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Size of tropical cyclone (TC) is often asymmetric in nature. Yet, there is a lack of systematic, clean, and intuitive definition/expression to specify the asymmetry of TC size. Here, we introduce a novel index, TC size asymmetry index (SAI), which specifies both the degree and pattern of the asymmetry synthetically. In particular, the symbolic form of SAI is vividly designated for identifying the latter. The SAI proposes 1 quasi-symmetric pattern and 28 asymmetric patterns in total. The 41-year (1979–2019) global climatology of SAI shows that the distribution of the degree of TC size asymmetry is trimodal. Elementarily, the degree and pattern of asymmetry are found to be TC intensity, TC movement, time, and space dependent. The introduction of SAI provides an insight into the subject and lays an important foundation for future applications and research. Furthermore, besides meteorology, it could inspire other fields to index the geometric asymmetries of other kinds. [ABSTRACT FROM AUTHOR]

Background: Patients with cancer may be at increased risk of osteoporosis and fracture; however, gaps exist in the existing literature and the association between cancer and fracture requires further examination. Methods: We conducted a population-based cohort study of Ontario patients with cancer (breast, prostate, lung, gastrointestinal, haematologic) diagnosed between January 2007 to December 2018 and 1:1 matched non-cancer controls. The primary outcome was incident fracture (end of follow-up December 2019). Multivariable Cox regression analysis was used to estimate the relative fracture risk with sensitivity analysis accounting for competing risk of death. Results: Among 172,963 cancer patients with non-cancer controls, 70.6% of patients with cancer were <65 years old, 58% were female, and 9375 and 8141 fracture events were observed in the cancer and non-cancer group, respectively (median follow-up 6.5 years). Compared to non-cancer controls, patients with cancer had higher risk of fracture (adjusted HR [aHR] 1.10, 95% CI 1.07–1.14, p < 0.0001), which was also observed for both solid (aHR 1.09, 95% CI 1.05–1.13, p < 0.0001) and haematologic cancers (aHR 1.20, 95% CI 1.10–1.31, p < 0.0001). Sensitivity analysis accounting for competing risk of death did not change these findings. Conclusions: Our study indicates that patients with cancer are at modest risk of fractures compared to non-cancer controls. [ABSTRACT FROM AUTHOR]

Major adverse cardiovascular and cerebrovascular events (MACCE) is an important cause of morbidity and mortality during perioperative period. In this study, we looked for national trends in perioperative MACCE and its components as well as cancer types associated with high rates of perioperative MACCE during major cancer surgeries. This study was a retrospective analysis of the National Inpatient Sample, 2005–2014. Hospitalizations for surgeries of prostate, bladder, esophagus, pancreas, lung, liver, colorectal, and breast among patients 40 years and greater were included in the analysis. MACCE was defined as a composite measure that included in-hospital all-cause mortality, acute myocardial infarction (AMI), and ischemic stroke. A total of 2,854,810 hospitalizations for major surgeries were included in this study. Of these, 67,316 (2.4%) had perioperative MACCE. Trends of perioperative MACCE showed that it decreased significantly for AMI, death and any MACCE, while stroke did not significantly change during the study period. Logistic regression analysis for perioperative MACCE by cancer types showed that surgeries for esophagus, pancreas, lung, liver, and colorectal cancers had significantly greater odds for perioperative MACCE. The surgeries identified to have greater risks for MACCE in this study could be risk stratified for better informed decision-making and management. [ABSTRACT FROM AUTHOR]

Background: Evaluating the relevance of published health utilities to the context of a cost-utility analysis (CUA) remains an essential, yet often overlooked, task. Objective: The objective of this study was to provide guidance on this process through the development of the Health utility Application Tool (HAT). Methods: We conducted semi-structured telephone interviews with Canadian stakeholders from reimbursement bodies, academia, and the pharmaceutical industry to identify current practices and perspectives of the application of the health utility literature to CUAs. An online survey with international members of the general health economics and outcomes research community was also conducted to gather opinions on key concepts. Results: Based on the themes emerging from the interviews and online questionnaire, the HAT includes questions prompting investigators to consider the following constructs: similarity of the clinical condition in the health utility study and the CUA; similarity of health utility study participant demographics and the demographics of the CUA's target population; similarity of the health state descriptions in the health utility study and the CUA; and the method of assigning utility weights. Considerations of transparency prompted additional items, including: means by which the health utility study was identified; type of respondents; study design; and measure used to collect health utility estimates. Conclusion: The HAT is intended to guide the evaluation of the applicability of published health utilities for a CUA, thus promoting transparency and accountability in the selection of model inputs. [ABSTRACT FROM AUTHOR]

In evaluating new oncology medicines, two common modeling approaches are state transition (e.g., Markov and semi-Markov) and partitioned survival. Partitioned survival models have become more prominent in oncology health technology assessment processes in recent years. Our experience in conducting and evaluating models for economic evaluation has highlighted many important and practical pitfalls. As there is little guidance available on best practices for those who wish to conduct them, we provide guidance in the form of 'Key steps for busy analysts,' who may have very little time and require highly favorable results. Our guidance highlights the continued need for rigorous conduct and transparent reporting of economic evaluations regardless of the modeling approach taken, and the importance of modeling that better reflects reality, which includes better approaches to considering plausibility, estimating relative treatment effects, dealing with post-progression effects, and appropriate characterization of the uncertainty from modeling itself. [ABSTRACT FROM AUTHOR]

The sensitivity of the simulation of tropical cyclone (TC) size to microphysics schemes is studied using the Advanced Hurricane Weather Research and Forecasting Model (WRF). Six TCs during the 2013 western North Pacific typhoon season and three mainstream microphysics schemes-Ferrier (FER), WRF Single-Moment 5-class (WSM5) and WRF Single-Moment 6-class (WSM6)-are investigated. The results consistently show that the simulated TC track is not sensitive to the choice of microphysics scheme in the early simulation, especially in the open ocean. However, the sensitivity is much greater for TC intensity and inner-core size. The TC intensity and size simulated using the WSM5 and WSM6 schemes are respectively higher and larger than those using the FER scheme in general, which likely results from more diabatic heating being generated outside the eyewall in rainbands. More diabatic heating in rainbands gives higher inflow in the lower troposphere and higher outflow in the upper troposphere, with higher upward motion outside the eyewall. The lower-tropospheric inflow would transport absolute angular momentum inward to spin up tangential wind predominantly near the eyewall, leading to the increment in TC intensity and size (the inner-core size, especially). In addition, the inclusion of graupel microphysics processes (as in WSM6) may not have a significant impact on the simulation of TC track, intensity and size. [ABSTRACT FROM AUTHOR]

There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reactions of C(sp2)-H and C(sp3)-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)-H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp3)-H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids. [ABSTRACT FROM AUTHOR]

Two closely related trans-membrane C-type lectins dendritic cell-specific intracellular adhesion molecules (ICAM)-3 grabbing non-integrin (DC-SIGN or CD209) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN also known as DC-SIGNR, CD209L or CLEC4M) directly recognize a wide range of micro-organisms of major impact on public health. Both genes have long been considered to share similar overall structure and ligand-binding characteristics. This review presents more recent biochemical and structural studies, which show that they have distinct ligand-binding properties and different physiological functions. Of importance in both these genes is the presence of an extra-cellular domain consisting of an extended neck region encoded by tandem repeats that support the carbohydrate-recognition domain, which plays a crucial role in influencing the pathogen-binding properties of these receptors. The notable difference between these two genes is in this extra-cellular domain. Whilst the tandem-neck-repeat region remains relatively constant size for DC-SIGN, there is considerable polymorphism for L-SIGN. Homo-oligomerization of the neck region of L-SIGN has been shown to be important for high-affinity ligand binding, and heterozygous expression of the polymorphic variants of L-SIGN in which neck lengths differ could thus affect ligand-binding affinity. Functional studies on the effect of this tandem-neck-repeat region on pathogen-binding, as well as genetic association studies for various infectious diseases and among different populations, are discussed. Worldwide demographic data of the tandem-neck-repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups are presented. These findings support the neck region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome (SARS) is caused by infection of a previously undescribed coronavirus (CoV). L-SIGN, encoded by CLEC4M (also known as CD209L), is a SARS-CoV binding receptor that has polymorphism in its extracellular neck region encoded by the tandem repeat domain in exon 4. Our genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. L-SIGN is expressed in both non-SARS and SARS-CoV–infected lung. Compared with cells heterozygous for L-SIGN, cells homozygous for L-SIGN show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. Thus, homozygosity for L-SIGN plays a protective role during SARS infection. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated left atrial (LA) remodeling using cardiac MRI (CMR) in patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer during and after trastuzumab therapy. Methods: In this prospective 2-center longitudinal study, 41 women with HER2-positive breast cancer received adjuvant trastuzumab for 12 months, in addition to standard chemotherapy. Serial CMRs were performed at baseline, 6, 12, and 18 months after initiation of trastuzumab. LA volumes were measured by a blinded reader. Linear mixed model was used to evaluate longitudinal changes. Results: Of 41 women (mean age 52 ± 11 [SD] years; 56% received anthracycline), one patient experienced trastuzumab-induced cardiotoxicity (TIC) for which trastuzumab was interrupted for one cycle. Mean baseline left ventricular ejection fraction (LVEF) was 68.0 ± 5.9% and LA ejection fraction (LAEF) was 66.0 ± 6.6%. Compared to baseline, LAEF decreased significantly at 6 months (62.7 ± 5.7%, p = 0.027) and 12 months (62.2 ± 6.1%, p = 0.003), while indexed LA minimum volume (LAmin) significantly increased at 12 months (11.6 ± 4.9 ml/m2 vs 13.8 ± 4.5 ml/m2, p = 0.002). At 18 months, all changes from baseline were no longer significant. From baseline to 6 months, change in LAEF correlated with change in LVEF (Spearman's r = 0.41, p = 0.014). No significant interactions (all p > 0.10) were detected between time and anthracycline use for LA parameters. Conclusions: Among trastuzumab-treated patients with low incidence of TIC, we observed a small but significant decline in LAEF and increase in LAmin that persisted for the duration of therapy and recovered 6 months after therapy cessation. These findings suggest that trastuzumab has concurrent detrimental effects on atrial and ventricular remodeling. Key Points: • In trastuzumab-treated breast cancer patients evaluated by cardiac MRI, left atrial ejection fraction declined and minimum volume increased during treatment and recovered to baseline after trastuzumab cessation. • Changes in left atrial ejection fraction correlated with changes in left ventricular ejection fraction in the first 6 months of trastuzumab treatment. • Trastuzumab therapy is associated with concurrent detrimental effects on left atrial and ventricular remodeling. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented as a reply to a letter concerning the association of CLEC3M homozygosity and protection against SARS coronavirus infection.

Purpose: The National Institutes of Health's policy for the inclusion of females in clinical research was a pivotal step towards the consideration of sex as a biological variable, which is of particular importance in oncology, given differential incidence and outcomes of cancer between the sexes, and known pharmacodynamic, pharmacokinetic, and immunological differences. Therefore, we aim to investigate if such biological sex-based differences translate to clinically meaningful outcome differences from recently approved systemic oncology therapies. Methods: A systematic review of randomized control trials (RCTs) cited in Food and Drug Administration, European Medicines Agency, and Health Canada approvals was conducted. Chemotherapy, targeted agents, and immunotherapy RCTs reporting sex-based sub-group analyses for overall/progression-free survival (OS/PFS) were considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized. Sensitivity analyses for survival endpoints, drug type, and cancer site were conducted. Results: Ninety-nine RCTs were included, representing 62,384 patients (23,574 (38%) female). Pooled OS HRs [95% CIs] were 0.77 [0.72–0.81] and 0.76 [0.72–0.79] for females and males, respectively (P = 0.73), and 0.51 [0.47–0.56] and 0.57 [0.53–0.61] (P = 0.08) for PFS. Sensitivity analyses yielded similar results. No RCTs reported sex-based toxicity or quality-of-life (QOL) data. Conclusion: Female and male patients appear to derive comparable benefits from recently approved systemic oncology therapies. Future RCTs are encouraged to report sex-based toxicity and QOL data. [ABSTRACT FROM AUTHOR]

Background: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment.Objective: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia.Methods: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data.Results: Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration.Conclusions: Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models. [ABSTRACT FROM AUTHOR]

Purpose: In the past decade, literature has called attention to financial toxicities experienced by cancer patients. Though studies have addressed research questions in high-income countries, there remains a paucity of in-depth reviews regarding low- and middle-income countries (LMICs). Our scoping review provides an overview of treatment-related financial toxicities experienced by cancer patients in LMICs. Methods: A systematic search was conducted in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. English peer-reviewed articles that (a) explored patients' experience with financial toxicity due to cancer treatment (b) were specific to LMICs as defined by the World Bank and (c) focused on qualitative data were included. Details regarding participants and main findings were extracted and synthesized. Results: The search yielded 6290 citations, and 42 studies across 3 low-income, 9 lower-middle-income and 8 upper-middle-income countries. Main themes identified included cancer patients encountered various material hardships, managed costs with different coping behaviours and experienced negative psychological responses to their financial burden. Higher levels of financial toxicities were associated with patient characteristics such as lower socio-economic status and lack of insurance, as well as patient outcomes such as lower quality of life. Conclusion: Cancer patients in LMIC experience deleterious financial toxicities as a result of treatment. This comprehensive characterization of financial toxicities will better allow health systems to adopt evidence-based mitigation strategies to reduce the financial burden on patients. [ABSTRACT FROM AUTHOR]

Objective: This study aims at investigating the stressors that increased the risk of somatic symptoms in the general Chinese population. Methods: Chinese participants ( n = 202) were recruited in a population-based household survey. Somatic symptoms were measured by the Patient Health Questionnaire-15, while potential stressors that increased the risk of somatic symptoms were measured by the Perceived Stress Scale, Hospital Anxiety and Depression Scale, Insomnia Severity Index and ENRICHD Social Support Instrument. Results: Structured multiphase regression modeling showed that female gender (estimated coefficient = 1.47, 95 % CI .7-2.24, p < .001), history of childhood adversities (estimated coefficient = .41, 95 % CI .06-.76, p = .023), employed (estimated coefficient = .87, 95 % CI .003-1.74, p = .049), a high level of anxiety (estimated coefficient = .26, 95 % CI .17-.36, p < .001) and severe insomnia (estimated coefficient = .11, 95 % CI .04-.18, p = .003) are significant stressors for increasing the risks of somatic symptoms in the Chinese population. Conclusion: Physical and psychological symptoms are intertwined. It was recommended that reducing anxiety and improving sleep quality would be helpful to reduce somatic symptoms. These findings help in early identification and treatment of Chinese adults with persisting somatization. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic gastric cancer have poor survival outcomes and may experience high symptom burden. We evaluated symptom trajectory and risk factors for increased symptom severity among metastatic gastric cancer patients during the last 6 months of life. Methods: We conducted a retrospective cohort study among patients ≥ 18 years diagnosed with metastatic gastric cancer from January 2007 to December 2014 in the province of Ontario, Canada. We included patients who died during the study period and who reported at least one Edmonton Symptom Assessment System (ESAS) score during the last 6 months of life. We described the proportion of patients who reported moderate-to-severe symptom scores (≥ 4) by month. Multivariable logistic regression models were created to identify risk factors for moderate-to-severe symptom scores. Results: Seven hundred eighty-eight eligible patients with 3286 unique symptom scores completed during their last 6 months of life were identified. The highest prevalence of moderate-to-severe scores was observed for tiredness and lack of appetite, while nausea and depression had the lowest prevalence of elevated scores. The prevalence of moderate-to-severe was consistently high for all symptoms, particularly approaching end-of-life. Timing of ESAS scores, receipt of cancer-directed therapy, urban residence, and female sex were associated with increased odds of reporting moderate-to-severe symptom scores. Conclusion: Patients with metastatic gastric cancer experience significant symptom burden at the end-of-life. Routine screening with patient-reported outcome tools may assist in shared decision-making and effective palliative care by ensuring patients' health status and supportive care needs are identified promptly at the time of clinical encounters. [ABSTRACT FROM AUTHOR]

The 'real-world' patient population of metastatic melanoma is not fully represented in clinical trials investigating checkpoint inhibitors. We described therapy discontinuation in an unselected population-based cohort of adults with metastatic melanoma who started therapy with pembrolizumab, nivolumab, or nivolumab/ipilimumab from January 2015 to August 2017. Therapy discontinuation was defined as a gap between doses beyond 120 days, and/or initiation of another cancer therapy. We estimated drug-specific rate ratios for therapy discontinuation adjusted for age, sex, comorbidities, health care use, and past cancer therapies. We included 876 metastatic melanoma patients initiating pembrolizumab (44.3%), nivolumab/ipilimumab (31.2%), and nivolumab (24.5%). At 12 months of follow-up, the probabilities of therapy discontinuation were 49.9% (95% confidence interval, CI 43.6–56.5) for pembrolizumab, 58.8% (95% CI 50.5–67.3) for nivolumab, and 59.2% (95% CI 51.7–66.8) for nivolumab/ipilimumab. Stratified analyses based on prior cancer therapy, brain metastases at baseline, and sex showed similar trends. In multivariable analyses, compared with pembrolizumab, patients starting nivolumab (rate ratio 1.38, 95% CI 1.08–1.77) or nivolumab/ipilimumab (rate ratio 1.30, 95% CI 1.02–1.65) were more likely to discontinue therapy. Our findings indicate frequent discontinuations of checkpoint inhibitors at one year. The lower discontinuation associated with pembrolizumab should be confirmed in further studies. [ABSTRACT FROM AUTHOR]

Background: It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits. Methods: We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously. Results: Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30-0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68-0.96), docetaxel (OS HR 0.56, 95 % CR 0.33-0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52-0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care. Conclusions: This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials. [ABSTRACT FROM AUTHOR]

Purpose: Palonosetron, a 5-hydroxytryptamine 3 receptor antagonist (5-HTRA) with a strong binding affinity and long half-life, has been used in numerous trials for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). We systematically reviewed the efficacy and safety of palonosetron compared to other 5-HTRAs in CINV prophylaxis. Methods: A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing palonosetron to other 5-HTRAs in CINV prophylaxis. Primary endpoints were the percentage of patients achieving a complete response (CR), complete control (CC), no emesis, no nausea, or taking no rescue medications. Secondary endpoints were the percentage of patients suffering from 5-HTRA-related adverse events. Results: Sixteen RCTs were identified with 2,896 patients randomized to palonosetron and 3,187 patients randomized to other 5-HTRAs. Palonosetron was consistently statistically superior in CR, CC, no emesis, or no nausea and was sometimes superior in no rescue medication. Subgroup analyses demonstrated similarity in efficacy between highly and moderately emetogenic chemotherapy cohorts. In the acute phase, statistical superiority of palonosetron was found for trials that did not allow dexamethasone; conversely, RCTs that administered dexamethasone to all patients were nonsignificant. Palonosetron was statistically significantly safer in dizziness and mean QTc interval change and similar in constipation, headache, and diarrhea. Clinical superiority of palonosetron was reached in 3 of 19 analyzed efficacy and safety endpoints. Conclusions: Palonosetron is safer and more efficacious than other 5-HTRAs. Future antiemetic guidelines should discuss the merits of including palonosetron as a first-line treatment. [ABSTRACT FROM AUTHOR]

This study investigated the expression and methylation profiles of SOX2, a stem cell--related transcription factor, in placentas and gestational trophoblastic disease. The methylation status of SOX2 promoter region in 55 hydatidiform moles, 4 choriocarcinoma, 23 first trimester, and 15 term placentas was evaluated by methylation-specific polymerase chain reaction. The methylated allele was found in 4.4% (1/23) of first trimester placentas, 26.7% (4/15) term placentas, and 56.4% (31/55) of hydatidiform moles and all choriocarcinoma samples and cell lines. A significant reduction in SOX2 messenger RNA expression was found in the hydatidiform moles (P 1/4 .027) when compared with that in the placentas. SOX2 messenger RNA expression was significantly correlated with SOX2 hypermethylation (P < .001). SOX2 expression was restored in choriocarcinoma cell lines following treatment to 5-Aza -2'-deoxycytidine and/or Trichostatin A, demethylation and histone deacetylase inhibitors, respectively, and the response was synergistic. Epigenetic mechanisms may play important role on the transcriptional regulation of SOX2 and contribute to pathogenesis of gestational trophoblastic disease. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B is a major disease that causes serious public health problems worldwide. The loss of HBeAg expression due to point mutations or single nucleotide polymorphisms (SNPs) in the precore/basal core promoter region of the hepatitis B virus (HBV) is associated with hepatocellular cirrhosis and carcinoma. Simultaneous screening for these mutations is strongly advocated for monitoring disease development in HBV-infected patients. The aim of this study is to apply arrayed primer extension (APEX) for the detection of HBV SNPs at the precore/basal core promoter. Methods and results: We optimized APEX for simultaneous detection of eight potential sites of SNPs in the precore/basal core promoter region of HBV. The precore/basal core promoter regions of HBV from 36 HBV-infected patients were amplified by PCR. After purification and DNA fragmentation, the short, single-stranded HBV DNA fragments were allowed to hybridize with the oligonucleotides corresponding to the sites of SNPs immobilized on glass slides, followed by incorporation of different fluorescently labeled dideoxynucleotides. This allows fast and unequivocal discrimination between wild-type and mutant genotypes with high dideoxynucleotide incorporation efficiency, sensitivity, and specificity. The coexistence of both genotypes was also detected; this was undetected by DNA sequencing. Conclusion: The simultaneous detection of SNPs in HBV precore/basal core promoter by APEX enables large-scale diagnostic analysis, which can be extended to the whole HBV genome. [ABSTRACT FROM AUTHOR]

Developing bio-compatible smart materials that assemble in response to environmental cues requires strategies that can discriminate multiple specific stimuli in a complex milieu. Synthetic materials have yet to achieve this level of sensitivity, which would emulate the highly evolved and tailored reaction networks of complex biological systems. Here we show that the output of a naturally occurring network can be replaced with a synthetic material. Exploiting the blood coagulation system as an exquisite biological sensor, the fibrin clot end-product was replaced with a synthetic material under the biological control of a precisely regulated cross-linking enzyme. The functions of the coagulation network remained intact when the material was incorporated. Clot-like polymerization was induced in indirect response to distinct small molecules, phospholipids, enzymes, cells, viruses, an inorganic solid, a polyphenol, a polysaccharide, and a membrane protein. This strategy demonstrates for the first time that an existing stimulus-responsive biological network can be used to control the formation of a synthetic material by diverse classes of physiological triggers. [ABSTRACT FROM AUTHOR]