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S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuximab resistance signature (170 identities); S1C:Gene expression profiles in FaDu-Snail cells (2.5 folds with FPKM>1, 477 genes)

Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation–mediated de novo resistance. Here, we investigated the driver gene mutation–independent mechanism for cetuximab resistance in HNSCC.Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance.Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial–mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-β (LTβ), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTβ interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTβ activates the NF-κB pathway through a LTβ receptor–independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR–LTβ interaction reverses resistance.Conclusions: Our findings elucidate the mechanism of driver gene mutations–independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388–401. ©2017 AACR.

Includes legends to 5 supplementary figures, supplementary methods, and supplementary references

Generation and characterization of the cetuximab-resistant head and neck cancer cells

In promoting the SDGs (Sustainable Development Goals), increasing attention has been given to environmental pollution and abnormal climate issues. In particular, a large number of products made of plastic materials have caused harm to the environment. Secondly, with the improvement of average spending power, many parents are more willing to buy toys for their children. However, the lifespan of kid’s toys is often short, and most materials are made of plastic, which also causes issues as they are not easy to break down and are difficult to recycle. This study investigates the concept of the product life cycle in kid’s toys and explores the decision-making factors of green design. First, analysis and induction were conducted through literature collection. Through semi-structured interviews with experts, the design dimensions related to the green design of kid’s toys and the elements that affect the willingness of consumption by consumption values and behavior were obtained. After the questionnaire survey and data analysis, the design factors and purchasing decision factors of green design for the product life cycle and consumption values and behavior of kid’s toys were obtained. Finally, combined with kid’s toy design, green design, product life cycle and consumers’ consumption values and behavior, the decision-making factors for the green design of kid’s toys were extracted, which included (1) using non-toxic materials; (2) designing for maintainability and disassembly of the toy; (3) refining the toys to be artistic and collectable; (4) upgrading the educational functions of toys; (5) improving the recycling of toys; (6) emphasizing green packing; (7) creating a green brand and increasing product visibility; and (8) advocating the value of green design for toys. In addition to supplying green design considerations for kid’s toys to designers and companies, the results can also be used as an important reference with regard to the research topics of product life cycle, toy design and development for the sustainable designs of products.

This article provides a method to convert landfill-designated municipal solid waste (MSW, paper-rich and food-rich) to bioproducts through integrated bioprocessing, also a way of improving the MSW ...

ParABS, an important DNA partitioning process in chromosome segregation, includes ParA (an ATPase), ParB (a parS binding protein) and parS (a centromere-like DNA). The homologous proteins of ParA and ParB in Helicobacter pylori are HpSoj and HpSpo0J, respectively. We analyzed the ATPase activity of HpSoj and found that it is enhanced by both DNA and HpSpo0J. Crystal structures of HpSoj and its DNA complexes revealed a typical ATPase fold and that it is dimeric. DNA binding by HpSoj is promoted by ATP. The HpSoj–ATP–DNA complex non-specifically binds DNA through a continuous basic binding patch formed by lysine residues, with a single DNA-binding site. This complex exhibits a DNA-binding adept state with an active ATP-bound conformation, whereas the HpSoj–ADP–DNA complex may represent a transient DNA-bound state. Based on structural comparisons, HpSoj exhibits a similar DNA binding surface to the bacterial ParA superfamily, but the archaeal ParA superfamily exhibits distinct non-specific DNA-binding via two DNA-binding sites. We detected the HpSpo0J–HpSoj–DNA complex by electron microscopy and show that this nucleoid-adaptor complex (NAC) is formed through HpSoj and HpSpo0J interaction and parS DNA binding. NAC formation is promoted by HpSoj participation and specific parS DNA facilitation.

Leptospirosis is the most common zoonotic disease caused by pathogenic Leptospira, which is classified into three groups according to virulence. Its pathogenic and intermediate species contain leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic strains. In this study, we presented the crystal structure of LSS_11580 (rLRR20) from pathogenic L. santarosai serovar Shermani. X-ray diffraction at a resolution of 1.99 Å revealed a horseshoe-shaped structure containing seven α-helices and five β-sheets. Affinity assays indicated that rLRR20 interacts with E-cadherin on the cell surface. Interestingly, its binds to the extracellular (EC) 1 domain in human epithelial (E)-cadherin, which is responsible for binding to another E-cadherin molecule in neighboring cells. Several charged residues on the concave face of LRR20 were predicted to interact with EC1 domain. In the affinity assays, these charged residues were replaced by alanine, and their affinities to E-cadherin were measured. Three vital residues and mutation variants of LRR20, namely D56A, E59A, and E123A, demonstrated significantly reduced affinity to E-cadherin compared with the control. Besides, we also demonstrated that rLRR20 induced the expression of neutrophil gelatinase-associated lipocalin (NGAL) in HK2 cells. The low ability of the three mutation variants to induce NGAL expression further demonstrates this induction. The present findings indicate that LRR20 from pathogenic Leptospira binds to E-cadherin and interacts with its EC1 domain. In addition, its induction of NGAL expression in HK2 cells is associated with acute kidney injury in human.

In a design department&rsquo, s practice course there are often group exercises that include intensive interactions between students in the classroom or in the internship factory. In addition, students will deepen the interaction between peers due to course groupings or borrowing of model tools, etc. This study intended to carry out a differential analysis and discussion of the differences among design students from different backgrounds under the three factors of peer relationships, learning motivation, and learning effectiveness. The research method was based on literature analysis and a questionnaire survey, and the research objects were sophomores and seniors in four classes. Statistical analysis methods included the independent sample T-test, one-way ANOVA, and factor and cluster analysis, which were used to summarize different learning styles. The results showed that the students had significant differences of varying degrees in the three factor dimensions. Regarding gender, &ldquo, care about classmates&rsquo, lives&rdquo, in peer relationships scored higher for the females than the males, and the rest had no effect. Regarding educational system, &ldquo, care about the classmates&rsquo, life&rdquo, and &ldquo, sharing life trivia&rdquo, was included in peer relationships. &ldquo, keep the enthusiasm in the course of learning&rdquo, was included in the learning motivation. &ldquo, recognition for self-directed learning&rdquo, ability improvement&rdquo, was included in learning effectiveness. The three factors all had significant differences, and the differences for full-time students were higher than for night school students. Regarding grade, there were significant differences in &ldquo, friends will value my comments&rdquo, in peer relationships, &ldquo, understand course content&rdquo, in learning motivation, and &ldquo, data collection ability&rdquo, understanding team member expertise&rdquo, in learning effectiveness, and seniors scored higher than sophomores in these areas. In addition, the ANOVA and post-hoc tests revealed significant differences in learning the processes between different groups. In peer relationships, full-time seniors scored higher than the other groups, in learning motivation and learning effectiveness, full-time seniors scored higher than night school sophomores. In addition, the overall factors of the full-time seniors were higher than those of the other groups. In the analysis of different learning factors, under the premise of the variation of 58.975%, three factors were extracted by principal axis for analysis with Promax rotation. The different learning factors can be summarized in &ldquo, emphasizing ability improvement&rdquo, &ldquo, care about peer friendship&rdquo, careful and active learning&rdquo, Classification of learning styles under the three factor dimensions was based on two-stage cluster analysis to obtain two clustering results, including &ldquo, enthusiastic and friendly&rdquo, active and autonomous&rdquo, The results showed that the mastery of self-learning time and the learning experience performance have a key influence on the learning motivation and learning effectiveness of design students from different backgrounds. In addition, the results also showed a new opportunity for course improvement and teaching innovation at night schools. The final results of this study could be used as an important reference for research on peer relationships, learning motivation, and learning effectiveness in design education.

This study presents structure and function of the sodium-dependent phosphate transporter, TmPiT-Pi/Na., Inorganic phosphate (Pi) is a fundamental and essential element for nucleotide biosynthesis, energy supply, and cellular signaling in living organisms. Human phosphate transporter (hPiT) dysfunction causes numerous diseases, but the molecular mechanism underlying transporters remains elusive. We report the structure of the sodium-dependent phosphate transporter from Thermotoga maritima (TmPiT) in complex with sodium and phosphate (TmPiT-Na/Pi) at 2.3-angstrom resolution. We reveal that one phosphate and two sodium ions (Pi-2Na) are located at the core of TmPiT and that the third sodium ion (Nafore) is located near the inner membrane boundary. We propose an elevator-like mechanism for sodium and phosphate transport by TmPiT, with the TmPiT-Na/Pi complex adopting an inward occluded conformation. We found that disease-related hPiT variants carry mutations in the corresponding sodium- and phosphate-binding residues identified in TmPiT. Our three-dimensional structure of TmPiT provides a framework for understanding PiT dysfunction and for future structure-based drug design.

Background Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown. The aim of our study was to determine the effect of theophylline on COPD patients presenting with sepsis. Methods This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients with COPD who were hospitalized for sepsis between 2000 and 2011 were divided into theophylline users and non-users. The primary outcome was 30-day mortality. The secondary outcome was in-hospital death, intensive care unit admission, and need for mechanical ventilation. Cox proportional hazard model and conditional logistic regression were used to calculate the risk between groups. Results A propensity score-matched cohort of 51,801 theophylline users and 51,801 non-users was included. Compared with non-users, the 30-day (HR 0.931, 95% CI 0.910–0.953), 180-day (HR 0.930, 95% CI 0.914–0.946), 365-day (HR 0.944, 95% CI 0.929–0.960) and overall mortality (HR 0.965, 95% CI 0.952–0.979) were all significantly lower in theophylline users. Additionally, the theophylline users also had lower risk of in-hospital death (OR 0.895, 95% CI 0.873–0.918) and need for mechanical ventilation (OR 0.972, 95% CI 0.949–0.997). Conclusions Theophylline use is associated with a lower risk of sepsis-related mortality in COPD patients. Pre-hospital theophylline use may be protective to COPD patients with sepsis.

Through individual teacher action research methods, this study designs two courses for design rendering techniques and portfolio design, and conducts planning and operation of classroom management, teaching strategies and innovative design of teaching materials, and explores students' learning attitude, creative performance and willingness to learn independently. Performance. It is hoped that this will enhance students' psychological self-expectation and gain effective learning and ability development in design performance and willingness to learn independently. Through the teaching guidance, after-school tutoring and awakening students' self-learning and the various stages of the publication of the works, the students' achievement factors and feedback on autonomous learning are obtained. The study found that students will have significant growth in learning performance through guidance and after-school interaction during the course of the course, and thus the awakening of autonomous learning. Unconscious, there are great differences in learning and interaction performance. There are three reasons for this: 1. Insufficient basic ability and lack of self-confidence, learning disabilities, 2. Basic ability, but inertia, 3. Self-feeling and rejection growing up. In addition, students who develop self-learning, regardless of their ability to improve, also have a high degree of interaction, and have significantly grown in their performance and extracurricular knowledge. In this study, the teaching results obtained through the design rendering techniques and portfolio design of the two courses, in addition to improving students' independent learning, but also conducive to the training of students' design ability. The research results provided can also be provided to the planning application and academic research reference of other related design courses.

Background and objective Recent observational studies have shown that sleep apnoea (SA) is associated with increased risk of incident CKD. However, the contribution of SA relative to common traditional CKD risk factors remains unknown. The aims of this study were to investigate the long-term risk of incident CKD events following SA diagnosis and compare the relative contributions of SA, diabetes and hypertension. Methods Data were retrieved from Taiwan's National Health Insurance Research Database during the period between 2000 and 2010 for this retrospective cohort study. The cohorts are composed of patients (age ≥ 20 years) newly diagnosed with SA and matched subjects without SA. The two cohorts were followed until the occurrence of CKD, death or the end of 2010. Results The sample is composed of 43 434 individuals (8687 patients with SA and 34 747 matched non-SA subjects). A total of 157 new CKD events in patients with SA and 298 events in the matched non-SA cohort were recorded during a mean follow-up period of 3.9 years (incidence rates, 4.5 and 2.2/per 1000 person-years). The risk of CKD development was greater among patients with SA than in the matched non-SA cohort (adjusted hazard ratio (aHR) 1.58, 95% confidence interval ( CI): 1.29–1.94). The contribution of SA to the CKD hazard was similar to that of hypertension (aHR 1.17, 95% CI: 0.68–2.01, P = 0.56), whereas that of diabetes remained significantly higher (aHR 2.17, 95% CI: 1.21–3.90, P = 0.01). Conclusion SA was associated with an increase in the risk of CKD incidence similar to that of hypertension. See Editorial, page 578

In a large observational database study of add-on treatments to metformin, the addition of dipeptidyl peptidase-4 (DPP-4) inhibitors was associated with a lower risk for all-cause mortality, stroke...

This research, based on the technical energy of lighting, integrates its application with various product design ideas and introduces OLED technology into different fields to develop new product features and values. This research also use HDT (Human Design Technology) to search user's requirements and check design items of drinking water equipment. The results of this study summarize several application design types: 1. Large Size screen information display application, 2. Improve the illumination design of night instruction, 3. Using OLED high color rendering technology to change the appearance of color products. As for the future product application of OLED technology, this study proposed two points for future research recommendations: 1. For the product surface screen, OLED can provide more diversification of display space technology applications; 2. It's necessary to improve the OLED in the long-term display color decline and the Imprinting phenomenon, in order to implement the application of the product design.

Modern wars have prohibited people from communication with one another for a long time. This separation has actually caused corporate governance problems. As an example, if a significant enough portion of shareholders cannot attend a shareholders’ meeting and vote, not only can no lawful resolutions be made due to mandatory quorum requirements, but those shareholders are easily oppressed by controlling shareholders. How can the law protect the property rights of shareholders who cannot attend such meetings while upholding efficient corporate governance? In this paper, we took the experience of the Chinese Civil War as an example to answer the questions. We did archival work on ad hoc legislation in 1964 and its amendment in 1992 in response to this situation. In addition, we scrutinized the solutions proposed during the legislative process, analysed them from a legal and economics perspective, and offer our own proposal. We found that the 1992 amendment freezes shareholders’ voting rights and deducts their shares when calculating the total number of shares. The involuntary non-voting stock policy deviates from the “one share one vote” principle and causes oppression indirectly; thus, it is obviously not an appropriate measure. We propose that auctioning those shares would be a more efficient and property-right-protective alternative to adopt.

After World War II ended, Nationalist China adjudicated 883 non-major war criminals. To provide grounds for judgment, the Legislative Yuan, the central legislative authority, passed the War Criminal Trial Act (WCTA) in 1946. The WCTA was similar to, but not necessarily the same as, international law. This paper asks: What was the difference between the WCTA, a domestic law, and international law? What did the difference imply? How did the judiciary respond to the WCTA? This paper compares the content of the international and national laws and delves into administrative and judicial archives to answer the questions. This paper found that the WCTA departed from international law in many aspects. It stipulated a broader scope, adopted a stricter liability, and intended to promote Chinese nationalism. At the time, the legislators were not delegates elected by citizens, but specialists appointed by the ruling party, so the WCTA represented the opinion of the political sectors. However, the Judicial Yuan, which was responsible for unifying legal interpretation, limited the scope of the WCTA, hindered the purpose of promoting Chinese nationalism, and restrained the political sector’s revenge on Taiwanese people by interpreting the WCTA per international law. Because Judicial Yuan meetings were composed of Supreme Court senior judges, its interpretations represented the elite legal professionals’ view. The legislature and the judiciary were competing interpreters of international law. This paper concludes that elite legal professionals’ belief in “pursuing a civilized state” triumphed in this competition at the end.

Spo0J (stage 0 sporulation protein J, a member of the ParB superfamily) is an essential component of the ParABS (partition system of ParA, ParB, and parS)-related bacterial chromosome segregation system. ParB (partition protein B) and its regulatory protein, ParA, act cooperatively through parS (partition S) DNA to facilitate chromosome segregation. ParB binds to chromosomal DNA at specific parS sites as well as the neighboring nonspecific DNA sites. Various ParB molecules can associate together and spread along the chromosomal DNA. ParB oligomer and parS DNA interact together to form a high-order nucleoprotein that is required for the loading of the structural maintenance of chromosomes proteins onto the chromosome for chromosomal DNA condensation. In this report, we characterized the binding of parS and Spo0J from Helicobacter pylori (HpSpo0J) and solved the crystal structure of the C-terminal domain truncated protein (Ct-HpSpo0J)-parS complex. Ct-HpSpo0J folds into an elongated structure that includes a flexible N-terminal domain for protein-protein interaction and a conserved DNA-binding domain for parS binding. Two Ct-HpSpo0J molecules bind with one parS. Ct-HpSpo0J interacts vertically and horizontally with its neighbors through the N-terminal domain to form an oligomer. These adjacent and transverse interactions are accomplished via a highly conserved arginine patch: RRLR. These interactions might be needed for molecular assembly of a high-order nucleoprotein complex and for ParB spreading. A structural model for ParB spreading and chromosomal DNA condensation that lead to chromosome segregation is proposed.

Summary Objective The potential association between healthcare workers (HCWs) and the risk of clinically active tuberculosis (TB) in countries with intermediate TB burdens remains unclear. Methods A nationwide, population-based cohort study was performed by using Taiwan National Health Insurance Database during 2000–2010. We included HCWs and non-HCWs without history of tuberculosis matched at a 1:1 ratio according to age, sex, monthly income, underlying comorbidities, and concomitant medications. All subjects were followed from the date of enrollment until TB occurrence, death, or 31 December 2010. Results The study population comprised 11,811 healthcare workers and 11,811 matched subjects. 62 HCWs and 38 control subjects developed TB during a median follow-up period of 9.4 years. The incidence of TB was higher among HCWs than among matched subjects (61.08 vs . 37.81 per 100,000 person-years). The risk of TB was also greater among HCWs (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.08–2.43), particularly for pulmonary TB in comparison with extrapulmonary TB (aHR, 1.56; 95% CI, 1.02–2.39). Among different job categories of HCWs, we found that only nurses had a significantly increased risk of developing TB (aHR, 2.55; 95% CI, 1.37–4.72) compared to the matched cohort. Conclusions HCWs are associated independently with a higher risk of developing TB in this intermediate-burden country. Therefore, the importance of TB surveillance among HCWs should be emphasized.

Background— Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors. Methods and Results— A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched cohort, IE survivors had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.40–1.80), hemorrhagic stroke (aHR, 2.37; 95% CI, 1.90–2.96), myocardial infarction (aHR, 1.44; 95% CI, 1.17–1.79), readmission for heart failure (aHR, 2.24; 95% CI, 2.05–2.43), sudden death or ventricular arrhythmia (aHR, 1.69; 95% CI, 1.44–1.98), and all-cause death (aHR, 2.27; 95% CI, 2.14–2.40). Risk factors for repeat IE were older age, male sex, drug abuse, and valvular replacement after an initial episode of IE. Conclusion— Despite treatment, the risk of long-term major adverse cardiac events was substantially increased in IE survivors.

Background Relevant clinical studies have been small and have not convincingly demonstrated whether the perioperative initiation of beta‐blockers should be considered in patients with diabetes mellitus undergoing noncardiac surgery. Methods and Results In this nationwide propensity score–matched study, we included patients with diabetes mellitus undergoing noncardiac surgery between 2000 and 2011 from Taiwan's National Health Insurance Research Database. Patients were classified as beta‐blocker and non–beta‐blocker cohorts. We further stratified beta‐blocker users into cardioprotective beta‐blocker (atenolol, bisoprolol, metoprolol, or carvedilol) and other beta‐blocker users. To investigate time of initiation of beta‐blocker use, initiation time was stratified into 2 periods (>30 and ≤30 days preoperatively). The outcomes of interest were in‐hospital and 30‐day mortality. After propensity score matching, we identified 50 952 beta‐blocker users and 50 952 matched controls. Compared with non–beta‐blocker users, cardioprotective beta‐blocker users were associated with lower risks of in‐hospital (odds ratio 0.75, 95% CI 0.68–0.82) and 30‐day (odds ratio 0.75, 95% CI 0.70–0.81) mortality. Among initiation times, only the use of cardioprotective beta‐blockers for >30 days was associated with decreased risk of in‐hospital (odds ratio 0.72, 95% CI 0.65–0.78) and 30‐day (odds ratio 0.72, 95% CI 0.66–0.78) mortality. Of note, use of other beta‐blockers for ≤30 days before surgery was associated with increased risk of both in‐hospital and 30‐day mortality. Conclusions The use of cardioprotective beta‐blockers for >30 days before surgery was associated with reduced mortality risk, whereas short‐term use of beta‐blockers was not associated with differences in mortality in patients with diabetes mellitus.

BACKGROUND We aimed to examine the risk of subsequent cardiovascular events in patients with CKD discharged after sepsis. METHODS Using the data on CKD patients from Taiwan9s National Health Insurance Research Database, we identified sepsis subjects who survived between 2000 and 2010, and each survivor was propensity-score-matched to one nonsepsis hospitalized controls.Cox regression models were used to estimate the hazard ratios of clinical outcomes, including major adverse cardiovascular events, all-cause death and hospitalization for heart failure. RESULTS Among 66,961 sepsis survivors,. sepsis survivors in comparison to matched hospitalized nonsepsis control subjects, had greater risks of major adverse cardiovascular events (HR, 1.35; 95% confidence interval [CI], 1.31–1.38), myocardial infarction (HR, 1.39; 95% CI, 1.32–1.47) ischemic stroke (HR, 1.46; 95% CI, 1.40–1.52), all-cause mortality (HR, 1.56; 95% CI, 1.54–1.58), and hospitalization for heart failure (HR, 1.55; 95% CI, 1.51–1.59). CONCLUSIONS Our findings highlight that sepsis in CKD population was associated with significantly increased risk of cardiovascular events among survivors.

Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation–mediated de novo resistance. Here, we investigated the driver gene mutation–independent mechanism for cetuximab resistance in HNSCC. Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance. Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial–mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-β (LTβ), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTβ interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTβ activates the NF-κB pathway through a LTβ receptor–independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR–LTβ interaction reverses resistance. Conclusions: Our findings elucidate the mechanism of driver gene mutations–independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388–401. ©2017 AACR.

Helicobacter pylori cell binding factor 2 (HpCBF2) is an antigenic virulence factor belonging to the SurA-like peptidyl-prolyl cis-trans isomerase family with implications for pathogenicity in the human gastrointestinal tract. HpCBF2 possesses PPIase activity and could act as a periplasmic chaperone to regulate outer membrane protein assembly. Here, we measured the isomerization and chaperone activity of HpCBF2, and determined the crystal structure of HpCBF2 in complex with an inhibitor, indole-2-carboxylic acid (I2CA), at 2.4A resolution. HpCBF2-I2CA forms a homodimer encasing a large central hydrophobic cavity with a basket-like structure, and each monomer contains a PPIase and a chaperone domain. In the HpCBF2-I2CA dimer, the two PPIase domains separate by a distance of 22.8A, while the two chaperone domains arrange in a domain-swap manner. The PPIase domains bound with I2CA ligand face towards the chaperone domains and are shielded by surrounding hydrophobic residues. With the aid of SAXS experiments, we also revealed domain motion between the apo- and I2CA-bound states of HpCBF2. The domain motion in HpCBF2 might be necessary for the isomerization activity of PPIase and the accommodation of the unfolded and partially folded peptides to refold by chaperone domain.

Recent observational studies have shown that sleep apnoea (SA) is associated with increased risk of incident CKD. However, the contribution of SA relative to common traditional CKD risk factors remains unknown. The aims of this study were to investigate the long-term risk of incident CKD events following SA diagnosis and compare the relative contributions of SA, diabetes and hypertension.Data were retrieved from Taiwan's National Health Insurance Research Database during the period between 2000 and 2010 for this retrospective cohort study. The cohorts are composed of patients (age ≥ 20 years) newly diagnosed with SA and matched subjects without SA. The two cohorts were followed until the occurrence of CKD, death or the end of 2010.The sample is composed of 43,434 individuals (8687 patients with SA and 34,747 matched non-SA subjects). A total of 157 new CKD events in patients with SA and 298 events in the matched non-SA cohort were recorded during a mean follow-up period of 3.9 years (incidence rates, 4.5 and 2.2/per 1000 person-years). The risk of CKD development was greater among patients with SA than in the matched non-SA cohort (adjusted hazard ratio (aHR) 1.58, 95% confidence interval ( CI): 1.29-1.94). The contribution of SA to the CKD hazard was similar to that of hypertension (aHR 1.17, 95% CI: 0.68-2.01, P = 0.56), whereas that of diabetes remained significantly higher (aHR 2.17, 95% CI: 1.21-3.90, P = 0.01).SA was associated with an increase in the risk of CKD incidence similar to that of hypertension. See article, page 578.

article i nfo Background:Guidelinesforhypertensionmanagementrecommendeitherangiotensin-convertingenzymeinhib- itors (ACEIs) or angiotensin II receptor blockers (ARBs) as first-line therapies for diabetes population. No head- to-head trial has been conducted to determine the priority of ACEI/ARB use for major adverse cardiac events (MACEs) in diabetes mellitus. Methods: Data on patients with newly diagnosed diabetes treated with ACEIs or ARBs were collected from Taiwan's National Health Insurance Research Database for the period 2000-2010. A total of 30,777 ARB users and 21,436 ACEI users were identified. One ARB user was matched to one ACEI user by propensity score. Intention-to-treat (ITT) and as-treated (AT) models were used. The primary outcomes were myocardial infarc- tion, ischemic stroke, and all-cause mortality. The secondary outcomes were hospitalization for acute kidney in- jury and hyperkalemia. Findings: Compared with ACEI users (n = 21,436), ARB users (n = 30,777) showed no significant difference in the outcomes of myocardial infarction (hazard ratio (HR): 0.92; 95% confidence interval (CI): 0.80 to 1.07), ische- mic stroke (HR: 0.95; 95% CI: 0.87 to 1.04), or all-cause mortality (HR: 0.95; 95% CI: 0.89 to 1.01) in the ITT anal- ysis. The risks of hospitalization for acute kidney injury and hyperkalemia also did not differ between groups. ACEI and ARB use also had similar effects on MACEs and adverse effects in the AT analysis. Conclusions: This large cohort study supports the comparative effectiveness of ACEIs and ARBs in terms of MACE outcomes in patients with incident diabetes.

Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive. In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted. In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis. Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations.