We evaluated the performance of seven existing risk scoring systems in predicting advanced colorectal neoplasia in an asymptomatic Chinese cohort. We prospectively recruited 5,899 Chinese subjects aged 50–70 years in a colonoscopy screening programme(2008–2014). Scoring systems under evaluation included two scoring tools from the US; one each from Spain, Germany, and Poland; the Korean Colorectal Screening(KCS) scores; and the modified Asia Pacific Colorectal Screening(APCS) scores. The c-statistics, sensitivity, specificity, positive predictive values(PPVs), and negative predictive values(NPVs) of these systems were evaluated. The resources required were estimated based on the Number Needed to Screen(NNS) and the Number Needed to Refer for colonoscopy(NNR). Advanced neoplasia was detected in 364 (6.2%) subjects. The German system referred the least proportion of subjects (11.2%) for colonoscopy, whilst the KCS scoring system referred the highest (27.4%). The c-statistics of all systems ranged from 0.56–0.65, with sensitivities ranging from 0.04–0.44 and specificities from 0.74–0.99. The modified APCS scoring system had the highest c-statistics (0.65, 95% C.I. 0.58–0.72). The NNS (12–19) and NNR (5-10) were similar among the scoring systems. The existing scoring systems have variable capability to predict advanced neoplasia among asymptomatic Chinese subjects, and further external validation should be performed.
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
codon bias; evolution of heterochromatin; gene size; melting characteristics; transposons
HIV-1 subtype B and CRF01_AE are the predominant infecting subtypes among men who have sex with men (MSM) in Singapore. The genetic history, population dynamics and pattern of transmission networks of these genotypes remain largely unknown. We delineated the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and the recently characterized CRF51_01B strains circulating among the MSM population in Singapore. A total of 105 (49.5%) newly-diagnosed treatment-naïve MSM were recruited between February 2008 and August 2009. Phylogenetic reconstructions of the protease gene (HXB2: 2239 – 2629), gp120 (HXB2: 6942 – 7577) and gp41 (HXB2: 7803 – 8276) of the env gene uncovered five monophyletic transmission networks (two each within subtype B and CRF01_AE and one within CRF51_01B lineages) of different sizes (involving 3 – 23 MSM subjects, supported by posterior probability measure of 1.0). Bayesian coalescent analysis estimated that the emergence and dissemination of multiple sub-epidemic networks occurred between 1995 and 2005, driven largely by subtype B and later followed by CRF01_AE. Exponential increase in effective population size for both subtype B and CRF01_AE occurred between 2002 to 2007 and 2005 to 2007, respectively. Genealogical estimates suggested that the novel CRF51_01B lineages were probably generated through series of recombination events involving CRF01_AE and multiple subtype B ancestors. Our study provides the first insight on the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and CRF51_01B viral strains circulating among MSM in Singapore.
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2874-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
c-Met represents an important emerging therapeutic target in cancer. Here, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation resulting in markedly inhibited growth and invasion of NPC cells. Strikingly, inhibition of c-Met resulted in marked downregulation of TIGAR (TP53-induced Glycolysis and Apoptosis Regulator) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in growth inhibition induced by c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings represent a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provides the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.
c-Met tyrosine kinase inhibitor; TIGAR; NADPH
The iminodiacetate dianion in the title compound, [Zn(C4H5NO4)(C12H8N2)(H2O)]·1.5H2O, chelates to the ZnII center with its N and two O atoms. The metal atom is also chelated by the N-heterocycle and coordinated by one water molecule, leading to a distorted octahedral environment. The dianion, and coordinated and uncoordinated water molecules interact through O—H⋯O hydrogen bonds, generating a three-dimensional network. One of the two uncoordinated water molecules has half-site occupancy. The crystal studied was a non-merohedral twin with a 15% twin component.
The iminodiacetate dianion in the title compound, [Co(C4H5NO4)(C12H8N2)(H2O)]·H2O, chelates to the cobalt(II) atom, its N and two O atoms occupying the fac sites of the distorted octahedron around the metal atom. The metal atom is also chelated by the N-heterocycle. The dianion, and coordinated and uncoordinated water molecules interact through hydrogen bonds, generating a layer motif. The crystal studied was a racemic twin with a 0.62 (2):0.38 (2) domain ratio.
This study developed a clinical scoring system to predict the risks of PN among screening participants for colorectal cancer. We recruited 5,789 Chinese asymptomatic screening participants who received colonoscopy in Hong Kong (2008–2014). From random sampling of 2,000 participants, the independent risk factors were evaluated for PN using binary regression analysis. The odds ratios for significant risk factors were used to develop a scoring system, with scores stratified into ‘average risk’ (AR):0–2 and ‘high risk’ (HR):3–5. The other 3,789 subjects formed an independent validation cohort. Each participant received a score calculated based on their risk factors. The performance of the scoring system was evaluated. The proportion of PN in the derivation and validation cohorts was 12.6% and 12.9%, respectively. Based on age, gender, family history, body mass index and self-reported ischaemic heart disease, 85.0% and 15.0% in the validation cohort were classified as AR and HR, respectively. Their prevalence of PN was 12.0% and 18.1%, respectively. Participants in the HR group had 1.51-fold (95% CI = 1.24–1.84, p < 0.001) higher risk of PN than the AR group. The overall c-statistics of the prediction model was 0.71(0.02). The scoring system is useful in predicting the risk of PN to prioritize patients for colonoscopy.
Increased myocardial triglyceride (TG) content has been recognized as a risk factor for cardiovascular disease. However, its relation with cardiac function in patients on recovery from acute heart failure (HF) remains unclear. In this cross-sectional study, we sought to investigate the association between myocardial TG content measured on magnetic resonance spectroscopy (1H-MRS) and left ventricular (LV) function assessed on cardiovascular magnetic resonance (CMR) in patients who were hospitalized with HF.
A total of 50 patients who were discharged after hospitalization for acute HF and 21 age- and sex-matched controls were included in the study. Myocardial TG content and LV parameters (function and mass) were measured on a 3.0 T MR scanner. Fatty acid (FA) and unsaturated fatty acid (UFA) content was normalized against water (W) using the LC-Model algorithm. The patient population was dichotomized according to the left ventricular ejection fraction (LVEF, <50 % or ≥ 50 %).
H-MRS data were available for 48 patients and 21 controls. Of the 48 patients, 25 had a LVEF <50 % (mean, 31.2 %), whereas the remaining 23 had a normal LVEF (mean, 60.2 %). Myocardial UFA/W ratio was found to differ significantly in patients with low LVEF, normal LVEF, and controls (0.79 % vs. 0.21 % vs. 0.14 %, respectively, p = 0.02). The myocardial UFA/TG ratio was associated with LV mass (r = 0.39, p < 0.001) and modestly related to LV end-diastolic volume (LVEDV; r = 0.24, p = 0.039). We also identified negative correlations of the myocardial FA/TG ratio with both LV mass (r = -0.39, p < 0.001) and LVEDV (r = -0.24, p = 0.039).
As compared with controls, patients who were discharged after hospitalization for acute HF had increased myocardial UFA content; furthermore, UFA was inversely related with LVEF, LV mass and, to a lesser extent, LVEDV. Our study may stimulate further research on the measure of myocardial UFA content by 1H-MRS for outcome prediction.
ClinicalTrial.gov: NCT02378402. Registered 27/02/2015
Electronic supplementary material
The online version of this article (doi:10.1186/s12968-016-0228-3) contains supplementary material, which is available to authorized users.
Heart failure; Left ventricular systolic function; Magnetic resonance spectroscopy; Myocardial triglyceride content; Cardiovascular magnetic resonance
The predictors of poor bowel preparation in colorectal cancer screening participants have not been adequately studied, and the association between the quality of bowel preparation and adenoma detection has not been firmly established. This study examined the determinants of poor bowel preparation, and evaluated its relationship with adenoma detection.
We included subjects aged between 50 and 70 years who received colonoscopy between 2008 and 2014 in a colorectal cancer screening program in Hong Kong. The quality of the bowel preparation was assessed by colonoscopists, and the factors associated with poor bowel cleansing were evaluated by a binary logistic regression analysis. A multivariate regression model was constructed to evaluate if poor bowel preparation was associated with detection of colorectal neoplasia.
From 5470 screening participants (average age 57.7 years, SD 4.9), 1891 (34.6%) had poor or fair bowel preparation. The average cecal intubation time was 7.0 minutes (SD 5.4; range 1.22–36.9 minutes) and the average colonoscopy withdrawal time was 10.8 minutes (SD 6.9; range 6.0–107.0 minutes). Among all, 26.5% had colorectal neoplasia and 5.5% had advanced neoplasia. Older age (≥60 years; adjusted odds ratio [AOR] = 1.19–1.38, P = 0.02–0.04), male sex (AOR = 1.38, 95% confidence interval [CI] 1.19–1.60, P < 0.001), and current smoking (AOR = 1.41, 95% CI 1.14–1.75, P = 0.002) were significantly associated with poor/fair bowel preparation. Poorer cleansing resulted in significantly lower detection rate of neoplasia (AOR = 0.35–0.62) and advanced neoplasia (AOR = 0.36–0.50) irrespective of polyp size.
Steps to improve proper procedures of bowel preparation are warranted, especially among subjects at risk of poor bowel preparation. Strategies should be implemented to improve bowel cleansing, which is now demonstrated as a definite quality indicator.
The Global Alliance for Chronic Diseases comprises the majority of the world’s public research funding agencies. It is focussed on implementation research to tackle the burden of chronic diseases in low- and middle-income countries and amongst vulnerable populations in high-income countries. In its inaugural research call, 15 projects were funded, focussing on lowering blood pressure-related disease burden. In this study, we describe a reflexive mapping exercise to identify the behaviour change strategies undertaken in each of these projects.
Using the Behaviour Change Wheel framework, each team rated the capability, opportunity and motivation of the various actors who were integral to each project (e.g. community members, non-physician health workers and doctors in projects focussed on service delivery). Teams then mapped the interventions they were implementing and determined the principal policy categories in which those interventions were operating. Guidance was provided on the use of Behaviour Change Wheel to support consistency in responses across teams. Ratings were iteratively discussed and refined at several group meetings.
There was marked variation in the perceived capabilities, opportunities and motivation of the various actors who were being targeted for behaviour change strategies. Despite this variation, there was a high degree of synergy in interventions functions with most teams utilising complex interventions involving education, training, enablement, environmental restructuring and persuasion oriented strategies. Similar policy categories were also targeted across teams particularly in the areas of guidelines, communication/marketing and service provision with few teams focussing on fiscal measures, regulation and legislation.
The large variation in preparedness to change behaviour amongst the principal actors across these projects suggests that the interventions themselves will be variably taken up, despite the similarity in approaches taken. The findings highlight the importance of contextual factors in driving success and failure of research programmes. Forthcoming outcome and process evaluations from each project will build on this exploratory work and provide a greater understanding of factors that might influence scale-up of intervention strategies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-015-0331-0) contains supplementary material, which is available to authorized users.
Implementation science; Hypertension; Behaviour change theory; Collaborative research; Low- and middle-income countries
Natural regulatory networks contain many interacting components that allow for fine-tuning of switching and memory properties. Building simple bistable switches, synthetic biologists have learned the design principles of complex natural regulatory networks. However, most switches constructed so far are so simple (e.g. comprising two regulators) that they are functional only within a limited parameter range. Here, we report the construction of robust, tunable bistable switches in Escherichia coli using three heterologous protein regulators (ExsADC) that are sequestered into an inactive complex through a partner swapping mechanism. On the basis of mathematical modeling, we accurately predict and experimentally verify that the hysteretic region can be fine-tuned by controlling the interactions of the ExsADC regulatory cascade using the third member ExsC as a tuning knob. Additionally, we confirm that a dual-positive feedback switch can markedly increase the hysteretic region, compared to its single-positive feedback counterpart. The dual-positive feedback switch displays bistability over a 106-fold range of inducer concentrations, to our knowledge, the largest range reported so far. This work demonstrates the successful interlocking of sequestration-based ultrasensitivity and positive feedback, a design principle that can be applied to the construction of robust, tunable, and predictable genetic programs to achieve increasingly sophisticated biological behaviors.
Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.
Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.
Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.
This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.
BDNF; breast cancer; cognition; genetics; rs6265
Paraneoplastic syndromes are rare first manifestations of breast cancer. In this report, we present two cases of a 58-year-old woman and a 69-year-old woman presenting with acute symptoms of paraneoplastic cerebellar degeneration (PCD) and dermatomyositis, respectively, as the first sign of breast malignancy. The patient diagnosed with PCD presented initially with ataxia, was serum anti-Yo antibody negative, and subsequently investigated to have poorly differentiated intraductal breast carcinoma. Cerebellar symptoms regressed following breast cancer surgery and chemotherapy, highlighting the better neurological prognosis associated with anti-Yo antibody negative PCD. The rarity of these presentations highlights the necessity to include an occult malignancy in the differential diagnosis when attending to such patients.
Breast cancer; Paraneoplastic; Cerebellar degeneration; Dermatomyositis
An international symposium for nanosafety was held recently at the Nanyang Technological University in Singapore. Topics relating to understanding nanomaterial properties, tools, and infrastructure required for predicting hazardous outcomes, measuring nanomaterial exposure levels, systems approach for risk assessment and public’s perception of nanotechnology were covered. The need for a multidisciplinary approach, across both natural and social sciences, for developing sustainable nanotechnology solutions was heavily emphasized. This commentary highlights the major issues discussed and the commitment of the nanosafety research community in Singapore to contribute collectively to realise the vision of sustainable nanotechnology.
Nanoparticles; nanotechnology; nanotoxicology; occupational health; risk assessment
New chemotherapeutic agents are urgently required to combat the global spread of multi-drug resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase, InhA, is one of the few clinically-validated targets in tuberculosis drug discovery. Here, we report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally-active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH-dependent manner and blocked the enoyl-substrate binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of infection by Mycobacterium tuberculosis. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.
During November 2012–July 2013, a marked increase of adenovirus type 7 (Ad7) infections associated with severe disease was documented among pediatric patients in Singapore. Phylogenetic analysis revealed close genetic links with severe Ad7 outbreaks in China, Taiwan, and other parts of Asia.
Human adenovirus; viruses; Ad7; outbreak; Asia; China; Singapore; Malaysia; invasive disease; death; mechanical ventilation
Frequent tumor relapse in hepatocellular carcinoma (HCC) has been commonly attributed to the presence of residual cancer stem cells (CSCs) after conventional treatments. We have previously identified and characterized CD133 to mark a specific CSC subset in HCC. In the present study, we found endogenous and secretory annexin A3 (ANXA3) to play pivotal roles in promoting cancer and stem cell-like features in CD133+ liver CSCs through a dysregulated JNK pathway. Blockade of ANXA3 with an anti-ANXA3 monoclonal antibody in vitro as well as in human HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, ANXA3 expression in HCC patient sera closely associated with aggressive clinical features. Our results suggest that ANXA3 can serve as a novel diagnostic biomarker and that the inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC.
•ANXA3 potentiates cancer and stem cell-like properties in CD133+ liver CSCs•ANXA3 is internalized via caveolae-mediated endocytosis and activates the JNK pathway•A novel neutralizing anti-ANXA3 antibody is developed•ANXA3 is a novel biomarker for HCC diagnosis
Ma and colleagues report the role of enhanced endogenous and secretory ANXA3 in the maintenance of cancer stem cell-like properties in CD133+ liver CSCs. ANXA3 is internalized via a caveolae-dependent endocytosis and activates the JNK pathway. Treatment of HCC with ANXA3 monoclonal antibody resulted in decreased tumor growth, self-renewal, and liver CSC proportions.
Traditional Chinese medicine (TCM) treatments are often prescribed based on individuals' pattern diagnoses. A systematic review of randomized controlled trials in Chinese and English literatures on TCM pattern-based treatment for depression has therefore been conducted. A total of 61 studies, 2504 subjects, and 27 TCM patterns were included. Due to the large variation of TCM pattern among participants, we only analyzed the top four commonly studied TCM patterns: liver qi depression, liver depression and spleen deficiency, dual deficiency of the heart, and spleen and liver depression and qi stagnation. We found that Xiaoyao decoction was the most frequently used herbal formula for the treatment of liver qi depression and liver depression with spleen deficiency, while Chaihu Shugan decoction was often used for liver depression and qi stagnation. Bai Shao (Paeonia lactiflora Pall.) and Chai Hu (Bupleurum chinense DC.) were commonly used across different TCM patterns regardless of the prescribed Chinese herbal formulas. The rationale underlying herb selection was seldom provided. Due to the limited number of studies on TCM pattern-based treatment of depression and their low methodological quality, we are unable to draw any conclusion regarding which herbal formulas have higher efficacy and which TCM patterns respond better to CHM.
This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.
A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.
444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.
The high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.
This is one of the largest multicentered, cohort studies conducted to evaluate the proinflammatory biomarkers associated with cognitive impairment in breast cancer patients.
While elevated interleukin (IL)-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment.
Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients.
Patients and methods
Chemotherapy-receiving breast cancer patients (stages I–III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte–macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder™) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain.
Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: −0.78; 95% confidence interval (CI) −1.34 to −0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022).
While elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.
breast cancer; cognitive disturbance; chemobrain; cytokines; cognitive impairment; FACT-Cog
Background: Gastrointestinal electromodulation therapy is a novel alternative for achieving diabetes control without traditional bariatric surgery. We compared the efficacy of a meal-initiated implantable gastric contractility modulation (GCM) device with that of insulin therapy in obese Chinese type 2 diabetes (T2D) patients, for whom oral antidiabetes drugs (OADs) had failed.
Patients and Methods: Sixteen obese (body mass index, 27.5–40.0 kg/m2) T2D patients with a glycated hemoglobin (HbA1c) level of >7.5% on maximal doses of two or more OADs were offered either insulin therapy (n=8) or laparoscopic implantation of a GCM (n=8). We compared changes in body weight, waist circumference (WC), and HbA1c level 1 year after surgery.
Results: The GCM and insulin groups had similar baseline body weight and HbA1c. At 12 months, body weight (−3.2±5.2 kg, P=0.043) and WC (−3.8±4.5 cm, P=0.021) fell in the GCM group but not in the insulin group (P<0.05 for between-group difference). At 6 and 12 months, the HbA1c level fell by 1.6±1.1% and 0.9±1.6% (P=0.011), compared with 0.6±0.3% and 0.6±0.3% (P=0.08) for the insulin group (P=0.15 for between-group difference). The mean 24-h systolic blood pressure (BP) fell by 4.5±1.0 mm Hg in the GCM group (P=0.017) but not in the insulin group. The GCM group required fewer antidiabetes medications (P<0.05) and BP-lowering drugs (P<0.05) than the insulin group. A subgroup analysis showed that patients with a triglyceride level of <1.7 mmol/L had a tendency toward a lower HbA1c level (P=0.090) compared with the controls.
Conclusions: In obese T2D patients for whom OADs had failed, GCM implantation was a well-tolerated alternative to insulin therapy, with a low triglyceride level as a possible predictor for glycemic response.
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: Does repeat thymectomy improve symptoms in patients with refractory myasthenia gravis after thymectomy? A total of 189 papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The outcome measures included operative mortality and morbidity, as well as long-term remission rate. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All the studies were small (4–21 patients), retrospective, single institutional case series. There was considerable heterogeneity in the studies. The interval between the first and second operation ranged from less than a year to over 10 years. The operative approach of the initial operation included transcervical, trans-sternal and substernal approaches. The maximal medical therapy received by the patients prior to reoperation varied from anticholinesterase alone to cytotoxic therapy and regular plasmapheresis. The severity of symptoms ranged from Osserman Class IIa to V. The operative approach to re-thymectomy included resternotomy, thoracoscopy and a combination of both. There was no perioperative mortality. One study reported injury to the innominate vein at resternotomy in 3 (14.3%) patients. One study reported myasthenic crisis in 2 patients in the postoperative period. Only one study reported complete remission in 2 patients. In general, however, 52–95% of patients reported some improvement. There was no consistent, objective measure of improvement in these studies. We conclude that repeat thymectomy for patients with refractory myasthenia gravis after previous thymectomy is safe especially for patients whose first procedure was transcervical. Complete remissions are rare but, in these small series, 60–70% of patients report improvement. Clinical improvement appears to be associated with the presence of residual thymic tissue at the second operation, but these cannot be reliably identified on preoperative imaging. Patient selection remains driven by symptoms.
Review; Myasthenia gravis; Thymectomy; Reoperations