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Article ; Online: Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery.

Lee, Caleb S / Leong, Kam W

2020 Volume 66, Page(s) 78–87

Abstract: Though the blood-brain barrier (BBB) is vital for the maintenance of brain homeostasis, it also accounts for a high attrition rate of therapies targeting the central nervous system (CNS). The challenge of delivery across the BBB is attributed to a ... ...

Abstract	Though the blood-brain barrier (BBB) is vital for the maintenance of brain homeostasis, it also accounts for a high attrition rate of therapies targeting the central nervous system (CNS). The challenge of delivery across the BBB is attributed to a combination of low permeability through an endothelium closely knit by tight and adherens junctions, extremely low rates of endothelial transcytosis, and efflux transporters. In the past decade, enormous research efforts have been spent to develop BBB penetration strategies using biochemical or physical stimuli, aided by BBB-on-chips or microphysiological BBB models to facilitate in vitro studies. Here, we discuss recent advances in BBB-chip technology that have enabled effective preclinical screenings of brain targeting therapeutics and external stimulation, such as sonoporation and electroporation, for improved BBB penetration.
MeSH term(s)	Biological Transport ; Blood-Brain Barrier ; Brain ; Drug Delivery Systems ; Pharmaceutical Preparations
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2020-07-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2020.06.009
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Zs.A 3071: Show issues

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Article ; Online: Efficacy of Wolbachia-mediated sterility to reduce the incidence of dengue: a synthetic control study in Singapore.

Lim, Jue Tao / Bansal, Somya / Chong, Chee Seng / Dickens, Borame / Ng, Youming / Deng, Lu / Lee, Caleb / Tan, Li Yun / Chain, Grace / Ma, Pei / Sim, Shuzhen / Tan, Cheong Huat / Cook, Alex R / Ng, Lee Ching

The Lancet. Microbe

2024

Abstract: Background: Due to the absence of available therapeutics and good vaccines, vector control solutions are needed to mitigate the spread of dengue. Matings between male Aedes aegypti mosquitoes infected with the wAlbB strain of Wolbachia and wildtype ... ...

Abstract	Background: Due to the absence of available therapeutics and good vaccines, vector control solutions are needed to mitigate the spread of dengue. Matings between male Aedes aegypti mosquitoes infected with the wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected A aegypti male mosquitoes to suppress dengue incidence. Methods: In this synthetic control study, we conducted large-scale field trials in Singapore involving release of wAlbB-infected A aegypti male mosquitoes for dengue control via vector population suppression, from epidemiological week (EW) 27, 2018, to EW 26, 2022. We selected two large towns (Yishun and Tampines) to adopt an expanding release strategy and two smaller towns (Bukit Batok and Choa Chu Kang) to adopt a targeted-release approach. Releases were conducted two times a week in high-rise public housing estates. All intervention and control locations practised the same baseline dengue control protocol. The main outcome was weekly dengue incidence rate caused by any dengue virus serotype. We used incidence data collected by the Singapore Ministry of Health to assess the efficacy of the interventions. To compare interventions, we used the synthetic control method to generate appropriate counterfactuals for the intervention towns using a weighted combination of 30 control towns between EW 1, 2014 and EW 26, 2022. Findings: Our study comprised an at-risk population of 607 872 individuals living in intervention sites and 3 894 544 individuals living in control sites. Interventions demonstrated up to 77·28% (121/156, 95% CI 75·81-78·58) intervention efficacy despite incomplete coverage across all towns until EW 26, 2022. Intervention efficacies increased as release coverage increased across all intervention sites. Releases led to 2242 (95% CI 2092-2391) fewer cases per 100 000 people in intervention sites during the study period. Secondary analysis showed that these intervention effects were replicated across all age groups and both sexes for intervention sites. Interpretation: Our results demonstrated the potential of Wolbachia-mediated incompatible insect technique for strengthening dengue control in tropical cities, where dengue burden is the greatest. Funding: Singapore Ministry of Finance, Ministry of Sustainability, and the National Environment Agency, and the Singapore National Robotics Program.
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Journal Article
ISSN	2666-5247
ISSN (online)	2666-5247
DOI	10.1016/S2666-5247(23)00397-X
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Article ; Online: Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies.

Takahashi, Shunji / Bando, Hideaki / Kinoshita, Ichiro / Modi, Shanu / Tsurutani, Junji / Bang, Yung-Jue / Sato, Yuta / Nakatani, Shunsuke / Lee, Caleb / Sugihara, Masahiro / Okuda, Yasuyuki / Iwata, Hiroji

Japanese journal of clinical oncology

2024 Volume 54, Issue 4, Page(s) 434–443

Abstract: Background: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed ...

Abstract	Background: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. Methods: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. Results: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-‍34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-‍81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). Conclusion: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. Clinical trial information: FIH study, NCT02564900; DDI study, NCT03383692.
MeSH term(s)	Humans ; Male ; Middle Aged ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use ; Camptothecin/therapeutic use ; Camptothecin/analogs & derivatives ; Carcinoma/drug therapy ; Immunoconjugates/adverse effects ; Immunoconjugates/therapeutic use ; Receptor, ErbB-2/metabolism ; Salivary Glands/metabolism ; Trastuzumab/adverse effects ; Trastuzumab/therapeutic use ; Female
Chemical Substances	Antibodies, Monoclonal, Humanized ; Camptothecin (XT3Z54Z28A) ; ERBB2 protein, human (EC 2.7.10.1) ; Immunoconjugates ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; trastuzumab deruxtecan (5384HK7574)
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	190978-2
ISSN	1465-3621 ; 0368-2811
ISSN (online)	1465-3621
ISSN	0368-2811
DOI	10.1093/jjco/hyad181
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Zs.A 1298: Show issues

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Article ; Online: Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

Perez, Edith A / Dang, Chau / Lee, Caleb / Singh, Jasmeet / Wang, Kongming / Layton, J Bradley / Gilsenan, Alicia / Hackshaw, Michelle D / Cortes, Javier

Breast cancer research and treatment

2022 Volume 194, Issue 1, Page(s) 1–11

Abstract: Purpose: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this ... ...

Abstract	Purpose: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). Methods: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. Results: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. Conclusion: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.
MeSH term(s)	Ado-Trastuzumab Emtansine/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Biosimilar Pharmaceuticals/therapeutic use ; Breast Neoplasms/pathology ; Female ; Humans ; Incidence ; Lapatinib/adverse effects ; Maytansine ; Neoplasms, Second Primary/etiology ; Receptor, ErbB-2/metabolism ; Trastuzumab
Chemical Substances	Biosimilar Pharmaceuticals ; Lapatinib (0VUA21238F) ; Maytansine (14083FR882) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; Ado-Trastuzumab Emtansine (SE2KH7T06F)
Language	English
Publishing date	2022-05-19
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-021-06469-0
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Zs.A 1655: Show issues

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Article: Human vascular organoids with a mosaic

He, Siyu / Zhu, Yuefei / Chauhan, Shradha / Tavakol, Daniel Naveed / Lee, Jong Ha / Berris, Rayna Batya-Leia / Xu, Cong / Lee, Jounghyun H / Lee, Caleb / Cai, Sarah / McElroy, Shannon / Vunjak-Novakovic, Gordana / Tomer, Raju / Azizi, Elham / Xu, Bin / Lao, Yeh-Hsing / Leong, Kam W

bioRxiv : the preprint server for biology

2024

Abstract: Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating ... ...

Abstract	Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we created induced pluripotent stem cells (iPSCs) embodying the Proteus syndrome-specific AKT
Language	English
Publishing date	2024-01-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.26.577324
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Article: Nanotechnology for Pain Management: Current and Future Therapeutic Interventions.

Bhansali, Divya / Teng, Shavonne L / Lee, Caleb S / Schmidt, Brian L / Bunnett, Nigel W / Leong, Kam W

Nano today

2021 Volume 39

Abstract: Pain is one of the most common medical conditions and affects more Americans than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on opioid analgesics and remain unsatisfactory. The life-threatening side effects and ... ...

Abstract	Pain is one of the most common medical conditions and affects more Americans than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on opioid analgesics and remain unsatisfactory. The life-threatening side effects and addictive properties of opioids demand new therapeutic approaches. Nanomedicine may be able to address these challenges as it allows for sensitive and targeted treatments without some of the burdens associated with current clinical pain therapies. This review discusses the physiology of pain, the current landscape of pain treatment, novel targets for pain treatment, and recent and ongoing efforts to effectively treat pain using nanotechnology-based approaches. We highl ight advances in nanoparticle-based drug delivery to reduce side effects, gene therapy to tackle the source of pain, and nanomaterials-based scavenging to proactively mediate pain signaling.
Language	English
Publishing date	2021-06-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2224882-1
ISSN	1878-044X ; 1748-0132
ISSN (online)	1878-044X
ISSN	1748-0132
DOI	10.1016/j.nantod.2021.101223
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Article ; Online: PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system.

Lee, Jounghyun H / Shores, Kevin L / Breithaupt, Jason J / Lee, Caleb S / Fodera, Daniella M / Kwon, Jennifer B / Ettyreddy, Adarsh R / Myers, Kristin M / Evison, Benny J / Suchowerska, Alexandra K / Gersbach, Charles A / Leong, Kam W / Truskey, George A

APL bioengineering

2023 Volume 7, Issue 4, Page(s) 46103

Abstract: Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering ... ...

Abstract	Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P- equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article
ISSN	2473-2877
ISSN (online)	2473-2877
DOI	10.1063/5.0167440
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Article ; Online: Using spatial genetics to quantify mosquito dispersal for control programs.

Filipović, Igor / Hapuarachchi, Hapuarachchige Chanditha / Tien, Wei-Ping / Razak, Muhammad Aliff Bin Abdul / Lee, Caleb / Tan, Cheong Huat / Devine, Gregor J / Rašić, Gordana

BMC biology

2020 Volume 18, Issue 1, Page(s) 104

Abstract: Background: Hundreds of millions of people get a mosquito-borne disease every year and nearly one million die. Transmission of these infections is primarily tackled through the control of mosquito vectors. The accurate quantification of mosquito ... ...

Abstract	Background: Hundreds of millions of people get a mosquito-borne disease every year and nearly one million die. Transmission of these infections is primarily tackled through the control of mosquito vectors. The accurate quantification of mosquito dispersal is critical for the design and optimization of vector control programs, yet the measurement of dispersal using traditional mark-release-recapture (MRR) methods is logistically challenging and often unrepresentative of an insect's true behavior. Using Aedes aegypti (a major arboviral vector) as a model and two study sites in Singapore, we show how mosquito dispersal can be characterized by the spatial analyses of genetic relatedness among individuals sampled over a short time span without interruption of their natural behaviors. Results: Using simple oviposition traps, we captured adult female Ae. aegypti across high-rise apartment blocks and genotyped them using genome-wide SNP markers. We developed a methodology that produces a dispersal kernel for distance which results from one generation of successful breeding (effective dispersal), using the distance separating full siblings and 2nd- and 3rd-degree relatives (close kin). The estimated dispersal distance kernel was exponential (Laplacian), with a mean dispersal distance (and dispersal kernel spread σ) of 45.2 m (95% CI 39.7-51.3 m), and 10% probability of a dispersal > 100 m (95% CI 92-117 m). Our genetically derived estimates matched the parametrized dispersal kernels from previous MRR experiments. If few close kin are captured, a conventional genetic isolation-by-distance analysis can be used, as it can produce σ estimates congruent with the close-kin method if effective population density is accurately estimated. Genetic patch size, estimated by spatial autocorrelation analysis, reflects the spatial extent of the dispersal kernel "tail" that influences, for example, the critical radii of release zones and the speed of Wolbachia spread in mosquito replacement programs. Conclusions: We demonstrate that spatial genetics can provide a robust characterization of mosquito dispersal. With the decreasing cost of next-generation sequencing, the production of spatial genetic data is increasingly accessible. Given the challenges of conventional MRR methods, and the importance of quantified dispersal in operational vector control decisions, we recommend genetic-based dispersal characterization as the more desirable means of parameterization.
MeSH term(s)	Aedes/genetics ; Aedes/physiology ; Animal Distribution ; Animals ; Genetic Variation ; Mosquito Control ; Mosquito Vectors/genetics ; Mosquito Vectors/physiology ; Singapore ; Spatial Analysis ; Time Factors
Language	English
Publishing date	2020-08-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/s12915-020-00841-0
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Article ; Online: Gravitrap deployment for adult Aedes aegypti surveillance and its impact on dengue cases.

Ong, Janet / Chong, Chee-Seng / Yap, Grace / Lee, Caleb / Abdul Razak, Muhammad Aliff / Chiang, Suzanna / Ng, Lee-Ching

PLoS neglected tropical diseases

2020 Volume 14, Issue 8, Page(s) e0008528

Abstract: House Index, Container Index, and Breteau Index are the most commonly used indices for dengue vector surveillance. However, these larval indices are a poor proxy for measuring the adult population-which is responsible for disease transmission. ... ...

Abstract	House Index, Container Index, and Breteau Index are the most commonly used indices for dengue vector surveillance. However, these larval indices are a poor proxy for measuring the adult population-which is responsible for disease transmission. Information on the adult distribution and density are important for assessing transmission risk as well as for developing effective control strategies. This study introduces a new entomological index, Gravitrap aegypti index (GAI), which estimates the adult female Aedes aegypti population in the community and presents its association with dengue cases. Gravitraps were deployed across 34 treatment sites in Singapore from September 2013 to September 2016. The GAI, derived from the Gravitrap surveillance data, was analysed to investigate the spatio-temporal patterns of the Ae. aegypti population in Singapore. The index was further categorised into low, moderate, and high-risk groups and its association with dengue cases were examined. A Before-After Control Impact analysis was performed to evaluate the epidemiology impact of Gravitrap system on dengue transmission. The Ae. aegypti population exhibits a seasonal pattern, and spatial heterogeneity in Ae. aegypti abundance was observed among treatment sites. The Ae. aegypti population was also found to be unevenly distributed among floors of an apartment block, with low floors (floors 1-4) having a higher abundance of mosquitoes trapped than mid (floors 5-8) and high (floors ≥9) floors. Areas with high GAI were shown to have higher dengue case count. Gravitrap has also demonstrated to be a good dengue control tool. The contribution of cases by treatment sites to the national numbers was lower after Gravitraps deployment. The GAI, which is of better relevance to dengue transmission risk, could be recommended as an indicator for decision making in vector control efforts, and to monitor the spatio-temporal variability of the adult Aedes population in the country. In addition, findings from this study indicate that Gravitraps can be used as a dengue control tool to reduce dengue transmission.
MeSH term(s)	Aedes/physiology ; Aedes/virology ; Animals ; Dengue/epidemiology ; Dengue Virus ; Disease Outbreaks/prevention & control ; Environment ; Female ; Insect Vectors ; Mosquito Control/instrumentation ; Mosquito Control/methods ; Population Density ; Singapore
Language	English
Publishing date	2020-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0008528
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online: Efficacy of Wolbachia-mediated sterility to suppress dengue

a synthetic control study

2023

Abstract: In a study conducted in Singapore, a country prone to dengue outbreaks due to its climate and urban population, researchers examined the effectiveness of releasing male Aedes aegypti mosquitoes infected with Wolbachia (wAlbB strain) to reduce dengue ... ...

Abstract	In a study conducted in Singapore, a country prone to dengue outbreaks due to its climate and urban population, researchers examined the effectiveness of releasing male Aedes aegypti mosquitoes infected with Wolbachia (wAlbB strain) to reduce dengue transmission. These infected males, when mating with wild-type females, produced non-viable eggs, leading to vector suppression. Extensive field trials involving over 600,000 residents in four townships were conducted from 2018 to 2022. The results showed a 57% decline in total dengue incidence and a 64% decline in clustered dengue incidence. This approach offers promise for large-scale dengue control in regions facing rising dengue cases, providing a critical solution in combating the disease.
Keywords	Quantitative Biology - Populations and Evolution ; Quantitative Biology - Quantitative Methods
Publishing date	2023-11-16
Publishing country	us
Document type	Book ; Online
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