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This study is aimed toward investigating the evolution of each Correa's step after Helicobacter pylori eradication in a long-term follow-up and exploring the factors correlated with a high-risk of gastric cancer.A total of 1824 H. pylori-infected subjects were enrolled to receive screening endoscopy. Among them, 491 received surveillance endoscopy. The patients were divided into Correa's steps I to VI, from normal to gastric cancer. A group-based trajectory model was used to classify patients as persistent high-risk status or not.The prevalence rates of positive corpus-predominant gastritis index (CGI) were 20%-40% in all age groups and Correa's steps IV-V increased35% after 50 years based on screening endoscopy. Successful eradication of H. pylori regressed CGI after the 1st year-and-thereafter (P 0.05) and decreased Correa's step progression (Relative risk 0.66 [95% CI 0.49-0.89], P = 0.01); however, it did not regress OLGA and OLGIM. Not only in steps IV-V, but also in step III, the patients had a risk of developing gastric cancer (11.13-76.41 and 4.61 per 1000 person-years). Age (Hazard ratio 1.012 [1.003-1.020], P = 0.01), OLGA stages ≥ I (2.127 [1.558-2.903], P 0.001), and OLGIM stages ≥ I (1.409 [1.119-1.774], P = 0.004) were correlated independently with a persistent high-risk status.The patients in Correa's steps III-V, but not I-II, were at risk of gastric cancer after H. pylori eradication. Age, OLGA stages ≥ I, and OLGIM stages ≥ I were independent factors correlated to a persistent high-risk of gastric cancer. The data may be useful when scheduling surveillance endoscopy for subjects in each Correa's step (NCT04527055).

Purpose: In this study, we evaluated the concordance of targeted sequencing results between paired ctDNA and tumor samples from early breast cancers scheduled for curative surgery with or without adjuvant therapy. If high concordance was observed, pre-operative ctDNA testing could serve as a non-invasive surrogate for variants meant to be revealed after definite surgery. On the other hand, poor concordance may hamper wide clinical absorption of liquid biopsy early breast cancer. Materials and Methods: The study VGH-TAYLOR: Comprehensive precision medicine research on the heterogeneity of Taiwanese breast cancer patients, consisted of three years enrollment and approximately four years follow-up after enrollment. Individual subject was assigned into Group 1 [planned to received surgery as first-line treatment and followed by adjuvant therapy, Group 2 [planned to receive neoadjuvant therapy as the first-line treatment and followed by surgery], and Group 3 [diagnosed with de novo and treatment naïve stage IV breast cancer, or stage IV breast cancer with recurrence beyond three years after surgery]. Molecular profiling and potential biomarkers were determined using Oncomine Comprehensive Assay v3 from FFPE tissues and Oncomine Breast cfDNA Assay v2 from plasma. Oncomine Comprehensive Assay is a targeted sequencing of NGS experiments were performed with TMO comprehensive using FFPE tissues, included 161 cancer-releant genes and types of mutation detected such as frameshift, missense, synonymous, SNV, Indel, and CNV. Oncomine Breast cfDNA Assay detects breast-derived cfDNA including hotspot genes: AKT1, EGFR, ERBB2, ERBB3, ESR1, FBXW7, KRAS, PIK3CA, SF3B1, TP53 (~152 hotspots), CNVs: CCND1, ERBB2, FGFR1, and full length TP53 (~80% coverage). Common genes interrogated by both ctDNA and TMO assay were identified, and concordance between paired targeted sequencing results from the same individuals were reported. Results: We reported the mutational landscape of initial 612 patients interrogated with the Oncomine Breast cfDNA assay; 239 out of 612 patients reported at least one mutation (39%). Among 246 patients assayed for both ctDNA and tumor tissue, cfDNA assay detected 73 (29.6%) and TMO comprehensive assay detected 201 (81.7%) breast cancers with at least one variant (c2 test, p=0.001). Sixty-seven (25.6%) were tested positive for both liquid and tissue assays, while cfDNA and TMO comprehensive assay detected additional 10 (4%) and 138 (56%) cases, which were not identified by the other platform. Table 1 details the distributions of called variants among common targeted genes. Conclusion: In current study, we evaluated the concordance of called variants between targeted sequencing from ctDNA and tumor tissue among an early breast cancer cohort in Taiwan. Only one-quarter of patients were positive for both cfDNA and TMO comprehensive assays from the same subject, indicating assay-specific sensitivity inevitably resulting in diagnostic discrepancy. Another plausible explanation came from the early stage nature of interrogated patients, which may inherit fewer ctDNA spillage from tumor and compromise detectability from liquid biopsy. The most prevalent mutant genes from both platforms were TP53 (68.3%) and KRAS (53.5%), both were well-known drivers in cancers. From breast cancer actionability, PIK3CA (39.4%) mutation is a biomarker for the FDA-approved PI3Ka inhibitor such as alpelisib, AKT1 (45.9%) mutation for agents such as capivasertib (AZD5363) and ipatasertib, and ERBB2 mutation for tyrosine kinase inhibitor such as neratinib. Our study showed that tumor should be the preferred source for targeted sequencing, and additional 4% of variants wound be revealed from liquid biopsy. Table 1. Distributions of variants from common targeted genes (n=6) from cfDNA and TMO comprehensive assay. Citation Format: Chi-Cheng Huang, Ling-Ming Tseng. Concordance of Targeted Sequencing from Circulating Tumor DNA and Paired Tumor Tissue [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-08.

Purpose Trastuzumab, a potent anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is conditionally reimbursed by the Taiwan National Health Insurance (NHI) for HER2-positive breast cancer (BC). Trastuzumab-induced cardiotoxicity studies have well characterized heart failure (HF) but fewer addressed arrhythmia, particularly the association of potential life threatening atrial fibrillation (Af) is poorly characterized. We aimed to study the trastuzumab-related risk of Af and HF using the claimed data of Taiwan NHI. Methods A nationwide retrospective cohort of patients with BC from the Taiwan NHI reimbursement database from January 2007 to December 2016 was analyzed. Propensity score matching and competing risk model analysis were used for adjusting confounding concurrent medication or comorbidities and competing events. The HF study was used to validate the method used. Results For Af, 12,472 trastuzumab users were matched with 12,472 non-trastuzumab users. For HF, 12,241 trastuzumab users and 12,241 non-users were enrolled. We found that trastuzumab users had significantly worse HF-free survival but not Af-free survival than non-trastuzumab users. In the competing risk analysis, the use of trastuzumab did not increase the risk of Af (hazard ratio [HR] 0.76, P = 0.0006) but was associated with HF (HR 1.19, P = 0.0052). The risk trends among stratifications by comorbidities and concurrent medication remained in similar directions for both Af and HF. Conclusion Trastuzumab in real-world practice was associated with an increased risk of HF, but was not associated with an increased risk of Af in BC patients. Trastuzumab-induced arrhythmogenic effects may be masked by concurrent heart-protecting measures, more prominent roles of comorbidities or concurrent medications under real-world settings. Further studies are required.

Periodontitis is a chronic disease associated with dental biofilm formation by bacteria. The primary clinical signs include plaque formation, gingivitis, gingival bleeding, and attachment loss. P-113, a 12-amino acid antimicrobial peptide, is derived from Histatin 5 (Hst5) secreted by the human parotid and submandibular salivary glands and has been reported to reduce plaque formation, gingivitis, and gingival bleeding. This study aimed to investigate the effect of P-113 on periodontal disease-associated bacteria and the relative abundance of bacteria using real-time polymerase chain reaction (real-time PCR) and Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Saliva samples were collected from participants for analyses. Real-time PCR results showed significant changes in the abundance of the periodontal disease-associated bacteria, Fusobacterium nucleatum and Tannerella forsythia, after the use of the P-113 mouthwash. After culturing in an anaerobic environment, MALDI-TOF MS analysis was performed. The results showed that the relative abundance of Streptococcus mitis decreased and that of beneficial Streptococcus salivarius increased after the use of the P-113 mouthwash. These results indicate the potential of P-113 mouthwash as a treatment that can influence the proportion of pathogens and probiotics to establish equilibrium in the salivary environment.

Side-channel resilience is a crucial feature when assessing whether a postquantum cryptographic proposal is sufficiently mature to be deployed. In this paper, we propose a generic and efficient adaptive approach to improve the sample complexity (i.e., the required number of traces) of plaintext-checking (PC) oracle-based sidechannel attacks (SCAs), a major class of key recovery chosen-ciphertext SCAs on lattice-based key encapsulation mechanisms (KEMs). This new approach is preferable when the constructed PC oracle is imperfect, which is common in practice, and its basic idea is to design new detection codes that can determine erroneous positions in the initially recovered secret key. These secret entries are further corrected with a small number of additional traces. This work benefits from the generality of PC oracle and thus is applicable to various schemes and implementations.Our main target is Kyber since it has been selected by NIST as the KEM algorithm for standardization. We instantiated the proposed generic attack on Kyber512 and then conducted extensive computer simulations against Kyber512 and FireSaber. We further mounted an electromagnetic (EM) attack against an optimized implementation of Kyber512 in the pqm4 library running on an STM32F407G board with an ARM Cortex-M4 microcontroller. These simulations and real-world experiments demonstrate that the newly proposed attack could greatly improve the state-of-the-art in terms of the required number of traces. For instance, the new attack requires only 41% of the EM traces needed in a majority-voting attack in our experiments, where the raw oracle accuracy is fixed.

Previously we had identified concurrent genes, which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is to discovery biomarkers not identifiable by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection.Thirty-one comparative genomic hybridization (CGH) and 83 GE microarrays were performed, with 29 breast cancers assayed from both platforms. Potential targets were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from CGH arrays. Concurrent genes and genes with significant GISTIC scores were used to derive the extended concurrent genes signature, which was consensus from leading edge analysis across all studies and a supervised partial least square (PLS) regression predictive model of disease-free survival was constructed.There were 1584 concurrent genes from 29 samples with both CGH and GE microarrays. Enriched concurrent genes sets for disease-free survival were identified independently from 83 GE arrays and another one with Han Chinese origin as well as three studies of Western origin. For five studies with disease-free survival follow up, prognostic discrepancy was observed between predicted high-risk and low-risk group patients.We concluded that through parallel analyses of CGH and GE microarrays, the proposed extended concurrent gene expression signature can identify biomarkers with prognostic values.

Infiltrative non-GBM gliomas are common primary intracranial malignancies, and postoperative adjuvant radiotherapy is recommended for most adult patients diagnosed with this disease to enhance local control and prolong intracranial progression-free survival (PFS). However, RT-related neurocognitive function (NCF) consequences should not be ignored. Early neurocognitive decline principally includes episodic memory, associated significantly with functions of the hippocampus. This prospective study aims to investigate the impact of adjuvant brain irradiation on neurocognitive performances and relevant oncological outcomes.Twenty-five patients with intracranial infiltrative non-GBM gliomas were enrolled when postoperative adjuvant RT was recommended. All recruited patients should receive baseline brain magnetic resonance imaging, and neuropsychological assessments before and 4 months after the RT course. A battery of neuropsychological measures, mainly including executive functions, memory, psychomotor speed and visuoconstructive ability, was used to evaluate NCFs of interest.Analyzing the delta values between post-irradiation and baseline NCF scores, we observed a robust trend reflecting cognitive stabilization rather than deterioration in almost all NCF. Both verbal and visual memory functions exhibited significant differences in the corresponding scaled scores (

Traumatic brain injury (TBI) patients with unconsciousness and normal initial head computed tomography (CT) present a clinical dilemma for physicians and neurosurgeons in the emergency department (ED). We recorded how long it took for patients to regain consciousness and evaluated the patients' characteristics.From 2018 to 2020, TBI patients with unconsciousness and normal initial head CT [Glasgow coma scale (GCS) score 13, negative CT scan and normal laboratory test results] were evaluated. Patients who regained consciousness were analyzed. Multivariate logistic regression (MLR) analyses were used to evaluate independent factors for regaining consciousness.A total of 77 patients were included in this study. Fifty-eight (75.3%) patients regained consciousness, most within one day (43.1%). Nineteen (24.7%) patients never regained consciousness. MLR analysis showed that initial GCS score (odds 1.85, p = 0.017), early airway protection in ED (odds 25.02, p = 0.018) and 72-h GCS score improvement by two points (odds 0.02, p = 0.001) were independent factors for regaining consciousness. Overall, 94.1% of patients who received early airway protection and improved 2 points in 72-h GCS score regained consciousness. The association between days to M5 status and days to M6 status (consciousness) was highly significant. Fewer days to M5 status were highly associated with needing fewer days to regain consciousness.For TBI patients with unconsciousness and normal initial head CT, a higher probability of regaining consciousness was observed in those who underwent early airway protection and who improved 2 points in 72-h GCS score. Regaining consciousness within a short period could be expected in patients with M5 status.

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease. This study was aimed at investigating the neuroprotective mechanisms of the ethyl acetate fraction of Terminalia chebula ethanol-soluble extract using PC12 cells treated with paraquat as a model system. The ethyl acetate fraction of T. chebula ethanol-soluble extract was prepared using 95% ethanol and ethyl acetate as described in our previous study. The neuroprotective potential of the ethyl acetate fraction of T. chebula ethanol-soluble extract was analyzed by evaluating the intracellular reactive oxygen species and calcium levels, apoptosis, caspase-3 and α-synuclein activities, as well as Bcl-2 and Bax expressions. The ethyl acetate fraction of T. chebula ethanol-soluble extract exhibited neuroprotective effects against paraquat-induced apoptosis in PC12 cells at concentrations ranging from 0.4 μg/mL to 0.6 μg/mL. The various neuroprotective mechanisms identified for the extract included reduction in reactive oxygen species levels; inhibition of increased calcium ion concentration; increased Bcl-2 expression; reduced Bax, caspase-3 and α-synuclein expression; and reduced nuclear shrinkage. This study elucidates the various mechanisms underlying the neuroprotective effects of the ethyl acetate fraction of T. chebula ethanol-soluble extract that may further aid the Parkinson’s disease pharmacological application of T. chebula.

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Colorectal cancer (CRC) is one of the most aggressive cancers with poor prognosis and high mortality. The study of the pathogenesis of CRC is a top priority in providing effective diagnostic and prognostic strategies for CRC. COPS3 protein is a subunit of the COP9 signaling body (CSN), which is closely associated with the development of multiple types of tumors. However, there are few studies on the role of COPS3 in colon adenocarcinoma (COAD). This study investigated the effects of COPS3 on proliferation, motility, and EMT of colorectal cancer cells and related mechanisms. COPS3 was highly expressed in COAD. The depletion of COPS3 suppressed the viability and stimulated the apoptosis of COAD cells. Depletion of COPS3 suppressed the motility and EMT process of COAD cells. Mechanically, we found that COPS3 could mediate MEK/ERK pathway and therefore affected the process of COAD cells. We thought that COPS3 could serve as a promising COAD target.

Social networks have become increasingly popular and are commonly used in everyday life. They also become the most convenient places to send information or receive advertisements. The multiplex network is an important study topic in social networks, in which many features could be appropriately represented in different layers. In this paper, we propose an approach to find the multiplex interaction relationships based on the action records of users on social networks. The multiplex user interactions are found and divided into three levels: high, normal and low. They are then used to check the friend and the follower relations such that users can find which friends or followers are active or not. In the experiments, the parameters are chosen based on Dunbar’s number, which is the number of social relationships that humans can have with high confidence. The results show the proposed approach is effective in helping users know the truly close friend relationships on a social network.

This paper proposed a framework called IAPA (Integrated Access Point Architecture) that applied an off-the-shelf AP (Access Point) device on WLAN (Wireless Local Area Network) as an IoT (Internet-of-Things) gateway to integrate Zigbee and Wifi. This Wifi-Zigbee AP (called WiZAP) has the advantages of low cost, small size and low power consumption. However, the coexistence of Wifi and Zigbee in unlicensed bands will introduce a serious data collision problem. In this paper, we propose a linear-time balance-first configuration strategy to adjust Wifi parameters to reduce data collision. A strategy to dynamically configure these parameters for MAC layer communication is also proposed. Experiments test the influence of network transmission in real application scenarios. Results show that our WiZAP can work efficiently with the coexistence of Wifi and Zigbee.

Recently, Zhang et al. proposed a lattice-based data outsourcing scheme with public integrity verification (DOPIV), which enables an original data owner to delegate a proxy to generate the signatures of data and outsource them to the cloud server. They employed a third party auditor (TPA) to check the integrity of the outsourced data and any TPA can verify the data integrity efficiently. Besides, DOPIV is claimed to achieve proxy-oriented secure data outsourcing as well as storage correctness guarantee. Unfortunately, we find that there may exist vulnerabilities in DOPIV which allows the cloud server to simply delete the received data without being noticed by the TPA. Fortunately, we have come up with a simple and efficient solution to thwart the proposed attack and our improved scheme maintains all the features claimed in DOPIV.

Purpose In this study we evaluated the concordance of targeted sequencing between paired circulating tumor DNA (ctDNA) and matched tumor samples from early breast cancers treated with curative intention. Most studies for liquid biopsy were performed for advanced disease, and we reported the scenario of early breast cancer. Materials and Methods The study VGH-TAYLOR comprised a subgroup of early-stage breast cancer. Molecular profiling was performed for both fresh-frozen paraffin-embedded (FFPE) tumor tissue and plasma using the Oncomine Comprehensive Assay v3 and the Oncomine Breast cfDNA Assay v2, respectively. Common genes interrogated by both platforms were identified, and concordance between paired targeted sequencing results from the same individual was reported. Results A total of 612 patients underwent liquid biopsy; 239 (39%) of which reported at least one mutation. Among 246 early-stage patients assayed for both ctDNA and matched tumor, cfDNA assay detected 73 (29.6%) and comprehensive assay detected 201 (81.7%) breast cancers with at least one alteration (c2 test, p = 0.001). Sixty-seven (25.6%) were tested positive for both platforms, while cfDNA and comprehensive assay detected additional 10 (4%) and 138 (56%) cases, respectively. The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while PIK3CA (39.4%), AKT1 (45.9%) and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Conclusion Only one-quarter of breast cancers were concordant between tumor and liquid biopsy from the same subject. Early-stage breast cancer might shed fewer ctDNA from tumor and compromise detectability of liquid biopsy. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers.

In recent years, the impact of climate change and extreme weather has not only expanded the scale of disasters, but also increased the frequency of disasters. In order to reduce the impact of natural disasters on cities, Making Cities Resilient (MCR) 2030 promoted by the international community has become an important issue. This study uses the "Ten Essentials" Toolkit for Resistant City constructed by the UNDRR to evaluate the disaster prevention and resilience capabilities of cities. However, the key to quantifying urban resilience is to link the indicators of the Disaster Resilience Scorecard with the operations of local government departments to strengthen urban resilience. Taking Taipei City as an example, this study uses the causal loop diagram (CLD) method to explore the business relationship between "Ten Essentials" and various bureaus, and builds a localized disaster resistance scorecard through expert meetings. CLD provides a visual map of the links between resilience indicators and local government operations, providing a clear conceptual model of operating resilient systems.It can be seen from the analysis results that through the questionnaire survey, Taipei City's disaster prevention and resilience capabilities have achieved satisfied results in various Essentials. Among them, "Organizational Resilience", "Enhancing Organizational Resilience and Disaster Resilience", "Increasing Infrastructure Resilience", and "Ensuring Effective Disaster Response" performed best. At the same time, it is necessary to continue to strengthen the actuarial calculation of disaster risks, enhance financial resilience through catastrophe funds, and implement various measures such as community disaster prevention and business continuity plans, so as to continue to strengthen Taipei's urban resilience in the future.

We reported few-photon detection and exciton binding-energy determination using tunneling-current spectroscopy of Ge-quantum dot (QD) single-hole transistors (SHTs) operating in the few-hole regime under 400 nm–1550 nm illumination. When the photon energy is smaller than the bandgap energy (1.46 eV) of the 20 nm Ge QD (for instance, under 1310 nm and 1550 nm illuminations), the peak voltage of tunneling current peaks remain intact even irradiation power is as high as mW. In contrast, 850 nm illumination (i.e., the photon energy is equal to the bandgap energy of the Ge QD) induces a considerable shift in the first hole-tunneling current peak towards positive VG (VG 0.08 V at 25.8 nW and 0.15 V at 112 nW) and even creates new additional photocurrent peaks at more positive VG (VG 0.2 V) at W irradiation. The abovementioned experimental observations were further strengthened for Ge-QD SHTs illuminated by 405 nm lasers with much lower power. The observed newly-photogenerated current peaks are ascribed to the interactions between few photoexcitons and single-hole tunneling within the Ge QD.

Calreticulin (CRT) is located in the endoplasmic reticulum (ER), it helps proteins fold correctly inside the ER, and acts as a modulator of Ca

BackgroundAdult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.MethodsEnvironmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.FindingsIn the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p2.5exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (pInterpretationThese results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.