{"id":7509,"date":"2026-01-06T08:44:27","date_gmt":"2026-01-06T00:44:27","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/phys\/?page_id=7509"},"modified":"2026-07-13T08:20:20","modified_gmt":"2026-07-13T00:20:20","slug":"publications-2026","status":"publish","type":"page","link":"https:\/\/medicine.nus.edu.sg\/phys\/research\/publications-2026\/","title":{"rendered":"Latest Publications"},"content":{"rendered":"\n

\n\t\t\tPublications – 2026\t<\/h1>\n\t\n\t\t\t\n\t\t\t\t\t\t\t2026\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2025\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2024\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2023\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2022\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2021\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2020\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2019\n\t\t\t\t\t<\/a>\n\t\t\t\n\t\t\t\t\t\t\t2018\n\t\t\t\t\t<\/a>\n\t\n\n\n\n\n\n\n
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Galectin-3 Regulates Smooth Muscle Contraction and Blood Pressure by Modulating CaV<\/sub>1.2 Channel Function<\/h1>\n<\/td>\n<\/tr>\n

Loh KWZ, Zhou Y, Liu C, Zhai J, Jaladanki CK, Jia Yi Neo C, Yu D, Liang MC, Shen M, Fan H, Liao P, Hu Z, Soong TW<\/strong>.<\/td>\n<\/tr>\n
Circulation<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Background:\u00a0<\/strong>Fine-tuning of CaV<\/sub>1.2 calcium channel activity by binding proteins represents a novel mechanism for regulating smooth muscle contraction and blood pressure (BP). This study aimed to elucidate the role of Gal-3 (galectin-3), a newly identified CaV<\/sub>1.2-binding protein, in the pathogenesis of hypertension.\n

Methods:\u00a0<\/strong>In vitro, ex vivo, and in vivo experiments involving molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements were used to evaluate the molecular mechanisms by which Gal-3 binds to and elevates membrane insertion of CaV<\/sub>1.2 channels. The experiments were performed in transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates; spontaneously hypertensive rats; or human patients. In vivo experiments involving delivery of the blocking iGal3BP (inhibitory galectin-3-binding peptide) into spontaneously hypertensive rats were performed to investigate its effect on BP.<\/p>\n

Results:\u00a0<\/strong>We identified Gal-3 as a novel binding partner and unexpected positive modulator of the CaV<\/sub>1.2 channel through binding to the intracellular II-III loop. Gal-3 increased total and surface expression, current density, and open probability of CaV<\/sub>1.2 channels. Both CaV<\/sub>1.2 and Gal-3 were upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle significantly lowered CaV<\/sub>1.2 protein and BP in mice. With specific binding sites identified within both Gal-3 and the CaV<\/sub>1.2 II-III loop, the peptide iGal3BP, designed to block CaV<\/sub>1.2-Gal-3 interaction, significantly reduced BP in spontaneously hypertensive rats by decreasing CaV<\/sub>1.2 protein expression. Repeated iGal3BP administration resulted in cumulative peptide accumulation in mesenteric arteries and produced a sustained reduction in BP, which demonstrated greater long-lasting antihypertensive efficacy compared with amlodipine and losartan. Administration of iGal3BP in combination with a negative modulatory Gal-1 mimetic peptide that mimics Gal-1-CaV<\/sub>1.2 interaction returned systolic BP to normotensive levels within 4 hours and lowered BP in hypertensive rats in a sustained manner for 35 days.<\/p>\nConclusions:\u00a0<\/strong>These results provide strong evidence that Gal-based CaV<\/sub>1.2 channel modulators are novel therapeutic pathways for normalizing BP.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Single-cell transcriptomics revealed molecular vulnerability in a human midbrain-like organoid model of Parkinson’s disease<\/h1>\n<\/td>\n<\/tr>\n

Xie JJ, Vitkauskas M, Do Q, Saw TY, Sun AX, Yang L, Soong TW<\/strong>, Lim KL, Tan EK, Ng HH, Liu J.<\/td>\n<\/tr>\n
iScience<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
The human midbrain-like organoid (hMLO) is a key model system for investigating pathological features of Parkinson’s disease (PD), yet how its molecular landscape relates to cellular vulnerability in PD remains unclear. We performed in-depth single-cell characterization of our previously established hMLO model up to 150 days\u00a0in vitro<\/i>. Our hMLOs exhibited physiological cell types and broad topographical patterning, consistent with features of the human fetal midbrain. We further identified four distinct dopamine-producing neurons (DaN) subtypes whose molecular profiles span a key transcriptomic axis in the selective vulnerability of DaNs in PD. Knockout of\u00a0PARK7<\/i>, a highly penetrant PD-causing gene, in hMLOs induced cell type-dependent molecular perturbations in mitochondrial activity and synapse biology, and recapitulated PD pathophysiology, including \u03b1-synuclein aggregation, Lewy Body-like inclusions, and DaN degeneration with extended culture. This study highlights the utility of our hMLO model in manifesting pathological features and cell type-specific vulnerability, enabling mechanistic studies into PD pathophysiology.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Disruption of\u00a0chrna5<\/i>\u00a0blunts aversion and adaptive transcriptomic responses to nicotine and alcohol<\/h1>\n<\/td>\n<\/tr>\n

Goel T, Raine J, Kibat C, Collado JW, Banerjee TD, Mathuru AS<\/strong>.<\/td>\n<\/tr>\n
iScience<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Addiction to nicotine and alcohol continues to be a leading cause of death and loss of productivity. Polymorphisms in\u00a0CHRNA5<\/i>\u00a0have been identified as risk factors in human genetic studies. Whether the\u00a0CHRNA5<\/i>\u00a0function is independently relevant to phenotypes associated with substance abuse and if genetic factors influence subsequent outcomes when exposure to psychoactive substances happens at an early age, are questions of interest. We generated a stable mutant line in zebrafish using the CRISPR-Cas9 technique. We found the\u00a0chrna5<\/i>-mutant fish exhibited an increased acute preference to both nicotine and alcohol in the self-administration zebrafish assay (SAZA). When subjected to multi-day exposures to either drug,\u00a0chrna5<\/i>\u00a0mutants exhibited greater behavioral changes, but reduced transcriptomic changes compared with wild-type siblings, suggesting an impaired homeostatic regulation following drug exposure.\u00a0chrna5<\/i>\u00a0mutants also exhibited drug-independent changes in appetite and circadian rhythms. We expect these results to give new insights into genetic predisposition that modulates vulnerability to nicotine and alcohol abuse.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Mechanopharmacology of cellular microenvironment stiffness: Therapeutic strategies for age-related diseases<\/h1>\n<\/td>\n<\/tr>\n

HaiYang W, Hui Juan CD, Zhao-Yong L, Thai T<\/strong>.<\/td>\n<\/tr>\n
Br J Pharmacol<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Ageing brings about various biochemical, structural and mechanical alterations within tissues, profoundly impacting cellular behaviour and function. One of the hallmark changes observed with ageing is an increase in cellular microenvironment stiffness, a biomechanical property influenced by intrinsic factors within the cell and extrinsic factors from the surrounding extracellular matrix (ECM). This shift in ECM stiffness has been implicated in the development and progression of several age-related diseases, but the exact molecular mechanisms underlying different organ tissues remain to be fully elucidated. This review examines the lung and ovaries, two organ tissues with distinct functions but interconnected by similar timing of changes in ECM stiffness with age. We discuss common pathways and factors that drive changes in the ECM stiffness of these organs. Such insights may pave the way for innovative treatments addressing the root causes of age-related diseases, ultimately enhancing the ageing population’s health span and quality of life. LINKED ARTICLES: This article is part of a themed issue Mechanopharmacology. To view the other articles in this section visit http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v183.4\/issuetoc.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Suboptimal Neural Drive for Muscle Output During Exertional Hyperthermia: A Functional Near-Infrared Spectroscopy (fNIRS) Study<\/h1>\n<\/td>\n<\/tr>\n

Michiko N, Alhadad SB, Tan XR, Lee JKW, Low ICC<\/strong><\/td>\n<\/tr>\n
Med Sci Sports Exerc<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Purpose:\u00a0<\/strong>Exertional hyperthermia impairs endurance performance. Although the central nervous system mediates premature fatigue, limited understanding of when and how neural perturbations arise during exertional hyperthermia hinders efforts to develop effective strategies to mitigate its impacts.\n

Methods:\u00a0<\/strong>Fifteen physically active males completed a familiarization trial and three randomized crossover controlled trials involving treadmill walking at 54 \u00b1 4% maximal oxygen consumption (mean \u00b1 SD) in a temperate environment (COOL; dry bulb temperature [Tdb]: 22.3 \u00b1 0.4\u00b0C, relative humidity [RH]: 68 \u00b1 10%), warm environment with (WARM+FC; Tdb: 32.0 \u00b1 0.2\u00b0C, RH: 71 \u00b1 2%) and without (WARM; Tdb: 32.1 \u00b1 0.2\u00b0C, RH: 70 \u00b1 2%) isolated facial fan cooling, until volitional exhaustion or rectal temperature of 39.5\u00b0C. Brachioradialis activation was assessed via electromyography (EMG) through maximal (MVC) and submaximal (sMVC) voluntary isometric handgrip contractions. Primary motor cortex oxygenation was continuously monitored using functional near-infrared spectroscopy (fNIRS). \u0394[Hbdiff] (difference between oxyhemoglobin and deoxyhemoglobin changes) indexed cortical activation. \u0394[Hbdiff]\/EMG quantified cortical activation relative to muscle activation.<\/p>\n

Results:\u00a0<\/strong>\u0394[Hbdiff]\/EMG was higher during MVC in WARM relative to COOL (P < 0.05) but similar across trials during sMVC. This was observed alongside reduced muscle activation (P < 0.05). Isolated facial cooling in WARM+FC trials did not mitigate heat-induced neural deficits observed during MVC.<\/p>\nConclusions:\u00a0<\/strong>Greater cortical activation is required to sustain similar muscle activation during exercise in warm compared with temperate conditions, suggesting a suboptimal neural drive for muscle output with exertional hyperthermia. This may contribute to the onset and development of central fatigue. fNIRS-derived markers may serve as early indicators to mitigate heat-induced deficits and enhance safety during exercise.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Differential Intestinal Epithelial Injury Following Passive and Exertional Hyperthermia<\/h1>\n<\/td>\n<\/tr>\n

Alhadad SB, Lim LSX, Lee JKW<\/strong>, Low ICC<\/strong><\/td>\n<\/tr>\n
Sports Med Open<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Background:\u00a0<\/strong>Passive and exertional hyperthermia can compromise gastrointestinal (GI) integrity, contributing to systemic complications and heat stroke. Intestinal epithelial injury, a potential early event in this cascade, is likely multi-factorial and context-dependent, influenced by thermal, metabolic and mechanical stress. We compared the effects of passive hyperthermia (PaH) and exertional hyperthermia (RUN) at matched peak body core temperature (Tc<\/sub>) on intestinal epithelial injury and endotoxin translocation to delineate the relative contributions of these mechanisms. A prolonged brisk walking (WALK) condition was included as an exploratory condition relevant to occupational heat exposures.\n

Methods:\u00a0<\/strong>In this randomised, counterbalanced, repeated-measures study conducted per CONSORT guidelines, 15 male endurance athletes (age: 26 \u00b1 3 years, VO2<\/sub>peak: 64 \u00b1 6 ml\/kg\/min) completed PaH, WALK and RUN. PaH involved warm water immersion (42.0 \u00b1 0.3 \u00b0C) to nipple level. WALK comprised 60 min at 6 km\/h, 7% incline, followed by 30 min at 6 km\/h, 1% incline to prolong exercise and facilitate continued heat storage if Tc<\/sub><39.5 \u00b0C after 60 min. RUN involved treadmill running at 69 \u00b1 2% VO2<\/sub>peak. PaH and RUN continued until Tc<\/sub>\u00a0reached 39.5 \u00b0C, volitional exhaustion or 60 min. Tc<\/sub>, heart rate (HR), perceptual responses, and concentrations of intestinal fatty acid binding protein (IFABP) and lipopolysaccharides (LPS) were assessed. Stepwise multiple linear regression was used to identify predictors of post-condition IFABP.<\/p>\n

Results:\u00a0<\/strong>Peak Tc<\/sub>\u00a0was similar between PaH (39.3 \u00b1 0.3 \u00b0C) and RUN (39.4 \u00b1 0.2 \u00b0C, P = 0.944), and lower in WALK (38.2 \u00b1 0.4 \u00b0C, both P < 0.001). Cumulative heat load assessed by area under the curve Tc<\/sub>\u226538 \u00b0C was similar between WALK (36.4 \u00b1 11.3 \u00b0C\/min) and RUN (34.3 \u00b1 7.5 \u00b0C\/min, P > 0.999) but lower in PaH (25.7 \u00b1 5.6 \u00b0C\/min, P < 0.05 vs. WALK, P < 0.01 vs. RUN). IFABP increased in RUN (745 \u00b1 432 pg\/ml vs. 1855 \u00b1 1465 pg\/ml, P < 0.001) and WALK (767 \u00b1 476 pg\/ml vs. 1144 \u00b1 995 pg\/ml, P < 0.05), but not in PaH (848 \u00b1 569 pg\/ml vs. 870 \u00b1 562 pg\/ml, P = 0.916). Post-condition IFABP was higher in RUN than PaH (P < 0.01) and WALK (P < 0.05), and similar between PaH and WALK (P > 0.999). LPS decreased in all conditions (all P < 0.05). Body fat percentage, body mass loss and body mass index explained 15% of the variance in post-condition IFABP.<\/p>\nConclusions:\u00a0<\/strong>Intestinal epithelial injury occurred following exertional, but not passive hyperthermia, at matched peak Tc<\/sub>. This highlights that combinations of thermal, metabolic and mechanical stress drive GI injury rather than Tc<\/sub>\u00a0elevation alone. Prolonged low-intensity exercise relevant to occupational exposures may incur sufficient cumulative heat load to induce subclinical intestinal injury. Interventions should consider managing exertional load alongside thermal strain to protect gastrointestinal health.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Schizophrenia: Genetics, neurological mechanisms, and therapeutic approaches<\/h1>\n<\/td>\n<\/tr>\n

Lim DXE, Yeo SY, Chia ZYA, Fernandis AZ, Lee J, Chua JJE<\/strong>.<\/td>\n<\/tr>\n
Neural Regen Res<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms, leading to mood disturbances, cognitive impairments, and social withdrawal. While anti-psychotic medications remain the cornerstone of treatment, they often fail to fully address certain symptoms. Additionally, treatment-resistant schizophrenia, affecting 30%-40% of patients, remains a substantial clinical challenge. Positive, negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic, serotonin, GABAergic, and muscarinic pathways in the brain. Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new, and reinforced prior, concepts on the genetic and neurological underpinnings of schizophrenia, including abnormalities in synaptic function, immune processes, and lipid metabolism. Concurrently, new therapeutics targeting different modalities, which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients, are currently being evaluated. Collectively, these efforts provide new momentum for the next phase of schizophrenia research and treatment.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n\n<\/tr>\n<\/tbody>\n<\/table>\n
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Modulating hyperpolarization-activated cyclic nucleotide-gated channels for neuropathic pain<\/h1>\n<\/td>\n<\/tr>\n

Tan AYY.<\/strong><\/td>\n<\/tr>\n
J Physiol<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
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Caffeine reverses sleep deprivation-induced synaptic and social memory deficits via adenosine receptor modulation in the male mouse hippocampal CA2 region<\/h1>\n<\/td>\n<\/tr>\n

LW Wong<\/strong>, MZ Bin Ibrahim, AL Kannan, S Sajikumar<\/strong><\/td>\n<\/tr>\n
Neuropsychopharmacology<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5\u2009h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKM\u03b6, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss-related cognitive dysfunction in neuropsychiatric disorders.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Development of cognitive engagement and motivation using AI chatbot-facilitated questioning in medical education<\/h1>\n<\/td>\n<\/tr>\n

JEG Embang, YHV Tan, SC Hooi, AHP Wong, LW Wong<\/strong><\/td>\n<\/tr>\n
Advances in Health Sciences Education<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Artificial intelligence tools such as ChatGPT offer new opportunities to support medical students’ learning through interactive questioning and instantaneous feedback. However, while ChatGPT may facilitate learning engagement through its accessibility, ChatGPT’s potential to foster higher-order thinking and sustained engagement remains underexplored. This study explored how ChatGPT-facilitated questioning relates to medical students’ cognitive engagement and motivation in a first-year foundational science module, integrating Self-Determination Theory, Expectancy-Value Theory, and Bloom’s Taxonomy as learning frameworks. A study was conducted among medical students pursuing a cardiovascular physiology course. Students generated course-related questions and used ChatGPT to obtain answers, which were subsequently evaluated by instructors. 31 student questions were independently coded by two reviewers according to Bloom’s cognitive domains. Perceived autonomy, competence, relatedness, interest\/enjoyment, and task value were collected using validated Self-Determination and Expectancy-Value Theory-based tools. Student-generated questions were coded according to Bloom’s cognitive domains, and open-ended feedback on the strengths and limitations of ChatGPT was synthesised through conventional content analysis. Survey results indicated higher perceived autonomy, competence, and task value among ChatGPT users compared with non-users, although differences were not statistically significant. Most student-generated questions also reflected lower to intermediate cognitive levels – ‘Understand<\/i>‘ (41.9%), and ‘Apply<\/i>‘ (45.2%), with few reaching ‘Analyse’<\/i>. Qualitative insights highlighted ChatGPT’s efficiency, accessibility, and cognitive support, alongside concerns regarding accuracy, superficial engagement, and limited interpersonal interactions. Integrated results suggest that ChatGPT may support self-directed motivation and learning but does not consistently facilitate higher-order thinking and social relatedness without instructor mediation. ChatGPT may offer benefits for medical education by supporting autonomy and perceived usefulness. However, motivation alone is insufficient to promote higher-order thinking. ChatGPT should be facilitated by educators to transform artificial intelligence use from information retrieval into reflective, dialogic inquiry. Integrating ChatGPT within collaborative learning may strengthen analytical reasoning and relational engagement in early medical training.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Re-imagining discharge summary training through artificial intelligence<\/h1>\n<\/td>\n<\/tr>\n

Chua CE, Ng IKS, Yuen K, Teo DB, Luke N<\/strong>.<\/td>\n<\/tr>\n
Medical Teacher<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
What is the educational challenge?<\/b>\u00a0Discharge summary (DS) writing is a core competency for junior physicians, yet persistent deficiencies in the quality, accuracy, and timeliness of these clinical documents are well-documented, with downstream repercussions in patient safety and continuity of care. Existing educational interventions rely heavily on faculty-intensive, small-group teaching models, which limits scalability and long-term sustainability. There is therefore a need to develop novel, more resource-efficient approaches to provide high-quality training in DS writing with individualised feedback.\n

What are the proposed solutions?<\/b>\u00a0We propose a new educational model that integrates artificial intelligence (AI)-generated feedback into a structured DS training programme. As a proof-of-concept, we conducted a small-scale evaluation comparing feedback quality from multiple AI platforms and a human trainer using a standardised rubric. Based on these findings, we designed an asynchronous Coursemology-based e-learning module incorporating customised generative-AI (cGen-AI) to generate draft feedback, with human moderation retained as a safety and quality assurance step. This model is currently in the pre-implementation phase.<\/p>\n

What are the potential benefits to a wider global audience?<\/b>\u00a0This conceptual human-in-the-loop AI model has the potential to deliver scalable, consistent, and individualised feedback while substantially reducing faculty and logistical workload. By enabling asynchronous practice and standardised assessment, it directly addresses sustainability challenges faced by DS training programmes internationally.<\/p>\nWhat are the next steps?<\/b>\u00a0Full implementation and evaluation including reliability, learner acceptance, and educational impact of this model is being planned for an entire medical student cohort to replace the existing small-group, faculty-facilitated sessions. The success of such cGen-AI approach for DS training can also be extended to other similar domains of medical training in the future.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Magnetic Reprogramming of Macrophages Stimulates Phagocytosis of Breast Cancer Cells via a TRPC1-STING Inflammatory Axis<\/h1>\n<\/td>\n<\/tr>\n

Sukumar VK, Tai YK, Iversen JN, Yeo O, Paul AP, Wu KY, Lim LHK<\/strong>, Franco-Obreg\u00f3n A<\/strong>,<\/td>\n<\/tr>\n
Smart Medicine<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
The reprogramming of tumor-associated macrophages (TAMs) from a pro-tumoral M2 to an anti-tumoral M1 phenotype is an attractive therapeutic strategy whose clinical translation is undermined by the systemic toxicity of currently available pharmacological approaches. Here, we demonstrate that non-invasive and localizable pulsed electromagnetic fields (PEMFs) induce macrophage reprogramming downstream of transient receptor potential canonical 1 (TRPC1) channel activation. Brief (10\u00a0min) PEMF exposure polarized macrophages toward an M1 phenotype by activating Stimulator of Interferon Genes (STING)-dependent NF-\u03baB inflammatory pathways that were abolished by TRPC1 knockdown or inhibition. PEMF exposure directly enhanced the immunogenicity of breast cancer cells and modified macrophage-cancer crosstalk to promote M1 macrophage polarization and the attraction of STING-activated macrophages to the cancer cells. In co-cultures, PEMF exposure stimulated macrophage-mediated phagocytosis of cancer cells in a STING- and TRPC1-dependent manner. In spheroids, PEMFs induced the reprogramming of TAMs to an M1 status and selectively enhanced infiltration of M1 macrophages, resulting in STING-mediated phagocytosis of cancer cells. In mice, 2\u00a0weeks of twice-weekly PEMF exposure resorbed engrafted tumors and selectively eliminated cancer cells within tumors while promoting immune cell recruitment. PEMFs offer a non-invasive manner to locally reprogram TAMs within the tumor microenvironment to preferentially eliminate cancer cells.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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DMTF1 up-regulation rescues proliferation defect of telomere dysfunctional neural stem cells via the SWI\/SNF-E2F axis<\/h1>\n<\/td>\n<\/tr>\n

Liang Y, Grinchuk OV, Cipta NO, Zeng Y, Chuah YH, Yoon J, Khong ZJ, Chow HY, Ng W, Ong CT, Ling SC, Ng SY, Loh YH, Ong DST<\/strong>.<\/td>\n<\/tr>\n
Sci Adv<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Impaired neural stem cell (NSC) proliferation\/activation is associated with brain aging, but the underlying mechanisms remain poorly understood. Here, we unexpectedly find that DMTF1, a transcription factor that regulates the Arf\/p53 axis in cancer, is down-regulated in the NSCs of a premature aging model driven by telomerase deficiency. DMTF1 up-regulation was able to rescue the impaired proliferation of telomere dysfunctional NSCs. Mechanistically, DMTF1 regulates the transcription of Arid2 and Ss18 genes, two subunits of the SWI\/SNF complexes that mediate H3K27ac at E2F gene promoters to promote NSC proliferation. Accordingly, Arid2 or Ss18 depletion phenocopies DMTF1 loss in reducing H3K27ac levels, expression of E2F target genes, and NSC proliferation. Thus, our study has identified DMTF1 as a potential therapeutic target to reverse the proliferation defect of aged NSC that is modeled by telomere attrition and unearthed a distinct genetic program controlled by DMTF1 in NSC.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Irf7<\/i>\u00a0Deficiency Confers Protection Against Influenza Infection, Independent of\u00a0irf3<\/i><\/h1>\n<\/td>\n<\/tr>\n

Cui J, Foo SSW, Kong WT, Lin C, Ampomah PB, Zharkova O, Chai LS, Sachaphibulkij K, Arora S, Kaliaperumal N, Lim HM, Connolly J, Fairhurst AM, Chen J, Lim LHK<\/strong>.<\/td>\n<\/tr>\n
Int J Biol Sci<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Interferon regulatory factors\u00a0irf3<\/i>\u00a0and\u00a0irf7<\/i>\u00a0are pivotal for antiviral immunity, yet their cell-type-specific contributions, particularly within macrophage and dendritic cell (DC) lineages, have not been fully elucidated. Here, employing a multi-omics strategy encompassing\u00a0in vitro<\/i>\u00a0assays,\u00a0in vivo<\/i>\u00a0influenza A virus (IAV) infection models, NanoString, transcriptomic analyses, and scGPT-based computational modeling, we dissect the divergent and context-dependent roles of\u00a0irf3<\/i>\u00a0and\u00a0irf7<\/i>. We demonstrate macrophages exhibit heightened sensitivity to TLR3 stimulation, a response critically dependent on\u00a0irf3<\/i>. Conversely, DCs respond more robustly to TLR7 activation and very weakly to TLR3 activation. Unexpectedly, global\u00a0Irf7<\/i>\u00a0-\/-<\/sup>\u00a0mice displayed enhanced survival against IAV-induced lethality, whereas global\u00a0Irf3<\/i>\u00a0-\/-<\/sup>\u00a0mice exhibited similar mortality to WT mice but demonstrated accelerated physiological recovery during the resolution phase, indicative of reduced disease severity rather than improved survival. Deep transcriptomic profiling of lung alveolar macrophages (AM), DC1, and DC2 subsets revealed distinct\u00a0irf3<\/i>\u00a0and\u00a0irf7<\/i>\u00a0dependent gene programs, with\u00a0irf7<\/i>\u00a0prominently driving responses in AM and DC2 populations post-IAV infection. Furthermore, scGPT simulations predicted\u00a0irf3<\/i>-associated regulation of pathways like IL-17 signaling distinct from\u00a0irf7<\/i>-biased control over Th17 differentiation and JAK-STAT signaling, suggesting a model where\u00a0irf3<\/i>\u00a0mainly drives rapid pathogen sensing and defence, whereas\u00a0irf7<\/i>\u00a0regulates sustained inflammation and adaptive immune coordination. Cross-species analyses confirmed conserved and divergent\u00a0irf3<\/i>\/irf7<\/i>\u00a0activities in human myeloid cells. Our findings provide a detailed framework of\u00a0irf3<\/i>\/irf7<\/i>\u00a0cell-specific functions, illuminating their nuanced interplay in orchestrating antiviral defence and offering potential targets for immunomodulation. This knowledge may inform the development of targeted antiviral therapeutic strategies and contribute to a more nuanced understanding of innate immune regulation.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
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Development of a nanoparticle-based immunotherapy targeting CD137 for nasopharyngeal carcinoma treatment<\/h1>\n<\/td>\n<\/tr>\n

Lee KY, Sun H, Mei Y, Nickles E, Lai CWX, Ponnalagu S, Prasad M, Liu H, Schwarz H.<\/strong><\/td>\n<\/tr>\n
Theranostics<\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
CD137 is a powerful T cell costimulatory molecule, and CD137 agonists are being evaluated for human cancer immunotherapy. Urelumab and utomilumab, are two agonistic anti-CD137 antibodies that are most advanced in clinical trials but suffer from liver toxicity and low potency, respectively. Here we describe the development of a new type and formulation of a CD137 agonist that combines high potency and a strong safety profile.\u00a0Methods:<\/b>\u00a0The extracellular domain of recombinant human CD137 ligand (rhCD137L) was conjugated onto mesoporous silica nanoparticles (MSNs) of approximately 50 nm in diameter, and the ratio of rhCD137L to MSNs was optimized based on their ability to costimulate the cytotoxic activity of T cells. As nasopharyngeal carcinoma (NPC) cells often express CD137, the\u00a0in vitro<\/i>\u00a0effect of rhCD137L-MSNs on T cell-mediated tumor cytotoxicity was evaluated using the NPC cell lines C666 and HK-1, each tested as CD137-expressing and -deficient variants. Results were compared with those obtained using MSNs conjugated with urelumab (ure-MSNs) or unconjugated urelumab. The biodistribution, therapeutic efficacy and toxicity of rhCD137L-MSNs were subsequently assessed in humanized mouse NPC models.\u00a0Results:<\/b>\u00a0rhCD137L-MSNs were of higher potency than ure-MSNs or unconjugated urelumab in inducing\u00a0in vitro<\/i>\u00a0T cell killing of the NPC cell lines C666 and HK-1, of both CD137-expressing and -deficient phenotypes. C666-CD137 and HK1-CD137 cells were eliminated more efficiently than the CD137-deficient cells.\u00a0In vivo<\/i>, in humanized mouse NPC models, both rhCD137L-MSNs and ure-MSNs inhibited tumor growth, with rhCD137L-MSNs being slightly more potent. This was reflected in an increase in T cell activation markers and an increased infiltration of effector memory CD8+<\/sup>\u00a0T cells into the tumor. In contrast to ure-MSNs, rhCD137-MSN treatment did not induce liver damage, thereby demonstrating a more favorable safety profile than ure-MSNs.\u00a0Conclusions:<\/b>\u00a0This study identifies a formulation of rhCD137L on MSNs that combines high potency with excellent safety.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n
\n

CD47 blockade-driven necroptosis complements BCL-2 inhibition-driven apoptosis in lymphoid malignancies<\/h1>\n<\/td>\n<\/tr>\n

Chong, S.J.F.,<\/strong> Valentin, R., Wang, J.\u00a0et al.<\/i><\/td>\n<\/tr>\n
J Hematol Oncol <\/a><\/td>\n<\/tr>\n
Abstract<\/td>\n<\/tr>\n
Immune checkpoint blockade of CD47 has shown promising results in lymphoid malignancies, with its effects attributed to enabling tumor-cell phagocytosis. However, alternate cytotoxic cell death mechanisms have been reported, potentially contributing to the overall anti-tumor activity. Although previous studies have highlighted a mechanism of caspase-independent cell death, this mechanism has yet to be well-characterized, thereby warranting further investigation to comprehensively understand the anti-tumor mechanism of CD47 blockade to facilitate optimal drug partner selection for combination therapy.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n","protected":false},"excerpt":{"rendered":"

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