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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.

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.

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.

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.

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.

Frequent gene duplications in the genome incessantly supply new genetic materials for functional innovation presumably driven by positive Darwinian selection. This mechanism in the desaturase gene family has been proposed to be important in triggering the pheromonal diversification in insects. With the recent completion of a dozen Drosophila genomes, a genome-wide perspective is possible. In this study, we first identified homologs of desaturase genes in 12 Drosophila species and noted that while gene duplication events are relatively frequent, gene losses are not scarce, especially in the desat1-desat2-desatF clade. By reconciling the gene tree with species phylogeny and the chromosomal synteny of the sequenced Drosophila genomes, at least one gene loss in desat2 and a minimum of six gene gains (resulting in seven desatF homologs, alpha-eta), three gene losses and one relocation in desatF were inferred. Upon branching off the ancestral desat1 lineage, both desat2 and desatF gained novel functions through accelerating protein evolution. The amino acid residues under positive selection located near the catalytic sites and the C-terminal region might be responsible for altered substrate selectivity between closely related species. The association between the expression pattern of desatF-alpha and the chemical composition of cuticular hydrocarbons implies that the ancestral function of desatF-alpha is the second desaturation at the four carbons after the first double bond in diene synthesis, and the shift from bisexual to female-specific expression in desatF-alpha occurred in the ancestral lineage of Drosophila melanogaster subgroup. A relationship between the number of expressed desatF homologs and the diene diversification has also been observed. These results suggest that the molecular diversification of fatty acid desaturases after recurrent gene duplication plays an important role in pheromonal diversity in Drosophila.

Our aim was to describe the impact of severe acute respiratory syndrome (SARS) on the status and chemotherapy of non-small-cell lung cancer (NSCLC) patients who had entered clinical trials, and to review how to differentiate the signs and symptoms of SARS from lung cancer and its treatment-related toxicities. A prospective case series involving 79 NSCLC patients who were enrolled in clinical trials undergoing chemotherapy at Taipei Veterans General Hospital, between April 1 and July 15, 2003, was studied. Whether or not there existed a delay, omission, or refusal of scheduled chemotherapy, was recorded. Whether or not our patients had been suspected of or treated as having SARS, was recorded. The patients filled out questionnaires regarding lung cancer treatment and the risk of getting SARS from the hospital. Among these patients, five were placed in an isolation unit to rule out SARS infection during this period of time, and no patient was documented to have suffered from a SARS infection after examinations. Of 373 scheduled chemotherapy injections in 79 patients, a delay in treatment occurred only 10 times. Three patients refused further chemotherapy because of a fear of getting SARS if they visited the hospital. Fifty-eight patients responded to our questionnaires. Thirty-seven patients (63.8%) were afraid of visiting hospital during this SARS infection period. Twenty-one patients (36.2%) felt that a SARS infection was more severe and fatal than their lung cancer. In conclusion, SARS is a new disease entity that is highly contagious. Its clinical manifestations overlap with the signs and symptoms of lung cancer. Thus, a clear differentiation between the two conditions is needed, especially for those patients who are under active anti-cancer treatment.

This paper analytically evaluates the strength of microcomponents fabricated using both wet and dry etching techniques. A finite element model (nanometer meshed) coupled with a macroscopically accepted energy criterion is used to predict the strength of four different microridge structures (geometries). Agreement between analytical predictions and experimental data on single crystal silicon is excellent and validates the use of macroscopic models to predict the strength of micromachined components fabricated with a wide range of processes. The model is used to evaluate design parameters such as the influence of height and ridge material on strength properties. The analytical portion of the study suggests that optimum ridge height exists to maximize the strength and by choosing tougher materials, the strength of the ridges may be improved by an order of magnitude. However, the significant strength improvement is not validated experimentally. The simulation results confirm that the geometries rather than etching flaws are critical issues when dealing with strength of micromachined components. Furthermore, standard macroscopic methods can be used to predict the strength of MEMS components at the micron size level.

Virus isolates resistant to 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)thymine (HEPT) and a highly potent HEPT derivative, [1-benzyloxymethyl-5-ethyl-6-(α-pyridylthio)uracil] (NSC 648400, E-BPTU), were selected in cell culture. Cross-resistance evaluation indicated that the two drug resistant virus isolates were phenotypically distinct from one another although each of the virus isolates was resistant to both of the HEPT derivatives The virus isolate resistant to NSC 648400 had a single amino acid change in the reverse transcriptase (Y181C) which resulted in cross-resistance to all of the nonnucleoside reverse transcriptase inhibitors evaluated, with the exception of calanolide A. The NSC 648400-resistant virus isolate exhibited 15-fold enhanced sensitivity to calanolide A. The virus isolate selected in the presence of HEPT exhibited a single amino acid change (P236L) which was not cross- resistant to other nonnucleoside RT inhibitors tested with the exception of the two HEPT derivatives. This HEPT-resistant virus isolate exhibited enhanced sensitivity (5- to 10-fold) to thiazolobenzimidazole. We have used both virus isolates with defined single amino acid changes in the RT and bacterially expressed RTs with site-directed amino acid substitutions to test the effects of a wide variety of mutations on the activity of NSC 648400 Single mutations at amino acids 101, 103, 106, 181, or 236 yielded virus with high resistance (>20-fold) to NSC 648400, while lower levels of resistance were seen with mutations at amino acids 98, 100, or 108. These results suggest that several changes in the conformation of the nonnucleoside inhibitor binding site of the HIV-1 reverse transcriptase can affect the inhibitory activity of the HEPT class of compounds.

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.

It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology and is uncommon in Taiwan. No cases of familial sarcoidosis have been reported in Taiwan. In this article, we report a mother and son pair who had sarcoidosis. The 56-year-old mother sought medical help for chronic cough for 3 months in 1993. Enlarged mediastinal lymph nodes were demonstrated on chest computed tomography. Besides, two small erythematous papules on her face were observed. Mediastinoscopic biopsy and skin biopsy showed non-caseating granulomatous inflammation. Sarcoidosis was thus diagnosed. The human leukocyte antigen (HLA)-typing of the patient was HLA-A2, A11, B35, B39, CW4, CW7, DR8 and DQ6. Eleven years later, her son was also diagnosed with sarcoidosis proved by mediastinoscopic biopsy. His HLA-typing was HLA-A2, A24, B39, B48, CW7, CW8, DR8 and DQ6. This is the first report of familial sarcoidosis in Chinese people. More cases are needed for further investigation of genetic predisposition among Chinese people.

Current vendor software for authority control is found to generate negative results for nonunique Chinese headings in the local catalog. After authority control, nonunique Chinese names in the bibliographic records are found routinely altered to match authority headings established in the Library of Congress (LC) authority file that are unrelated to the Chinese script of the bibliographic record. Headings with standard diacritics in the Wade-Giles romanization scheme are the most problematic. The name headings that are negatively affected in the authority control services need to be corrected before the LC Pinyin conversion project takes place around the year 2000 to prevent headings from being distorted further in the Pinyin conversion process. In this paper, I examine the reasons why vendor software produces negative results for nonunique Chinese names, and suggest measures for Chinese-Japanese-Korean (CJK) libraries in North America and vendors who supply authority-control services that include CJK data to improve the situation. These include vendor software upgrades, modifications to CJK Name Authority Cooperative procedures, etc. The authority control service at the University of North Carolina at Chapel Hill is used to illustrate the problem.

Redington Shores is located on the west coast of Florida on the barrier island, Sandy Key, in Pinellas County. A detached offshore breakwater, located to the west of Redington Shores, was constructed in 1986. The breakwater was designed by the US Army Engineer District, Jacksonville, to control beach erosion and re- duce beach nourishment requirements. This paper presents the beach response at Redington Shores to this breakwater. Initial shoreline response described in Dean and Pope (1987) for the pre- and post-construction period, september 1984 to November 1986, is summarized. The subsequent shoreline changes monitored and documented by the Jacksonville District (US Army Corps of Engineers 1989) for the post-construction period, April 1986 to February 1988, and the post- renourishment shoreline response data are analyzed and interpreted along with the regional wave climate.

The title compound crystallizes in the triclinic space group [Formula: see text] and the cell dimensions are a = 16.890(3), b = 9.586(2), c = 6.316(1) Å, α = 91.09(1), β = 93.50(1), γ = 93.04(1)°. X-ray intensity data were measured on a diffractometer, and the crystal structure was determined by direct methods. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.056 for 3454 observed reflections. Adjacent six-membered rings are approximately perpendicular to one another. The glycosidic torsion angle [C(6)—N(1)—C(1′)—O(4′)] is 96.2(2)°. In the acyclic moiety, both C—OH bonds are gauche with respect to C(4′)—O(4′). The gauche conformation is also dominant in solution, as determined by high-resolution 1H nmr spectroscopy. Results of nuclear Overhauser experiments lead to conclusions about the flexibility of the molecule.

In attempts to increase the specificity of thiol agents and protect the genetic material of the cell, which is very sensitive to radiation damage, the synthesis of a group of compounds was undertaken in which cysteamine is attached through its amino group to a series of purine and pyrimidine components of nucleic acids. The 5-position of pyrimidines and the 8-position of purines seem well suited for the attachment of groups to be introduced into nucleic acids. Attempts were also made to introduce the bis( BETA -thioethyl) amino group into suitable carrier molecules to yield doublearmed cysteamines. While attempts to isolate bis-( BETA -mercaptoethyl)amine were unsuccessful, the oxidized form of the compound, 1,2-dithia-5-azepane was prepared in good yield. Thus, the preparation of N-substituted 1,2-dithia-5azepanes appeared feasible. A number of uracilyl compounds were prepared by reaction sequences which are shown. BETA -Benzylthioethylamine, prepared by the reaction of ethyleneimine with alpha - toluenethiol, was found to react with 5-bromouracil to yield 5-L BETA - benzylthioethylamino) uracil, This compound could also be obtained by the addition of alpha -toluenethiol to 5-( BETA -chloroethylamino)uracil (onearmed uracil mustard). Debenzylation with sodium in liquid ammonia resulted in the formation of 5-( BETA -mercaptoethylamino)uracil. Attempts to isolate themore » compound were unsuccessful; however, oxidation readily yielded its disulfide form. Bis( BETA -benzylthioethyl)amine reacted with 5bromouracil to form 5-bis( BETA - benzylthtoethylamino)uracil. An alternative synthesis of the compound involved the addition of the sodium salt of benzyl mercaptan to 5-bis( BETA chloroethylamino)uracil (uracil mustard). Reduction of the bis-benzylthio compound with sodium in liquid ammonia followed by air oxidation yielded N-(5- uracilyl)-1,2-dithta5-azepane. N,N'-bis(8-adeninyl)cystamine was prepared in annlogous fashion from 8-( BETA -benzylthioethylamino)adenine, which in turn was obtained by the reaction of 8bromoadenine with BETA -benzylthioethylamine. Difficulties were encountered in isolating mercaptans as such because of the rapidity of air oxidation. (P.C.H.)« less

The free-volume theory of transport is used to analyze the concentration dependence of the solvent self-diffusion coefficient for two polystyrene-solvent systems. The agreement between predictions of free-volume theory and the experimental data is good.

In view of the effectiveness of aminoethyl mercaptan (cysteamine) and of 2-aminoethylisothiouronium (AET) salts in protecting animals against ionizing radiation, efforts were made to prepare even more active analogs of the compounds. Sulfur is considered to be essential to the radioprotective action of cysteamine analogs; however, the selenium analog of cysteamine can shield mice against radiation. Since the atomic radii of sulfur and of selenium are similar, sulfur and selenium analogs may be assumed to have the same ability of fit receptor sites. The selenium analog of AET was prepared by the reaction of selenourea with 2-bromoethylamine hydrobromide. Treatment of the selenouronium salt with NaOH yielded 2-selenoethylguanidine, which was isolated as the flavianate salt. The reaction of 2-aminoethylisoselenouronium hydrobromide with boiling water resulted in the formation of 2-aminoselenazoline. Through the reaction of 2- methylaminoethyl. 2dimethylaminoethyl, and 2-diethylaminoethyl halides with selenourea the corresponding 2-alkylaminoethyl selenouronium salts were obtained. Similarly, 3-aminopropylisoselenouronium hydrobromide was synthesized.