T cells from healthy volunteers. Tumor cell viability and apoptosis were consequently measured. IFNγ was identified secreted by CD8+ T cells and PBMCs. Therefore, RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. The irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and western blots. We found that the co-culture of tumor cells stimulated the increase of granzyme B and IFNγ in CD8+ T, but A549 exhibited resistance against CD8+ T cytotoxicity compared to HCC827. Irradiation inhibited A549 proliferation and enhanced apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. We found that IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1 (p &lt, 0.05). In RNAseq analysis, MCL1 was identified and increased by the IFNγ-STAT3 axis (p &lt, 0.05). We demonstrated that irradiation specifically inhibited phosphorylation on STAT1 and STAT3 in IFNγ-treated A549, resulting in reductions of PD-L1 and MCL1 (both p &lt, 0.05). Moreover, knockdowns of STAT3 and MCL1 increased the PBMCs-mediated anti-A549 effect. This study demonstrated that A549 expressed MCL1 to resist CD8+ T cell-mediated tumor apoptosis. In addition, we found that irradiation suppressed IFNγ-mediated STAT3 phosphorylation and PD-L1 and MCL1 expression, revealing a potential mechanism of radiotherapy augmenting immune surveillance.

Gut microbiota are reported to be associated with many diseases, including cancers. Several bacterial taxa have been shown to be associated with cancer development or response to treatment. However, longitudinal microbiota alterations during the development of cancers are relatively unexplored. To better understand how microbiota changes, we profiled the gut microbiota composition from prostate cancer-bearing mice and control mice at five different time points. Distinct gut microbiota differences were found between cancer-bearing mice and control mice. Akkermansiaceae was found to be significantly higher in the first three weeks in cancer-bearing mice, which implies its role in the early stage of cancer colonization. We also found that Bifidobacteriaceae and Enterococcaceae were more abundant in the second and last sampling week, respectively. The increments of Akkermansiaceae, Bifidobacteriaceae and Enterococcaceae were previously found to be associated with responses to immunotherapy, which suggests links between these bacteria families and cancers. Additionally, our function analysis showed that the bacterial taxa carrying steroid biosynthesis and butirosin and neomycin biosynthesis were increased, whereas those carrying naphthalene degradation decreased in cancer-bearing mice. Our work identified the bacteria taxa altered during prostate cancer progression and provided a resource of longitudinal microbiota profiles during cancer development in a mouse model.

Background Tumor cells progress to evade immunological attacks and prohibit activity of CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical application. However, the detail mechanism remains elusive. We aimed to uncover the mechanism of irradiation augmenting cytotoxic CD8+ T cells to suppress tumor progression in non-small-cell lung cancer (NSCLC). Methods EGFR-positive NSCLC cell lines were co-cultured with isolated PBMCs from healthy volunteers, cell viability and apoptosis were measured. RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. Irradiation was used to augment PBMCs-mediated anti-tumor effect and the irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and Western blots. Results Co-culture of tumor cells stimulates increase of granzyme B and IFNγ in CD8+ T, but A549 exhibits resistance against CD8+ T cytotoxicity. Irradiation inhibits A549 proliferation and enhances apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1. In RNAseq analysis, MCL1 was identified and increased by IFNγ-STAT3 axis in A549 cells, we found that irradiation specifically inhibits phosphorylation on STAT1 and STAT3 in IFNr-treated A549, resulting in reductions of PD-L1 and MCL1. Moreover, knockdowns of STAT3 and MCL1 increased PBMCs against irradiated A549 cells. Conclusion This study demonstrated that A549 expressed MCL1 against CD8+ T cell-mediated apoptosis. In addition, we found that irradiation suppressed STAT3 phosphorylation and IFNγ-mediated PD-L1 and MCL1 expression, revealing a potential mechanism of irradiation augmenting immune surveillance.

Electron transfer coupling is a critical factor in determining electron transfer rates. This coupling strength can be sensitive to details in molecular geometries, especially intermolecular configurations. Thus, studying charge transporting behavior with a full first-principle approach demands a large amount of computation resources in quantum chemistry (QC) calculation. To address this issue, we developed a machine learning (ML) approach to evaluate electronic coupling. A prototypical ML model for an ethylene system was built by kernel ridge regression with Coulomb matrix representation. Since the performance of the ML models highly dependent on their building strategies, we systematically investigated the generality of the ML models, the choice of features and target labels. The best ML model trained with 40 000 samples achieved a mean absolute error of 3.5 meV and greater than 98% accuracy in predicting phases. The distance and orientation dependence of electronic coupling was successfully captured. Bypassing QC calculation, the ML model saved 10-10

Semiconducting polymer dots (Pdots) have recently emerged as a new type of ultrabright fluorescent probe that has been proved to be very useful for biomedical imaging. However, Pdots often suffer from serious fluorescence aggregation-caused quenching (ACQ) especially for near-infrared (NIR) fluorescent Pdots. This article compared two strategies to overcome the ACQ effect in near-infrared emissive Pdot systems: aggregation-induced emission (AIE) and anti-aggregation-caused quenching (anti-ACQ). The results show that the anti-ACQ platform outperforms the AIE system. The fluorescence quantum yield of anti-ACQ-based Pdots can be over 50% and the average per-particle brightness of the Pdots is about 5 times higher than that of the commercially available quantum dots. To help understand why the monomer conformations could greatly affect the optical properties of Pdots, molecular dynamics simulations were performed for the first time in such complicated Pdot systems. To demonstrate applications for in vivo fluorescence imaging, both microangiography imaging on living zebrafish embryos and specific tumor targeting on mice were performed. We anticipate that these studies will pave the way for the design of new highly fluorescent Pdot systems.

Background and objectives Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort. Methods and results The cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998–2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42–0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40–0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54–2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33–2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid. Conclusions As with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but this is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan.

Background In North America and Western Europe, human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) has increased dramatically over the past 40 years, whereas HPV-negative OPSCC, typically associated with alcohol and tobacco as etiological factors, has declined. In Taiwan, the OPSCC rate is increasing; however, there is limited understanding of the role of HPV, as tobacco, alcohol, and betel quid use are still very prominent. Here we investigated the involvement of HPV and its prognostic implications for OPSCC in Taiwan. Methods and findings We studied a retrospective cohort of 541 OPSCCs undergoing care between 1998 and 2016 at the Chang Gung Memorial Hospital-Linkou, Taiwan. Clinical and risk exposure data were retrieved from hospital charts. Most cases were males (94%) and had concomitant (87%) exposure to alcohol (51%), tobacco (83%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue sections were immunostained for p16, a surrogate for active HPV, and DNA was tested for HPV detection and genotyping by Multiplex PCR-MassArray. Tumors with p16 and/or HPV DNA positivity were identified as HPV-positive. HPV status was assigned to 528 tumors. The prevalence of HPV-positive OPSCC was 28.4% (150/528), with a strong correlation between p16 and HPV DNA results (F Among males more tumors were HPV-negative than positive, but among the 34 females more tumors were HPV-positive (62% vs. 38%, p For all patients, HPV-positive OPSCC was associated with higher age at diagnosis (55.5 vs. 52.7 years, p = 0.004), and lower T-stage (p = 0.02). HPV-positivity in OPSCC tumors was an independent predictor of better overall survival (OS) (hazard ratio [HR] 0.57 [95% CI 0.41-0.80], p = 0.0009), and disease-free survival (DFS) (HR 0.53 [95% CI 0.40-0.72], p Conclusions Consistent with the increasing role of HPV on OPSCC globally, HPV is an important etiological factor in more than one-fourth of OPSCC cases from Chang Gung Hospital. Like in Western countries, HPV provides considerable independent survival benefits to OPSCC, but the added prognostic value is reduced by exposure to the risk factors, alcohol, smoking, and betel quid. There is a need to consider HPV as an etiologic factor in treatment and in cancer-prevention policies in Taiwan. AUTHOR SUMMARY Why was this study done? Oropharyngeal squamous cell carcinoma (OPSCC) caused by human papillomavirus (HPV) has been increasing with epidemic proportions in North America and West Europe during the last 40 years. Socioeconomic changes have propelled the advance of this disease, and transformation from the classic etiology of OPSCC, alcohol, and tobacco, to HPV. Contrarily, in Taiwan, OPSCC has been drastically increasing due to persistent heavy consumption of alcohol, smoking, and betel quid chewing, limiting the understanding of HPV contribution to OPSCC. This study investigated the role of HPV in OPSCC in Taiwan. What did the researchers do and find? We conducted a comprehensive retrospective cohort study for 541 OPSCC cases diagnosed between 1998-2016 at the Chang Gung Memorial Hospital-Linkou, Taiwan. We found that OPSCCs mostly occurred in men (94%) and risk factors, including use of alcohol, tobacco, and betel quid was high (87%). Active HPV was present in 28.4% of the cases, 25% of tumors from males and 62% of tumors from females were HPV-positive. HPV16 was the most prevalent genotype (76.9%), followed by HPV58 (7.5%). Most of the HPV-positive OPSCCs originated in the tonsils, and females were less likely to abuse alcohol, tobacco, and betel quid than the males. Furthermore, outcome analysis showed that for the whole cohort, HPV positivity was associated with significantly better OPSCC survival. Alcohol was a strong negative prognostic factor. The robust prognostic benefit of HPV persisted in the presence of all other risk factors. What do these findings mean? HPV is an important emerging etiologic factor of OPSCC in Taiwan, and an independent predictor for better prognosis. The strong association of HPV with OPSCC over a period of 18 years suggests that societal behavioral changes are occurring; and, that there is a potential for benefit from interventions to improve treatment and prevent HPV-positive OPSCC in Taiwan and South-East Asia.

// I-Chun Kuo 1, * , Huang-Kai Kao 2, 3, * , Yenlin Huang 4 , Chun-I Wang 1 , Jui-Shan Yi 1, 5 , Ying Liang 5 , Chun-Ta Liao 1, 3 , Tzu-Chen Yen 3, 6 , Chih-Ching Wu 1, 5, 7 and Kai-Ping Chang 1, 3, 5 1 Department of Otolaryngology - Head & Neck Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan 2 Department of Plastic & Reconstructive Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan 3 College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan 4 Departments of Pathology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan 5 Molecular Medicine Research Center, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan 6 Departments of Nuclear Medicine, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan 7 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan * These authors have contributed equally to this work Correspondence to: Kai-Ping Chang, email: dr.kpchang@gmail.com Chih-Ching Wu, email: luckywu@mail.cgu.edu.tw Keywords: OSCC, proteome, metastasis, prognosis, ERAP2 Received: September 30, 2016 Accepted: May 23, 2017 Published: June 27, 2017 ABSTRACT Oral cavity squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide and associated with poor prognosis and mortality. Discovery of proteins that can improve OSCC treatment is needed. Using comparative proteome profiling of primary cells derived from OSCC and adjacent noncancerous epithelium, endoplasmic reticulum aminopeptidases 2 (ERAP2) has been identified as an OSCC-associated protein. Compared with the adjacent normal tissues, ERAP2 levels were determined to be significantly elevated in OSCC tissues using quantitative real-time PCR and immunohistochemistry. Importantly, overexpression of ERAP2 was associated with positive N stage, advanced overall stage, positive perineural invasion, and tumor depth ( P = 0.041, 0.015, 0.010, and 0.032, respectively). The overall survival rates of patients without and with the ERAP2 overexpression were 71.9% and 56.0%, respectively ( P = 0.029). Furthermore, knockdown of ERAP2 inhibited the migration and invasion abilities of OSCC cells. Our results collectively show that ERAP2 overexpression is associated with the cervical metastasis and poorer prognosis of OSCC.

Epidermal growth factor receptor (EGFR) and activin A are both overexpressed in oral cavity squamous cell carcinoma (OSCC). We evaluated their clinical correlation and activin A-mediated EGFR regulation in this study. Overexpression of both transcripts/proteins indicated a poorer prognosis in OSCC patients. Knockdown of endogenous INHBA repressed the expression of EGFR and inhibited activin A-mediated canonical Smads, noncanonical phosphorylation of AKT (ser473) (p-AKT ser473) and SP1. Inhibition of PI3K signaling via its inhibitor attenuated p-AKT ser473 and in turn reduced SP1 and EGFR expression in the presence of recombinant activin A (rActivin A) in OSCC cells, as revealed via a luciferase assay and western blotting. However, canonical Smad signaling repressed the EGFR promoter, as revealed by a luciferase assay. The transcription factor SP1, its coactivator CBP/p300, and Smad proteins were recruited to the EGFR proximal promoter following rActivin A treatment, as revealed by chromatin immunoprecipitation (ChIP). Smad2/3/4 dramatically outcompeted SP1 binding to the EGFR proximal promoter following mithramycin A treatment. Activin A activates the PI3K and Smad pathways to compete for binding to overlapping SP1 consensus sequences on the EGFR proximal promoter. Nevertheless, canonical p-Smad2 was largely repressed in OSCC tumor tissues, suggesting that the activin A-mediated noncanonical pathway is essential for the carcinogenesis of OSCC.

Background DNA copy number variations (CNVs) are a hallmark of cancer, and the current study aimed to demonstrate the profile of the CNVs for oral cavity squamous cell carcinoma (OSCC) and elucidate the clinicopathological associations and molecular mechanisms of a potential marker derived from CNVs, mixed-lineage leukemia translocated to chromosome 3 protein (MLLT3), in OSCC carcinogenesis. Materials and Methods CNVs in 37 OSCC tissue specimens were analyzed using a high-resolution microarray, the OncoScan array. Gene expression was analyzed by real-time polymerase chain reaction in 127 OSCC and normal tissue samples. Cell function assays included cell cycle, migration, invasion and chromatin immunoprecipitation assays. Results We found a novel copy number amplified region, chromosome 9p, encompassing MLLT3 via the comparison of our data set with six other OSCC genome-wide CNV data sets. MLLT3 overexpression was associated with poorer overall survival in patients with OSCC (p = .048). MLLT3 knockdown reduced cell migration and invasion. The reduced invasion ability in MLLT3-knockdown cells was rescued with double knockdown of MLLT3 and CBP/p300-interacting transactivator with ED rich carboxy-terminal domain 4 (CITED4; 21.0% vs. 61.5%). Knockdown of MLLT3 impaired disruptor of telomeric silencing-1-like (Dot1L)-associated hypermethylation in the promoter of the tumor suppressor, CITED4 (p < .001), and hence dysregulated HIF-1α-mediated genes (TWIST, MMP1, MMP2, VIM, and CDH1) in OSCC cells. Conclusion We identified unique CNVs in tumors of Taiwanese patients with OSCC. Notably, MLLT3 overexpression is related to the poorer prognosis of patients with OSCC and is required for Dot1L-mediated transcriptional repression of CITED4, leading to dysregulation of HIF-1α-mediated genes. Implications for Practice This article reports unique copy number variations in oral cavity squamous cell carcinoma (OSCC) tumors of Taiwanese patients. Notably, MLLT3 overexpression is related to the poorer prognosis of patients with OSCC and is required for Dot1L-mediated transcriptional repression of CITED4, leading to dysregulation of HIF-1α-mediated genes.

The ability to correlate fullerene solubility with experimentally or computationally accessible parameters can significantly facilitate nanotechnology nowadays for a wide range of applications, while providing crucial insight into optimum design of future fullerene species. To date, there has been no single relationship that satisfactorily describes the existing data clearly manifesting the effects of solvent species, system temperature, and isomer. Using atomistic molecular dynamics simulations on two standard fullerene species, C60 and PCBM ([6,6]-phenyl-C61-butyric acid methyl ester), in a representative series of organic solvent media (i.e., chloroform, toluene, chlorobenzene, 1,3-dichlorobenzene, and 1,2-dichlorobenzene), we show that a single time constant characterizing the dynamic stability of a tiny (angstrom-sized) solvation shell encompassing the fullerene particle can be utilized to effectively capture the known trends of fullerene solubility as reported in the literature. The underlying physics differs substantially between the two fullerene species, however. Although C60 was previously shown to be dictated by a diffusion-limited aggregation mechanism, the side-chain-substituted PCBM is demonstrated herein to proceed with an analogous reaction-limited aggregation with the "reaction rate" set by the fullerene rotational diffusivity in the medium. The present results suggest that dynamic quantities-in contrast to the more often employed, static ones-may provide an excellent means to characterize the complex (entropic and enthalpic) interplay between fullerene species and the solvent medium, shed light on the factors determining the solvent quality of a nanoparticle solution, and, in particular, offer a practical pathway to foreseeing optimum fullerene design and fullerene-solvent interactions.

Introduction: Taiwan has a high rate of oropharyngeal squamous cell carcinoma (OPSCC). The etiologic factors are primarily tobacco and alcohol abuse. High-risk human papillomaviruses (hrHPV) have been reported in oral cancers in Taiwan, but their role in oropharyngeal cancer has not been studied. We investigated the possible role of hrHPV in OPSCC Taiwanese patients. Materials and Methods: We identified 546 OPSCC tumors from patients undergoing standard care and informed consent, between 1998 and 2016, at the Chang Gung Memorial Hospital (CGMH) in Taiwan. Formalin-fixed, paraffin-embedded (FFPE) tissue sections from 504 patients were screened by p16 immunostaining, a surrogate marker for active HPV (Ventana antibody, Cat. No. 725-4713, prediluted), and scored for intensity and proportion of positive tumor cells according to the 2018 College of American Pathologists recommendations. Genomic DNA was extracted from FFPE sections (AllPrep Kit, Qiagen) and HPV was detected and genotyped by Multiplex PCR-Mass Array (PCR-MA) analysis designed to detect 15 high-risk, 1 intermediate-risk, and 2 low-risk HPV types. Results: Of the 504 OPSCC tumors tested for p16, 104 (20.6%) were positive, 380 (75.4%) negative, and 20 (4.0%) could not be scored. Spearman nonparametric correlation analysis demonstrated a linear increase in p16 positivity with time from 1998 to 2015 in this Taiwanese population (r= 0.6320, p= 0.003; R2= 0.4901, p= 0.0012). To date, HPV genotyping in 179 Taiwan tumors showed that 38 (21.2%) were hrHPV positive, 120 (67.0%) negative, and 21 (11.7%) had insufficient DNA. Of the 38 HPV-positive tumors, HPV16 alone was found in 31 (81.6%), HPV39 and HPV59 were each found once in separate tumors, and several tumors had two HPV types present: HPV16 and HPV18 were present together in 2 tumors, and each of the following pairs were found in one tumor each: HPV16 with HPV35, HPV16 with HPV59, and HPV16 with HPV6. Of the tumors tested by both p16 and PCR-MA, there was 97% concordance between the results (130/134). Conclusion: Our preliminary findings indicate that the proportion of hrHPV positive OPSCC tumors in this Taiwanese population is increasing over the period from 1998 to 2015 in Taiwan. The concordance of p16 and HPV DNA is very high (p Citation Format: Guadalupe Lorenzatti Hiles, Chun-I Wang, Lisa M. Pinatti, Christine M. Goudsmit, Lila Peters, Hannah L. Briggs, Trey B. Thomas, Mohammed Charara, Reem A. Khatib, Macy A. Afsari, Anna C. Morris, Nadine Jawad, Devraj Som, Kai-Ping Chang, Thomas E. Carey, Heather M. Walline. High-risk human papillomavirus association with oropharyngeal squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B07.

// Chun-I Wang 1 , Yan-Yu Chen 2 , Chih-Liang Wang 4 , Jau-Song Yu 1, 2, 3 , Yu-Sun Chang 1, 2 , Chia-Jung Yu 1, 2, 3, 4 1 Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan 2 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 3 Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 4 Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan Correspondence to: Chia-Jung Yu, e-mail: yucj1124@mail.cgu.edu.tw Keywords: KPNA2, lung cancer, EGFR, mTOR, E2F1 Received: October 24, 2015 Accepted: March 06, 2016 Published: March 18, 2016 ABSTRACT Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specifically, rapamycin treatment induced proteasome-mediated KPNA2 protein decay and attenuated the transcriptional activation of KPNA2 by decreasing Dp1/E2F1 level in vivo. Immunoprecipitation assay further revealed that KPNA2 physically associated with the phospho-mTOR/mTOR and this association was abolished by rapamycin treatment. Collectively, our results show for the first time that KPNA2 is transcriptionally and post-translationally regulated by the mTOR pathway and provide new insights into targeted therapy for NSCLC.

The notion of (static) solvation shells has recently proved fruitful in revealing key molecular factors that dictate the solubility and aggregation properties of fullerene species in polar or ionic solvent media. Using molecular dynamics schemes with carefully evaluated force fields, we have scrutinized both the static and the dynamic features of the solvation shells of single C60 particle for three nonpolar organic solvents (i.e., chloroform, toluene, and chlorobenzene) and a range of system temperatures (i.e., T = 250-330 K). The central findings have been that, while the static structures of the solvation shell remain, in general, insensitive to the effects of changing solvent type or system temperature, the dynamic behavior of solvent molecules within the shell exhibits prominent dependence on both factors. Detailed analyses led us to propose the notion of dynamically stable solvation shell, effectiveness of which can be characterized by a new physical parameter defined as the ratio of two fundamental time constants representing, respectively, the solvent relaxation (or residence) time within the first solvation shell and the characteristic time required for the fullerene particle to diffuse a distance comparable to the shell thickness. We show that, for the five (two from the literature) different solvent media and the range of system temperatures examined herein, this parameter bears a value around unity and, in particular, correlates intimately with known trends of solubility for C60 solutions. We also provide evidence revealing that, in addition to fullerene-solvent interactions, solvent-solvent interactions play an important role, too, in shaping the dynamic solvation shell, as implied by recent experimental trends.

Starch electrophoresis was employed for the study of the lipoprotein patterns in inborn errors of lipid metabolism. Idiopathic hyperlipemia was characterized by marked increases of cholesterol and phospholipid in the alpha-2-lipoprotein fraction of the serum whereas idiopathic hypercholesteremia showed an increase of these lipids in the beta-lipoprotein fraction. The cholesterol and phospholipid contents in the alpha-1-lipoprotein fractions were diminished in both metabolic errors.

Histochemical and chemical studies of the acid mucopolysaccharide content of the aorta were made in rabbits fed cholesterol for up to seven months. Colloidal iron staining suggested an increase in acid mucopolysaccharide content of the aortas with mild atheromatous lesions but not when severe lesions were present. Chemical determination, however, revealed no increase in the concentration of acid mucopolysaccharide in early lesions, but did reveal a significant increase in the more severely atheromatous aortas of rabbits fed cholesterol for 6 months or more.

The low incidence of atherosclerosis in premenopausal women and the effects of gonadal extracts on serum lipids indicate the desirability of further clinical and biochemical studies. Ethinyl estradiol was administered to 12 persons with idiopathic hyperlipemia or idiopathic hypercholesteremia. Medication was given for an average period of 16 months and was well tolerated, despite moderate gynecomastia, diminished libido, or uterine bleeding. The effects on the levels of circulating lipids and the clinical feasibility of this therapy are discussed.

Lactescence of the serum in acute pancreatitis, supposedly a rare manifestation of this disorder, was first reported in 1865.1 More recently, the increased incidence of relapsing pancreatitis in persons with idiopathic hyperlipemia has been stressed.2 6 The occurrence of elevated serum lipid levels in experimental pancreatitis in the dog was reported in 1929.7 Systematic studies performed in this laboratory demonstrated elevations of all serum lipid fractions in experimental acute pancreatitis in rabbits and dogs.8 It therefore appears that transient lipemia may accompany acute pancreatitis and that acute pancreatitis may be a complication of idiopathic hyperlipemia. Diabetic acidosis, if present, may contribute to the elevation of circulating lipoids. 9 . 10 It seemed profitable to review the records of patients with acute pancreatitis seen at the Mount Sinai Hospital during the past 22 years, with special emphasis on those in whom serum lipid determinations were performed. A smaller group of six patients, observed during the past five years, in whom serial determinations of serum lipids had been performed, are presented in detail. Serum cholesterol was determined by the Sperry-Schoenheimer method, phospholipids by the Sperry modification of the FiskeSubbaRow method, and total lipids by the Bloor method. Serum amylase was determined by the method of Somogyi (normal range 80 to 180 units per 100 ml). Selection of pat1·ents. One hundred and three patients, hospitalized between the years 1936 and 1957, were selected for review. The diagnosis of acute pancreatitis was established in 65 patients; by surgical laparotomy in 47 persons and by autopsy in 18 (proved cases). The diagnosis in the remaining 38 patients was based on clinical, laboratory, and roentgenologic findings (presumptive cases). Patients with "chronic"

lipodystrophy in a 36-year old physician, 54 cases have been reported in the literature.~-l1 Almost all of the cases were diagnosed at autopsy, and only a few in vivo by exploratory laparotomy and biopsy of the mesenteric lymph nodes or of the small intestine. Treatment had been uniformly unsuccessful, with fatal termination 1 to 5 years after the onset of the illness. Only recently corticotropin, cortisone and hydrocortisone have been used in the treatment of this disease with encouraging results. Mendes De Leon and Coenegracht,5 Jones et al} Plummer et al.,9 Radding and Fiese,1° and Lepore ll have each reported a case of intestinal lipodystrophy which responded favorably to corticosteroid therapy. We wish to present the study of another patient with this disease-to our knowledge, the 55th case of intestinal lipodystrophy in the literature. This patient has been subjected to three prolonged courses of corticotropin, cortisone and hydrocortisone therapy during an observation period of 4Y2 years. It led to the impression that in­ testinal lipodystrophy is a controllable or perhaps a curable disease. CASE REPORT

Cortisone has a retarding effect on atherogenesis in cholesterol-fed rabbits, despite higher plasma cholesterol levels. This effect of cortisone is prevented by administration of hyaluronidase. The latter intensifies atherosclerosis and deposition of cholesterol in the liver.

Pulmonary infection, malabsorption and elevated immunoglobulin levels may be interrelated in CF. To examine the immunologic processes in these patients (pts), lymphocyte subsets were quantitated and correlated with Schwackman scores for overall clinical status (SS), nutritional status (SSn) and chest X-ray scores (SSx). Fifty-four CF pts, 31M, 23F, age 17±10 years were studied. Lymphocyte subsets were quantitated with monoclonal antibodies for T-cells (Leul), T “helpers” (Leu3) T “suppressors” (Leu2) and B-cells (surface immunoglobulin positive, sIg+) using an indirect immunofluorescent technique. Pt values were compared to controlls obtained concurrently. SS, SSn and SSx were determined independently. Analyses of relative numbers (%) of lymphocyte subsets revealed no apparent differences between pts and controls. However, absolute numbers of lymphocyte subsets revealed that pts had significantly higher sIg+ cell numbers than controls (expressed as logs, 2.15 vs. 1.83, p=.038) and decreased Leu2+ cells (9.7 vs. 10.2, p=0.006). Leu3+ cells correlated inversely with SS, SSn and SSx (r's>-.32), p's

Although the centralized, aggressive treatment of pulmonary disease has prolonged the life expectancy of pts with CF, most of these pts., especially the older ones, are chronically ill. Undermineralization of their skeletal system is not unexpected. Quantitative computed tomography (QCT) of the vertebrae is a new technique for assessing the trabecular bone mineral content (BMC) in the axial skeleton. The turnover rate of the trabecular bone is eight times greater than that of cortical bone, rendering QCT a highly sensitive method for measuring early metabolic changes. We measured the BMC in 66 pts with CF, (27 M, 39 F), age 3-48 yrs., and compared the results with 120 age-matched controls. Forty-four (23 M, 21 F) of the 66 (66.7%) were below the mean for their age. Twelve (4 M, 8 F) of the 66 (18.2%) were 2 SD below the mean. When the pts with low BMC were matched to their nutritional status, using Wt for Ht, tricep skin fold, and arm muscle area as criteria of their degree of malnurishment, there was a high correlation with each parameter. The reduced BMC's were, however, not found to be related with serum Ca or albumin levels. The BMC's of 22 pts (4 M, 18 F) in the present group were above the mean for their age-matched controls. None were 2 SD above the mean. The predominence of females (81.8%) in this group was quite surprising in that males with CF were known to do better than the females.

Parents of CF children are often over-enthusiastic to any new modality of management. This study reports adverse metabolic and psychological effects of a liquid formula in 4 children (ages 16, 13, 8 and 5 yrs) with CF who were placed on the diet by their parents. The 16 yr old developed recurrent hypoglycemia while the 13 yr old developed hyperglycemia and glycosuria, all of which disappeared upon returning to a conventional diet. Simultaneous determinations of blood glucose (BG), immuno-reactive insulin (IRI), and immune-reactive glucagon (IRG) over a 5 hr period following the formula were compared with those following a standard glucose tolerance test (GTT). An exaggerated hyperglycemia (peak 226-486 vs 136-288 mg%) at 60' was followed by a 2nd peak at 2-4 hrs (120-178 vs 61-103 mg%). The IRI and IRG were all low and flat except in the 16 yr old, who had high levels. It is postulated that the high carbohydrates (85%) in the diet precipitated the higher peak of BG and that rapid absorption of aminoacids (8%) and fat (7%) may account for the prolonged hyperglycemia through continuous conversion to glucose. Only the 16 yr old consented to repeat tests on and off the formula. The 13 yr old refused to resume the diet. Parental fears prohibited the testing of the 8 and 5 yr olds on the conventional diet lest the children not return to the formula. All chlldren accepted the diet to please their parents. However, both adolescents felt “trapped between the diet and death” and were relieved when the formula was discontinued for “metabolic” reasons.

Nine patients with cystic fibrosis (CF), age 24.7 +/- 7.2 (mean +/-S.D.) years, with FEF 25-75% 0.90 +/- 0.45 1/s (22% predicted) and residual volume (RV) 3.03 +/- 1.06 1 (278% predicted) participated in a six month trial of variable weight training (VWT) designed to strengthen the accessory muscles of respiration. Weight, pulmonary function tests (PFT), muscle size and strength, self concept and social function were measured at baseline, after a 3-month control period and after VWT. Compared to control period, differences after VWT were significant (p .01, two tailed t test) for weight gain (mean 2.9 kg), reduced RV (mean 1.77 1) increased chest diameter A-P and transverse (mean 6.15 and 6.89 cm respectively) increased upper arm circumference (mean 1.80 cm), and percent of all muscle groups at normal or better strength (mean increase 100%). No other changes in PFT, self concept or social function reached significance. VWT appears to reduce hyperinflation by strengthening and enlarging the accessory respiratory muscles.

Beginning with the very first interview of parents with CF children seen at this center, an on-going study of the genealogy of each family was conducted. The pedigrees of 220 families with 293 CF children provided satisfactory data for an analysis of their ethnic origins. The majority (55.5%) were from 3 ethnic groups, namely, Germans (19.4%), Irish (18.7%, and English (17.4%). The next frequent groups were French (8.8%), Scotch (7.9%), and Dutch (6.7%), totaling 23.4%. The rest were Swedes (3.3%), Italians (3.1%), Polish (3%), Norwegians (2.4%), Spanish (1.8%), and Russians (1.7%), adding to 15.3%. Danes, Hungarians, Austrians, Yugoslavians, Czechoslovakians, Portuguese, Greeks, Romenians, and Finnish, each less than 1%, made up the remaining 5.3%. There were 13 (6%) Jewish families whose ancestors were from Germany, Austria, Poland, Hungary, and Russia. Three other families had Jewish intermarriages in their pedigrees. There were also two Gypsy families of Romanian and Greek origin. Among the non-Caucasians, only 10 families were American Negroes and one family was Asian. The latter vas from Korean father of Chinese origin and an Okinawan mother who had no known intermarriages with the Caucasian race. Two other Caucasian families had Phillipine ancestors and one other family had an ancestor of Hawaiian Chinese. Intermarriages with the American Indians were present in at least 10% of the Caucasian population studied