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Global Lung Initiative 2012 spirometry reference values in a large Asian cohort of Malay, Chinese and Indian ancestry

Abdullah N, Borhanuddin B, Shah SA, Hassan T, Jamal R

Respirology, 2018 12;23(12):1173-1179.
PMID: 29790229 DOI: 10.1111/resp.13330

BACKGROUND AND OBJECTIVE: Although the multi-ethnic European Respiratory Society/Global Lung Initiative (ERS/GLI) 2012 reference values have been developed, the Taskforce has called for further validation specifically on subpopulations that were under represented such as the Malays, Chinese and Indians, in which the two latter ethnic groups represent about one-third of the world population. Thus, the aims of this study were to evaluate the appropriateness of the ERS/GLI 2012 reference values in a healthy adult Malaysian population and to construct a local lung function reference for the Malaysia population specific to the three major ethnic groups.

METHODS: Acceptable spirometry data were obtained from 30 281 healthy subjects aged 35-70 years comprising Malays, Chinese and Indians from the Malaysian Cohort. Local reference values were calculated using regression analysis and evaluated using ERS/GLI reference values to obtain GLI Z-scores.

RESULTS: The mean (SD) of the forced expiratory volume in 1 s (FEV1 ) for males were 2.67 (0.46), 2.89 (0.48) and 2.60 (0.46) and females were 1.91 (0.36), 2.13 (0.37) and 1.86 (0.35) for Malays, Chinese and Indians, respectively. For forced vital capacity (FVC), the mean (SD) for males were 3.03 (0.53), 3.28 (0.58) and 2.92 (0.53) and females were 2.15 (0.40), 2.38 (0.43) and 2.07 (0.41) for Malays, Chinese and Indians, respectively. The mean GLI Z-scores were less than -0.5 for FEV1 and FVC and more than 0.5 for FEV1 /FVC. A large percentage of subjects in all the three ethnic groups were defined lower than the lower limit of normal.

CONCLUSION: This present and large multi-ethnic Asian-based study demonstrates clinically significant deviation from ERS/GLI 2012 equations for spirometry. It highlights the importance of validating predicted equations for spirometry in local populations.
Fulltext Suture Granuloma 14 Years Following Partial Thyroidectomy Masquerading as Tuberculosis af The Sinus Tract

Abdul Hamid MF, Yu-Lin AB, Maharani Hassan T

Eurasian J Med, 2018 Jun;50(2):122-124.
PMID: 30002580 DOI: 10.5152/eurasianjmed.2018.0006

Suture granuloma rarely occurs after thyroid surgery using non-absorbable sutures. We report the case of a 63-year-old female with a chronic discharging sinus in the anterior neck region. She had a history of subtotal thyroidectomy at the age of 45. The sinus had been excised and was reported as granulomatous lesions suggestive of tuberculosis. She was treated with anti-tuberculous medications, but unfortunately, she developed side effects. Histopathological slides were re-evaluated, which showed evidence of foreign material under polarized light; hence, the diagnosis was revised to suture granuloma. In conclusion, although sinus tract discharges are commonly attributed to tuberculosis, physicians should consider suture granuloma if they encounter a patient who has undergone a surgical procedure in the past.
Fulltext Marijuana "bong" pseudomonas lung infection: a detrimental recreational experience

Kumar AN, Soo CI, Ng BH, Hassan T, Ban AY, Manap RA

Respirol Case Rep, 2018 02;6(2):e00293.
PMID: 29321937 DOI: 10.1002/rcr2.293

The use of Cannabis sativa, also known as marijuana, is believed to have dated back to thousands of years B.C. More than 200 decades later, it remains a popular recreational psychoactive substance that can be smoked through a water pipe. We report a case of marijuana smoking via a "bong" device, which has resulted in severe Pseudomonas aeruginosa necrotizing pneumonia treated with conservative medical therapy. This case highlights the importance of recognizing that life-threatening pneumonia can potentially be linked to marijuana and "bong" usage. Complicated cases should be considered for early surgical intervention.
Short communication: Diagnosis of lung cancer increases during the annual southeast Asian haze periods

Hassan A, Latif MT, Soo CI, Faisal AH, Roslina AM, Andrea YLB, et al.

Lung Cancer, 2017 11;113:1-3.
PMID: 29110834 DOI: 10.1016/j.lungcan.2017.08.025

There have been few but timely studies examining the role of air pollution in lung cancer and survival. The Southeast Asia haze is a geopolitical problem that has occurred annually since 1997 in countries such as Malaysia, Singapore and Indonesia. To date, there has been no study examining the impact of the annual haze in the presentation of lung cancer. Data on all lung cancers and respiratory admissions to Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 1st January 2010 to 31th October 2015 were retrospectively collected and categorized as presentation during the haze and non-haze periods defined by the Department of Environment Malaysia. We report a lung cancer incidence rate per week of 4.5 cases during the haze compared to 1.8 cases during the non-haze period (p<0.01). The median survival for subjects presenting during the haze was 5.2 months compared to 8.1 months for the non-haze period (p<0.05). The majority of subjects diagnosed during the haze period initially presented with acute symptoms. Although this study could not suggest a cause and effect relationship of the annual haze with the incidence of lung cancer, this is the first study reporting a local air pollution-related modifiable determinant contributing to the increase in presentation of lung cancer in Southeast Asia.
Fulltext Annual Southeast Asia haze increases respiratory admissions: A 2-year large single institution experience

Ming CR, Ban Yu-Lin A, Abdul Hamid MF, Latif MT, Mohammad N, Hassan T

Respirology, 2018 10;23(10):914-920.
PMID: 29923364 DOI: 10.1111/resp.13325

BACKGROUND AND OBJECTIVE: The Southeast Asia (SEA) haze is an annual problem and at its worst could produce respirable particles of concentrations up to 500 μg/m3 which is five times the level considered as 'unhealthy'. However, there are limited reports examining the direct clinical impact of the annual haze. This study examines the effects of the SEA haze on respiratory admissions.
METHODS: Data from all respiratory admissions in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 1st January 2014 to 31st December 2015 were collected retrospectively from chart and electronic database. A total of 16 weeks of haze period had been formally dated by the Department of Environment using the definition of weather phenomenon leading to atmospheric visibility of less than 10 km. Multivariable regression analyses were performed to estimate rate ratios and 95% CI.
RESULTS: There were 1968 subjects admitted for respiratory admissions in UKMMC during the study period. Incidence rates per week were significantly different between the two groups with 27.6 ± 9.2 cases per week during the haze versus 15.7 ± 6.7 cases per week during the non-haze period (P < 0.01). A total of 4% versus 2% was admitted to the intensive care unit in the haze and the non-haze groups, respectively (P = 0.02). The mean ± SD lengths of stay was 12.1 ± 5.2 days; the haze group had a longer stay (18.2 ± 9.7 days) compared to the non-haze groups (9.7 ± 3.9) (P < 0.001).
CONCLUSION: The annual SEA haze is associated with increased respiratory admissions.
Corrigendum to "Short communication: Diagnosis of lung cancer increases during the annual southeast Asian haze periods" [Lung Cancer 113 (2017) 1-3]

Hassan A, Latif MT, Soo CI, Faisal AH, Roslina AM, Ban Andrea YL, et al.

Lung Cancer, 2021 Apr;154:229.
PMID: 33678457 DOI: 10.1016/j.lungcan.2021.02.024
Challenges and future direction of molecular research in air pollution-related lung cancers

Shahadin MS, Ab Mutalib NS, Latif MT, Greene CM, Hassan T

Lung Cancer, 2018 04;118:69-75.
PMID: 29572006 DOI: 10.1016/j.lungcan.2018.01.016

Hazardous air pollutants or chemical release into the environment by a variety of natural and/or anthropogenic activities may give adverse effects to human health. Air pollutants such as sulphur dioxide (SO2), nitrogen oxides (NOx), carbon monoxide (CO), heavy metals and particulate matter (PM) affect number of different human organs, especially the respiratory system. The International Agency for Research on Cancer (IARC) reported that ambient air pollution is a cause of lung cancer. Recently, the agency has classified outdoor air pollution as well as PM air pollution as Group 1 carcinogens. In addition, several epidemiological studies have shown a positive association between air pollutants to lung cancer risks and mortality. However, there are only a few studies examining the molecular effects of air pollution exposure specifically in lung cancer due to multiple challenges to mimic air pollution exposure in basic experimentation. Another major issue is the lack of adequate adjustments for exposure misclassification as air pollution may differ temporo-spatially and socioeconomically. Thus, the purpose of this paper is to review the current molecular understanding of air pollution-related lung cancer and potential future direction in this challenging yet important research field.
Fulltext Alpha-1 antitrypsin augmentation therapy decreases miR-199a-5p, miR-598 and miR-320a expression in monocytes via inhibition of NFκB

Hassan T, de Santi C, Mooney C, McElvaney NG, Greene CM

Sci Rep, 2017 10 23;7(1):13803.
PMID: 29062067 DOI: 10.1038/s41598-017-14310-2

Alpha-1 antitrypsin (AAT) augmentation therapy involves infusion of plasma-purified AAT to AAT deficient individuals. Whether treatment affects microRNA expression has not been investigated. This study's objectives were to evaluate the effect of AAT augmentation therapy on altered miRNA expression in monocytes and investigate the mechanism. Monocytes were isolated from non-AAT deficient (MM) and AAT deficient (ZZ) individuals, and ZZs receiving AAT. mRNA (qRT-PCR, microarray), miRNA (miRNA profiling, qRT-PCR), and protein (western blotting) analyses were performed. Twenty one miRNAs were differentially expressed 3-fold between ZZs and MMs. miRNA validation studies demonstrated that in ZZ monocytes receiving AAT levels of miR-199a-5p, miR-598 and miR-320a, which are predicted to be regulated by NFκB, were restored to levels similar to MMs. Validated targets co-regulated by these miRNAs were reciprocally increased in ZZs receiving AAT in vivo and in vitro. Expression of these miRNAs could be increased in ZZ monocytes treated ex vivo with an NFκB agonist and decreased by NFκB inhibition. p50 and p65 mRNA and protein were significantly lower in ZZs receiving AAT than untreated ZZs. AAT augmentation therapy inhibits NFκB and decreases miR-199a-5p, miR-598 and miR-320a in ZZ monocytes. These NFκB-inhibitory properties may contribute to the anti-inflammatory effects of AAT augmentation therapy.
Fulltext Assessing the feasibility of confocal laser endomicroscopy in solitary pulmonary nodules for different part of the lungs, using either 0.6 or 1.4 mm probes

Hassan T, Thiberville L, Hermant C, Lachkar S, Piton N, Guisier F, et al.

PLoS One, 2017;12(12):e0189846.
PMID: 29267317 DOI: 10.1371/journal.pone.0189846

BACKGROUND: Malignant solitary pulmonary nodules (SPN) have become more prevalent, with upper lobes predilection. Probe-based confocal laser endomicroscopy (pCLE) provides in-vivo imaging of SPN. However, the stiffness of the 1mm confocal probe (AlveoFlex) causes difficult accessibility to the upper lobes. A thinner 600μm probe designed for bile duct exploration (CholangioFlex) has the potential to reach the upper lobes.
OBJECTIVES: To examine the accessibility of malignant SPNs in all segments of the lungs using either the 0.6mm or 1.4 mm probe and to assess the quality and inter observer interpretation of SPN confocal imaging obtained from either miniprobes.
METHODS: Radial(r)-EBUS was used to locate and sample the SPN. In-vivo pCLE analysis of the SPN was performed using either CholangioFlex (apical and posterior segments of the upper lobes) or AlveoFlex (other segments) introduced into the guide sheath before sampling. pCLE features were compared between the two probes.
RESULTS: Fourty-eight patients with malignant SPN were included (NCT01931579). The diagnostic accuracy for lung cancer using r-EBUS coupled with pCLE imaging was 79.2%. All the SPNs were successfully explored with either one of the probes (19 and 29 subjects for CholangioFlex and AlveoFlex, respectively). A specific solid pattern in the SPN was found in 30 pCLE explorations. Comparison between the two probes found no differences in the axial fibers thickness, cell size and specific solid pattern in the nodules. Extra-alveolar microvessel size appeared larger using CholangioFlex suggesting less compression effect. The kappa test for interobserver agreement for the identification of solid pattern was 0.74 (p = 0.001).
CONCLUSION: This study demonstrates that pCLE imaging of SPNs is achievable in all segments of both lungs using either the 0.6mm or 1.4mm miniprobe.
Fulltext Assessment of wind energy resource in the western region of Somaliland

Batran S, Jama M, Yousaf J, Hassan T, Ghazal M, Mokhlis HB

Heliyon, 2024 Jun 30;10(12):e32500.
PMID: 38994043 DOI: 10.1016/j.heliyon.2024.e32500

As the population of Somaliland continues to grow rapidly, the demand for electricity is anticipated to rise exponentially over the next few decades. The provision of reliable and cost-effective electricity service is at the core of the economic and social development of Somaliland. Wind energy might offer a sustainable solution to the exceptionally high electricity prices. In this study, a techno-economic assessment of the wind energy potential in some parts of the western region of Somaliland is performed. Measured data of wind speed and wind direction for three sites around the capital city of Hargeisa are utilized to characterize the resource using Weibull distribution functions. Technical and economic performances of several commercial wind turbines are examined. Out of the three sites, Xumba Weyne stands out as the most favorable site for wind energy harnessing with average annual power and energy densities at 80 m hub height of 317 kW/m2 and 2782 kWh/m2, respectively. Wind turbines installed in Xumba Weyne yielded the lowest levelized cost of electricity (LCOE) of not more than 0.07 $/kWh, shortest payback times (i.e., less than 7.2 years) with minimum return on investment (ROI) of approximately 150%.
Fulltext Cluster Analysis Evaluating PM2.5, Occupation Risk and Mode of Transportation as Surrogates for Air-pollution and the Impact on Lung Cancer Diagnosis and 1-Year Mortality

Abdul Wahab S, Hassan A, Latif MT, Vadiveel Y, Jeyabalan T, Soo CI, et al.

Asian Pac J Cancer Prev, 2019 07 01;20(7):1959-1965.
PMID: 31350951 DOI: 10.31557/APJCP.2019.20.7.1959

Objective: Epidemiological studies have reported the close relationship between risk for lung cancers and air pollution
in particular, for non-smoking related lung cancers. However, most studies used residential address as proxies which may
not estimate accurately an individual’s air pollution exposure. Therefore, the aim of this study was to identify risk factors
such as occupation and mode of transportation associated with lung cancer diagnosis and death. Methods: Subjects
with lung cancer (n=514) were evaluated both by chart reviews for clinical data and interviews to determine residential
address for ten years, main occupation and main mode of transportation. Annual particulate matter with diameter size
less than 2.5 micrometre (PM2.5) concentration were calculated based on particulate matter with diameter size less than
10 micrometre (PM10) data recorded by Malaysian Department of Environment. Logistic regression analysis, cluster
analysis and the Cox regression analysis were performed to the studied variables. Results: This study concurred with
previous studies that lung adenocarcinoma were diagnosed in predominantly younger, female non-smokers compared
to the other types of lung cancers. Lung adenocarcinoma subjects had annual PM2.5 that was almost twice higher than
squamous cell carcinoma, small cell carcinoma and other histological subtypes (p=0.024). Independent of smoking,
the κ -means cluster analysis revealed two clusters in which the high risk cluster involves occupation risk with air
pollution of more than four hours per day, main transportation involving motorcycle and trucks and mean annual PM2.5
concentration of more than 30 based on residential address for more than ten years. The increased risk for the high-risk
cluster was more than five times for the diagnosis of lung adenocarcinoma (OR=5.69, 95% CI=3.14-7.21, p<0.001).
The hazard ratio for the high-risk cluster was 3.89 (95% CI=2.12-4.56, p=0.02) for lung adenocarcinoma mortality at
1 year. Conclusion: High-risk cluster including PM2.5, occupation risk and mode of transportation as surrogates for
air-pollution exposure was identified and highly associated with lung adenocarcinoma diagnosis and 1-year mortality.
Microcrystalline cellulose: Isolation, characterization and bio-composites application-A review

Trache D, Hussin MH, Hui Chuin CT, Sabar S, Fazita MR, Taiwo OF, et al.

Int J Biol Macromol, 2016 Dec;93(Pt A):789-804.
PMID: 27645920 DOI: 10.1016/j.ijbiomac.2016.09.056

Considering its widespread usage in various fields, such as food, pharmaceutical, medical, cosmetic and polymer composites industries, microcrystalline cellulose (MCC) is becoming impellent due to increasing demand of alternatives to non-renewable and scarce fossil materials. Although it still suffers from some drawbacks, MCC has recently gained more interest owing to its renewability, non-toxicity, economic value, biodegradability, high mechanical properties, high surface area and biocompatibility. New sources, new isolation processes, and new treatments are currently under development to satisfy the increasing demand of producing new types of MCC-based materials on an industrial scale. Therefore, this review assembles the current knowledge on the isolation of MCC from different sources using various procedures, its characterization, and its application in bio-composites. Challenges and future opportunities of MCC-based composites are discussed as well as obstacles remaining for their extensive uses.
Lignin nanoparticles-reduced graphene oxide based hydrogel: A novel strategy for environmental applications

Sohni S, Hassan T, Khan SB, Akhtar K, Bakhsh EM, Hashim R, et al.

Int J Biol Macromol, 2023 Jan 15;225:1426-1436.
PMID: 36436599 DOI: 10.1016/j.ijbiomac.2022.11.200

In this work, facile fabrication of lignin nanoparticles (LNP)-based three-dimensional reduced graphene oxide hydrogel (rGO@LNP) has been demonstrated as a novel strategy for environmental applications. Herein, LNP were facilely synthesized from walnut shell waste through a direct chemical route. These LNP were incorporated into the continuous porous network of rGO network to fabricate rGO@LNP hydrogel. Characterization studies were carried out using various analytical techniques viz. scanning electron microscopy, Fourier transform IR spectroscopy, X-ray diffraction and thermogravimetric analysis. The efficiency of rGO@LNP hydrogel as adsorptive platform was evaluated by employing methylene blue and Pb2+ as model pollutants, whilst the effect of various experimental parameters was ascertained for optimal performance. Furthermore, Agar well diffusion method was used to check the antibacterial activities of the hydrogel using two bacterial pathogenic strains, i.e. Klebsiella pneumoniae (gram negative) and Enterococcus faecalis (gram positive). Results showed that after the inclusion of LNP into rGO hydrogel, there was a marked improvement in pollutant's uptake ability and compared to bare LNP and rGO, the composite hydrogel showed enhanced bactericidal effect. Overall, this approach is outstanding because of the synergy of functional properties of nano-lignin and rGO due to multi-interaction sites in the resulting hydrogel. The results presented herein support the application of rGO@LNP as innovative water filter material for scavenging broad spectrum pollutants and bactericidal properties.
Communication about positive BRCA1 and BRCA2 genetic test results and uptake of testing in relatives in a diverse Asian setting

Lee DS, Meiser B, Mariapun S, Hassan T, Yip CH, Mohd Taib NA, et al.

J Genet Couns, 2021 Jun;30(3):720-729.
PMID: 33245177 DOI: 10.1002/jgc4.1360

The vast majority of studies assessing communication of BRCA1/2 results with relatives and family uptake of BRCA1/2 testing have been conducted in Western societies, and a dearth of studies have been conducted in Asia among relatives of diverse carriers of pathogenic BRCA1/2 germline variants. This study aimed to present rates of BRCA1/2 result disclosure by probands and probands' motivators and barriers of family communication and predictive testing uptake among eligible relatives. It also examined patterns of disclosure and testing uptake among different types of relatives. Eighty-seven carriers with either breast or ovarian cancer, who had previously been found to be carriers of a pathogenic variant in BRCA1/2, were interviewed over the phone using a semi-structured interview guide. Fifty-six percent of patients were Chinese, 21% were Indian, and 23% were Malay. It was found that 62.0% of eligible first- and second-degree relatives were informed by the proband about the testing result and that 11.5% of eligible first- and second-degree relatives had genetic testing. First-degree relatives were more likely to have been informed and tested compared to second-degree relatives, as were sisters compared to brothers. The low rates of family communication and testing uptake documented in this study suggest that interventions should focus on encouraging probands to inform male and second-degree relatives and targeting such relatives to increase informed decisions and accessibility to testing. Promotion strategies should be culturally sensitive to optimize outcomes.
Mainstreaming genetic counselling for genetic testing of BRCA1 and BRCA2 in ovarian cancer patients in Malaysia (MaGiC study)

Yoon SYY, Ahmad Bashah NS, Wong SW, Mariapun S, Padmanabhan H, Hassan T, et al.

Ann Oncol, 2018 Nov;29 Suppl 9:ix176.
PMID: 32177935 DOI: 10.1093/annonc/mdy483.004
Fulltext A case-control study of breast cancer risk factors in 7,663 women in Malaysia

Tan MM, Ho WK, Yoon SY, Mariapun S, Hasan SN, Lee DS, et al.

PLoS One, 2018;13(9):e0203469.
PMID: 30216346 DOI: 10.1371/journal.pone.0203469

BACKGROUND: Breast cancer risk factors have been examined extensively in Western setting and more developed Asian cities/countries. However, there are limited data on developing Asian countries. The purpose of this study was to examine breast cancer risk factors and the change of selected risk factors across birth cohorts in Malaysian women.
METHODS: An unmatched hospital based case-control study was conducted from October 2002 to December 2016 in Selangor, Malaysia. A total of 3,683 cases and 3,980 controls were included in this study. Unconditional logistic regressions, adjusted for potential confounding factors, were conducted. The breast cancer risk factors were compared across four birth cohorts by ethnicity.
RESULTS: Ever breastfed, longer breastfeeding duration, a higher soymilk and soy product intake, and a higher level of physical activity were associated with lower risk of breast cancer. Chinese had the lowest breastfeeding rate, shortest breastfeeding duration, lowest parity and highest age of first full term pregnancy.
CONCLUSIONS: Our study shows that breastfeeding, soy intake and physical activity are modifiable risk factors for breast cancer. With the increasing incidence of breast cancer there is an urgent need to educate the women about lifestyle intervention they can take to reduce their breast cancer risk.
Fulltext Immunological corollary of the pulmonary mycobiome in bronchiectasis: the CAMEB study

Mac Aogáin M, Chandrasekaran R, Lim AYH, Low TB, Tan GL, Hassan T, et al.

Eur Respir J, 2018 07;52(1).
PMID: 29880655 DOI: 10.1183/13993003.00766-2018

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a "research priorities" consensus statement for bronchiectasis.Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S-28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes.The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and ClavisporaAspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations.The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients.
Distinct "Immunoallertypes" of Disease and High Frequencies of Sensitization in Non-Cystic Fibrosis Bronchiectasis

Mac Aogáin M, Tiew PY, Lim AYH, Low TB, Tan GL, Hassan T, et al.

Am J Respir Crit Care Med, 2019 04 01;199(7):842-853.
PMID: 30265843 DOI: 10.1164/rccm.201807-1355OC

RATIONALE: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear.
OBJECTIVES: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis.
METHODS: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined.
MEASUREMENTS AND MAIN RESULTS: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome.
CONCLUSIONS: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.
Fulltext Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer

Sullivan T, Thirthagiri E, Chong CE, Stauffer S, Reid S, Southon E, et al.

Hum Mutat, 2021 Feb;42(2):200-212.
PMID: 33314489 DOI: 10.1002/humu.24154

The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.
Fulltext Predicting the Likelihood of Carrying a BRCA1 or BRCA2 Mutation in Asian Patients With Breast Cancer

Ang BH, Ho WK, Wijaya E, Kwan PY, Ng PS, Yoon SY, et al.

J Clin Oncol, 2022 May 10;40(14):1542-1551.
PMID: 35143328 DOI: 10.1200/JCO.21.01647

PURPOSE: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women.
METHODS: In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration.
RESULTS: Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non-BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% (P value = .003), thereby improving the overall efficacy.
CONCLUSION: Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.

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