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"Lam, H. K"
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Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.
Gioblastoma tumours consist of different niches defined by histology. Here, the authors use proteomics and machine learning to assign protein expression programs to these niches, and reveal that KRAS and hypoxia are associated with drug resistance.
Journal Article
Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank Cohort Study
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in China, where the population is also exposed to high levels of passive smoking, yet little information exists on the effects of such exposure on COPD. We examined the relation between passive smoking and COPD and respiratory symptoms in an adult Chinese population.
We used baseline data from the Guangzhou Biobank Cohort Study. Of 20 430 men and women over the age of 50 recruited in 2003–06, 15 379 never smokers (6497 with valid spirometry) were included in this cross-sectional analysis. We measured passive smoking exposure at home and work by two self-reported measures (density and duration of exposure). Diagnosis of COPD was based on spirometry and defined according to the GOLD guidelines.
There was an association between risk of COPD and self-reported exposure to passive smoking at home and work (adjusted odds ratio 1·48, 95% CI 1·18–1·85 for high level exposure; equivalent to 40 h a week for more than 5 years). There were significant associations between reported respiratory symptoms and increasing passive smoking exposure (1·16, 1·07–1·25 for any symptom).
Exposure to passive smoking is associated with an increased prevalence of COPD and respiratory symptoms. If this association is causal, we estimate that 1·9 million excess deaths from COPD among never smokers could be attributable to passive smoking in the current population in China. Our findings provide strong evidence for urgent measures against passive smoking in China.
Journal Article
Ultrasound-guided dry needling versus traditional dry needling for patients with knee osteoarthritis: A double-blind randomized controlled trial
To compare the effect of ultrasound (US)-guided dry needling (DN) with traditional DN in the treatment of pain and dysfunction for patients with knee osteoarthritis (KOA). A double-blind, randomized controlled trial. Eighty-four participants (61.26±5.57 years) completed the study. G1 achieved significant improvement in VAS at 8 weeks compared to G2 and G3 (G1 vs. G2: MD = -15.61, 95% CI [-25.49, -5.51], p = 0.001; G1 vs. G3: MD = -19.90, 95% CI [-29.71, -10.08], p< 0.001). G1 achieved significant improvement in KOOS-pain at 8 weeks compared to G2 and G3 (G1 vs. G2: MD = 9.76, 95% CI [2.38, 17.14], p = 0.006; G1 vs. G3: MD = 9.48, 95% CI [2.31, 16.66], p = 0.010). KOOS-symptoms and KOOS-QoL were not statistically significant between groups. G2 had no significant difference of the perceptions as G1 with p = 0.128. G2 were successfully blinded to placebo US-guided DN. US-guided DN with exercise therapy may be more effective than traditional DN with exercise therapy or exercise therapy alone in reduce pain of KOA.
Journal Article
Finding Reliable Shortest Paths in Road Networks Under Uncertainty
The aim of this study is to investigate the solution algorithm for solving the problem of determining reliable shortest paths in road networks with stochastic travel times. The availability of reliable shortest paths enables travelers, in the face of travel time uncertainty, to plan their trips with a pre-specified on-time arrival probability. In this study, the reliable shortest path between origin and destination nodes is determined using a multiple-criteria shortest path approach when link travel times follow normal distributions. The dominance conditions involved in such problems are established, thereby reducing the number of generated non-dominated paths during the search processes. Two solution algorithms, multi-criteria label-setting and A* algorithms, are proposed and their complexities analyzed. Computational results using large scale networks are presented. Numerical examples using data from a real-world advanced traveller information system is also given to illustrate the applicability of the solution algorithms in practice.
Journal Article
Estimation of the value of travel time and of travel time reliability for heterogeneous drivers in a road network
Travel time reliability has been recognized as an important factor in cost–benefit analysis in a transportation network. To estimate the benefit and cost of travel time reliability, several network models have been proposed to estimate the monetary values both of travel time and of travel time reliability based on the driver’s route choice behavior. In this study, we propose a network model that addresses monetary values that are specific to each origin–destination pair in a road network. The proposed model is formulated as a utility maximization problem with constraints in a manner similar to studies that address the value of travel time only. The proposed model has the same equilibrium conditions as a multiclass user equilibrium traffic assignment problem with elastic demand in which the risk-averse driver’s route choice behavior is explicitly considered. By accounting for data availability, we propose a parameter estimation method based on the maximum likelihood method with two alternative approaches; namely link flow-based and route flow-based approaches. However, the two proposed methods require link flow data only. Numerical experiments are carried out to demonstrate the performance of the two proposed methods together with some insightful findings.
Journal Article
Effects of subjective successful aging on emotional and coping responses to the COVID-19 pandemic
Background
Middle-aged and older adults are more vulnerable to hospitalization and mortality if they are infected with the COVID-19 virus. The present study investigates the longitudinal effects of subjective successful aging on middle-aged and older adults’ emotional and coping responses to the COVID-19 pandemic, and explores an underlying mechanism through perceived time limitation during the pandemic.
Methods
A sample of 311 Hong Kong Chinese middle-aged and older adults (
M
age
= 64.58,
SD
= 10.14, Range = 45–90 years) were recruited from an Adult Development and Aging Project and participated in a questionnaire study via an online platform or phone interview. Their levels of subjective successful aging, perceived time limitation, and emotional and coping responses to the pandemic were measured.
Results
The respondents who perceived themselves as more successful in aging process reported more positive and fewer negative emotions compared with their counterparts with lower levels of subjective successful aging. The mediation analysis showed that perceived time limitation could partially account for the effects of subjective successful aging on emotional and coping responses.
Conclusions
Findings of this study unveil the beneficial effects of subjective views of successful aging on emotional and coping responses to the pandemic through alleviating their perception of time limitation.
Journal Article
A network equilibrium approach for modelling activity-travel pattern scheduling problems in multi-modal transit networks with uncertainty
An understanding of the interaction between individuals’ activities and travel choice behaviour plays an important role in long-term transit service planning. In this paper, an activity-based network equilibrium model for scheduling daily activity-travel patterns (DATPs) in multi-modal transit networks under uncertainty is presented. In the proposed model, the DATP choice problem is transformed into a static traffic assignment problem by constructing a new super-network platform. With the use of the new super-network platform, individuals’ activity and travel choices such as time and space coordination, activity location, activity sequence and duration, and route/mode choices, can be simultaneously considered. In order to capture the stochastic characteristics of different activities, activity utilities are assumed in this study to be time-dependent and stochastic in relation to the activity types. A concept of DATP budget utility is proposed for modelling the uncertainty of activity utility. An efficient solution algorithm without prior enumeration of DATPs is developed for solving the DATP scheduling problem in multi-modal transit networks. Numerical examples are used to illustrate the application of the proposed model and the solution algorithm.
Journal Article
A Stochastic Vehicle Routing Problem with Travel Time Uncertainty: Trade-Off Between Cost and Customer Service
On-time shipment delivery is critical for just-in-time production and quick response logistics. Due to uncertainties in travel and service times, on-time arrival probability of vehicles at customer locations can not be ensured. Therefore, on-time shipment delivery is a challenging job for carriers in congested road networks. In this paper, such on-time shipment delivery problems are formulated as a stochastic vehicle routing problem with soft time windows under travel and service time uncertainties. A new stochastic programming model is proposed to minimize carrier’s total cost, while guaranteeing a minimum on-time arrival probability at each customer location. The aim of this model is to find a good trade-off between carrier’s total cost and customer service level. To solve the proposed model, an iterated tabu search heuristic algorithm was developed, incorporating a route reduction mechanism. A discrete approximation method is proposed for generating arrival time distributions of vehicles in the presence of time windows. Several numerical examples were conducted to demonstrate the applicability of the proposed model and solution algorithm.
Journal Article
Niche deconvolution of the glioblastoma proteome reveals a distinct infiltrative phenotype within the proneural transcriptomic subgroup
Glioblastoma is often subdivided into three transcriptional subtypes (classical, proneural, mesenchymal) based on bulk RNA signatures that correlate with distinct genetic and clinical features. Potential cellular-level differences of these subgroups, such as the relative proportions of glioblastoma’s hallmark histopathologic features (e.g. brain infiltration, microvascular proliferation), may provide insight into their distinct phenotypes but are, however, not well understood. Here we leverage machine learning and reference proteomic profiles derived from micro-dissected samples of these major histomorphologic glioblastoma features to deconvolute and estimate niche proportions in an independent proteogenomically-characterized cohort. This approach revealed a strong association of the proneural transcriptional subtype with a diffusely infiltrating phenotype. Similarly, enrichment of a microvascular proliferation proteomic signature was seen within the mesenchymal subtype. This study is the first to link differences in the cellular pathology signatures and transcriptional profiles of glioblastoma, providing potential new insights into the genetic drivers and poor treatment response of specific subsets of glioblastomas.
Journal Article