Top read articles in the last 30 days
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Abstract
Allergen-specific monoclonal antibodies (mAbs) that block IgE binding to allergens are emerging as new therapeutics for treating allergies to pollen, peanuts, and cats. Alpha-Gal syndrome (AGS) is an allergy to galactose-α-1,3-Galactose (α-Gal), which is present in mammalian meat and tissue-derived products. Initially aiming to identify mAbs targeting α-Gal on malaria parasites, we isolated 42 α-Gal–specific mAbs from B cells of individuals who had been exposed to malaria but found that they bound weakly to the Plasmodium falciparum parasite. These mAbs predominantly used the IGHV3 gene family and had a wide range of mutation frequencies. We then screened these mAbs for their ability to bind α-Gal on AGS allergens and to block the binding of serum IgE of patients with AGS to AGS allergens. Thirteen mAbs bound to the AGS allergens angiotensin-I-converting enzyme (ACE), aminopeptidase-N (AP-N), and cetuximab, and 2 mAbs— AG028 as both IgA2 and IgM, and AG050 IgA1 — blocked the binding of serum IgE from patients with AGS to ACE and AP-N. Additionally, AG028 IgA2 and AG028 IgM suppressed ACE-mediated activation of basophils sensitized with serum of patients with AGS. This study supports the development of α-Gal–specific mAbs as a new intervention to prevent α-Gal allergy.
Authors
Hyeseon Cho, Youngsil Seo, Haewon Sohn, Shailesh K. Choudhary, Jeff Skinner, Ming Zhao, Ludmila Krymskaya, Weizhi Zhong, Justin Lack, Shanping Li, Boubacar Traore, Joshua Tan, Scott P. Commins, Peter D. Crompton
Total views: 5741
Abstract
BACKGROUND. Supraventricular tachycardia (SVT) and Wolff-Parkinson-White (WPW) are potentially highly symptomatic and, rarely, lethal arrhythmias associated with atrioventricular accessory pathways. While the etiology of accessory pathways remains largely unknown, they are frequently observed with Ebstein’s Anomaly, a congenital heart disease associated with maternal medicinal lithium use. Therefore, we evaluated whether in utero exposure to lithium from environmental sources is associated with the prevalence of accessory pathways. METHODS. We conducted a county-level ecological comparison of lithium levels in drinking water versus prevalence of WPW diagnoses among patients < 18-years-old in California using multivariable logistic regression. Children were analyzed given their high likelihood to reside in the same county during fetal development. WPW cases were identified using diagnostic codes. Positive and negative controls, including falsification endpoints, were analyzed. RESULTS. Among 2,329,090 patients (mean age 8.2 ± 5.9 years, 47.8% female), 686 (0.03%) were diagnosed with WPW. Areas where lithium levels ≥ 75th percentile were associated with 71% greater odds of WPW (OR 1.71, 95% CI 1.44 to 2.03). Areas above the lithium health-based screening limit had 29% greater odds of WPW (OR 1.29, 95% CI 1.05 to 1.58). Similar results existed in a New York statewide cohort. In validation analyses, areas where lithium levels ≥ 75th percentile were associated with a higher prevalence of SVT, syncope, palpitations, and catheter ablation procedures. CONCLUSIONS. Higher lithium levels in drinking water were associated with a greater prevalence of childhood-diagnosed WPW, implicating a potentially modifiable risk factor for the development of accessory pathways.
Authors
Justin T. Teraoka, Anushree Agarwal, Janet J. Tang, Thomas A. Dewland, Gregory M. Marcus
Total views: 4699
Abstract
Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibited NMJ transmission failure that correlated with muscle weakness severity. Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the postsynaptic NMJ membrane. Acute NaV1.4 inhibition with μ-conotoxin GIIIB in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans. Finally, ClC-1 chloride ion channel inhibition enhanced muscle excitability and improved NMJ transmission and muscle function in old rodents. Together, these findings demonstrate that NMJ transmission deficits are a key, reversible driver of sarcopenia and reveal a therapeutic target for addressing muscle weakness in aging.
Authors
W. David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A. Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah Ramadan, Philippa A. Rust, Jessica H. Myers, Fereshteh B. Darvishi, Anna R. Dashtmian, Lauren A. Fish, Deepti Chugh, Jane Bold, Jorge Quiroz, John Hutchison, Hiroshi Nishimune, Ross A. Jones, Xueyong Wang, Justin R. Fallon, Thomas H. Gillingwater, Mark M. Rich, Thomas Holm Pedersen, Brian C. Clark
Total views: 3775
Abstract
Diabetic retinopathy features early glial stress and neurovascular dysfunction, yet Müller glial programs linking inflammatory cues to oxidative injury remain unclear. We identify a spatially clustered interferon-stimulated gene 15 (ISG15)+ Müller glial subtype expanded in streptozotocin-induced diabetic mice. High glucose alone did not increase basal free ISG15 or detectable ISGylation (ISG15-dependent protein modification) in primary Müller glia, whereas conditioned medium from high glucose–exposed microglia induced both, recapitulated by IFN-β and attenuated by type I interferon receptor 1 inhibition. In vivo, Ifnb1 RNAscope signals were associated with microglia, retinal Ifnb1 expression increased in diabetic retinas, and microglial depletion reduced Ifnb1 expression and limited the expansion of ISG15+ Müller glia. Müller glia–specific Isg15 deletion preserved blood–retinal barrier integrity, reduced acellular capillaries and Evans blue leakage, and mitigated oxidative stress, lipid peroxidation, and glutathione redox imbalance. Loss of ISG15 or disruption of ISGylation blunted interferon-driven oxidative stress in Müller glia and reduced Müller glia–conditioned medium–dependent endothelial migration and tube formation. Mechanistically, IFN-β promoted peroxiredoxin 6 (PRDX6) ISGylation and proteasome-dependent degradation without altering Prdx6 transcripts. Thus, microglial IFN-β promotes an ISG15+ Müller glial subtype that compromises antioxidant defense and promotes early barrier injury in diabetic retinopathy.
Authors
Tian Niu, Yan Jiang, Xindan Xing, Qian Zhu, Xinyi Liu, Kangjia Lv, Junwei Fang, Kun Liu
Total views: 3723
Abstract
BACKGROUND Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown.METHODS This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full sibling pairs. Based on national health registers, 22 ADs were identified from 1969 to 2013. Aggregation and coaggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis were used to characterize the structure of shared genetic risk across ADs.RESULTS A total of 707,995 individuals (11.2%) were diagnosed with at least 1 AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08–0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity.CONCLUSION This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders.FUNDING The Swedish Society of Medicine, Region Värmland’s County Research Council, The Swedish Research Council, The Knut and Alice Wallenberg Foundation, Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and Karolinska Institutet.
Authors
Daniel Eriksson, Ralf Kuja-Halkola, Marie Holmqvist, Henrik Larsson, Agnieszka Butwicka, Soffia Gudbjörnsdottir, Olle Kämpe, Sophie Bensing, Jakob Skov
Total views: 3436
Abstract
Interferon lambda (IFN-λ) has emerged as a critical inducer of immune regulation in addition to its mucosal antiviral properties. However, the cellular and molecular mechanisms that govern its dual role during viral infections remain unclear. Here, we discovered that mucosal delivery of IFN-λ abrogates the herpes simplex virus type 2–induced (HSV-2-induced) vaginal tissue pathology observed in the absence of type I IFN signaling, through drastically inhibiting IL-6 production. At the same time, we demonstrated that IFN-λ rescued local production of CD4+ T cell–dependent IFN-γ, which is essential for protection against the development of toxic megacolon following genital HSV-2 infection. Mechanistically, we found that IFN-λ enhances the differentiation of CCR2+Ly6Chi cells into monocyte-derived antigen-presenting cells, thereby boosting T cell responses. In vivo depletion of CCR2+ cells abrogated this phenomenon. Together, these findings suggest that IFN-λ orchestrates a potent antiviral response, inhibiting hyperinflammatory responses while selectively augmenting effector T cell function. This study positions IFN-λ as a promising therapeutic candidate for enhancing local antiviral immunity and offers new insights into the regulation of immune responses in the context of mucosal viral infections.
Authors
Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar
Total views: 3259
Abstract
BACKGROUND We previously defined 4 hormone receptor+/human epidermal growth factor receptor 2– (HR+/HER2–) subtypes: SNF1 canonical luminal, SNF2 immunogenic, SNF3 proliferative, and SNF4 RTK driven. The FASCINATE-N proof-of-concept trial demonstrated that subtyping-directed precision treatment improves pathologic complete response in locally advanced HR+/HER2– breast cancer, yet efficacy remains suboptimal.METHODS We integrated transcriptomic, genomic, digital pathology, and clinical data from this trial (n = 230) and focused on exceptional responders to explore opportunities for refining treatment strategies.RESULTS In SNF1, we uncovered that perineural invasion diminished endocrine therapy efficacy, suggesting the potential benefit of incorporating perineural blockade. Digital pathology and spatial transcriptomics identified that the spatial architecture of the tumor-stromal-immune interface influenced apatinib efficacy in SNF4, highlighting the importance of interfering with the tumor microenvironment. In the SNF3 group, exceptionally well responders exhibited multiple mutations in DNA repair genes and cell cycle activation, correlating with the efficacy of poly (ADP-ribose) polymerase and CDK4/6 inhibitors. Additionally, we illustrated that lymphatic vessel infiltration was linked to improved immunotherapy outcomes in HR+/HER2– SNF2 tumors.CONCLUSION Overall, our study emphasizes the importance of multimodal assessments in optimizing precision treatments for HR+/HER2– breast cancer.FUNDING National Natural Science Foundation of China, grant numbers U25C2032, 82441028, and 82573645; The Shanghai Key Laboratory of Breast Cancer, grant number 12DZ2260100; The Human Phenome Data Center of Fudan University.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT05582499.
Authors
Yi Xiao, Fan Yang, Ying-Jia Qi, Li Chen, Hang Zhang, Si-Wei Zhang, Rui Shan, Liang Huang, Jun-Jie Li, Yi-Zhou Jiang, Zhi-Ming Shao
Total views: 3242
Abstract
Friedreich’s ataxia (FRDA) is a multisystemic neurodegenerative disorder caused by GAA repeat expansion in intron 1 of frataxin (FXN), resulting in FXN deficiency and mitochondrial dysfunction. Current therapies do not correct the underlying genetic defect. Here, we demonstrate that ex vivo CRISPR/Cas9 excision of the GAA expansion in hematopoietic stem and progenitor cells (HSPCs) provides durable, systemic therapy for FRDA. A single infusion of gene-edited Sca1+ HSPCs, mPPL-001, into myeloablative, humanized YG8JR mice resulted in long-term engraftment of donor-derived cells across hematopoietic and FRDA-affected tissues. mPPL-001 increased FXN expression and corrected multiple key pathogenic drivers of FRDA, including mitochondrial stress, microglial and macrophage activation, and inflammatory signaling. These coordinated effects improved motor functions, preserved cerebellar architecture, mitigated cardiac pathology, and promoted survival of insulin-producing β cells in the pancreatic islets of Langerhans. Collectively, these findings establish FXN-edited autologous HSPCs as a one-time, disease-modifying therapy for FRDA and support advancement toward a first-in-human trial.
Authors
Anusha Sivakumar, Alexis N. Corl, Keneth Jordan Muñoz, Subhashini Arumugam, Betul B. Gunes, Angelyn B. Solis, Rishika Murthy, Lilas Rony El-Hachem, Donald P. Pizzo, Ian A. Blair, Teerapat Rojsajjakul, Clementina Mesaros, Xinlong Wan, Joseph N. Rainaldi, Rafael A. Badell-Grau, Veenita Khare, Kevin Eric Thai, Kavya Biederman, Stephanie Cherqui
Total views: 3166
Abstract
Distress sharing within an ingroup instinctively motivates caregiving-like prosocial behavior in social animals and humans, yet how aversive social stimuli paradoxically trigger such behavior remains unclear. Here, we show that stress-state matching in observer mice elicits caregiving-like behaviors (allogrooming and injury-targeted allolicking) toward cagemates in pain, resulting in synchronized social buffering. Importantly, we identify that the excitation of vasopressin receptor 1a–expressing (V1aR-expressing) neurons in the central medial amygdala (CeM) underlies both emotional-state matching and subsequent allogrooming/allolicking. This excitation is accomplished by arginine vasopressin (AVP) release from presynaptic terminals of the hypothalamic paraventricular nucleus (PVN) to act specifically on postsynaptic V1aR in the CeM. The CeMV1aR neurons then project to the ventral tegmental area (VTA) to drive caregiving-like actions through positive reinforcement, manifested as prosocial preference and recurrent allogrooming/allolicking, and to produce anxiolysis in the caregiver. Collectively, we unravel a dedicated trisynaptic PVNAVP-CeMV1aR-VTA circuit driving and gating caregiving-like behaviors and advance the mechanistic understanding of AVP-V1aR signaling in prosociality.
Authors
Kai-Wen Geng, Rui-Rui Wang, Yan Yang, Yan Wang, Ting He, Chun-Li Li, Chong-Shun Xu, Jun Chen
Total views: 3164
Plasma nucleosome profiling reports on tumor burden and molecular subtypes in small cell lung cancer
Abstract
BACKGROUND Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis and marked transcriptional heterogeneity that may drive distinct therapeutic vulnerabilities. Clinical translation of molecular subtyping has been limited by restricted access to tumor biopsies, particularly at relapse.METHODS We applied chromatin immunoprecipitation of cell-free nucleosomes carrying active histone modifications followed by sequencing (cfChIP-seq) to 441 plasma samples from individuals with advanced SCLC, other neuroendocrine carcinomas, or non-SCLC cancers, as well as from healthy controls. Plasma cfChIP-seq profiles were integrated with matched tumor transcriptomes from 73 samples, including 41 time-matched pairs.RESULTS cfChIP-seq captured the epigenetic and transcriptional landscape of tumor-derived cell-free DNA (cfDNA), including SCLC tissue- and cell-of-origin signatures. A quantitative cfChIP-seq–derived SCLC score tracked radiographic tumor burden and was associated with prognosis. Signals at promoters of lineage-defining transcription factor genes, including ASCL1, NEUROD1, POU2F3, and ATOH1, correlated strongly with matched tumor RNA expression and supported noninvasive inference of SCLC transcriptional subtypes directly from plasma.CONCLUSION Plasma cfChIP-seq provides a practical liquid biopsy platform for real-time assessment of tumor burden, tumor state, and molecular subtype in SCLC. These findings support further development of cfChIP-seq for precision monitoring and subtype-informed therapeutic stratification in SCLC.TRIAL REGISTRATION ClinicalTrials.gov NCT02484404, NCT02487095, NCT02769962, NCT03554473, NCT03896503, and NCT02146170.FUNDING Center for Cancer Research; Intramural Program of the NCI (ZIA BC 011793); European Research Council (ERC) (Adg no. 101019560 “cfChIP”).
Authors
Gavriel Fialkoff, Nobuyuki Takahashi, Israa Sharkia, Jenia Gutin, Nadav Hermoni, Michael Nirula, Rajesh Kumar, Lorinc Pongor, Samantha Nichols, Linda Sciuto, Kanak Parmar, Parth Desai, Priya Suresh, Melissa Abel, Rajaa El Meskini, Myriam Maoz, Yakir Rottenberg, Shoshan Nevo, Hovav Nechushtan, Tamar Peretz, Diana Roame, Ayala Hubert, Jonathan E. Cohen, Azzam Salah, Mark Temper, Albert Grinshpun, Zoe Weaver-Ohler, Arun Rajan, William Douglas Figg Sr., Aviad Zick, Ronen Sadeh, Nir Friedman, Anish Thomas
Total views: 3067
Abstract
Polycystic ovary syndrome (PCOS), also known as polyendocrine metabolic ovarian syndrome (PMOS), is the most common endocrinologic disorder to affect women. Despite this, the pathophysiology of the disease is not entirely known. This has hindered the diagnosis of the disease and appropriate treatment for millions of individuals. In this Review, we discuss the proposed pathophysiology of PCOS from a translational perspective. We review the existing diagnostic criteria of PCOS and current management strategies. Finally, we discuss the long-term health sequelae associated with PCOS, future directions, and areas of needed research in this often-overlooked disease.
Authors
Jessica L. Chan, Irene Masini, Margareta D. Pisarska
Total views: 7730
Abstract
Sepsis is a systemic vascular disorder in which endothelial activation, dysfunction, and structural injury contribute to shock, microcirculatory failure, immunothrombosis, and multiorgan dysfunction. Sepsis-associated endotheliopathy is not a uniform process but a dynamic trajectory that evolves from adaptive endothelial activation toward functional disruption, structural injury, and organ-specific vascular failure. In this Review, we propose a phenotype- and trajectory-oriented framework that integrates clinical manifestations, molecular mechanisms, and translational assessment of endothelial dysfunction in sepsis. We focus on four major clinically recognizable modes of endothelial dysfunction that often overlap and evolve over the course of sepsis. We further discuss biology-anchored biomarker panels, bedside physiological surrogates, and serial trajectory-based assessment as complementary approaches for identifying endothelial states, refining risk stratification, and guiding future precision strategies. Finally, we describe implications for biomarker-enriched clinical trials, microvascular-informed resuscitation, and endotype-guided endothelial cell–targeted therapies. Viewing sepsis through the lens of dynamic endotheliopathy provides a framework linking vascular biology to clinically interpretable trajectories and may facilitate the development of personalized approaches to endothelial cell–directed care.
Authors
Song Qin, Ninan Dai, Fengyun Xu, Cindy Zhuang, Judith Hellman
Total views: 4155
Abstract
Cell-cycle dysregulation is a central driver of breast cancer progression and a major therapeutic vulnerability, particularly in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) disease. The clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy has transformed treatment paradigms and established cell-cycle targeting as a cornerstone of care. However, important challenges remain, including hematologic toxicity, incomplete and largely cytostatic responses, and the near-universal development of resistance. These limitations have highlighted the need for next-generation CDK-directed strategies capable of improving selectivity, extending disease control, and overcoming adaptive escape pathways. This Review examines the evolving landscape of CDK-targeted therapeutics in breast cancer, with particular emphasis on emerging CDK4-selective inhibitors, CDK2-directed approaches, and broader multi-CDK strategies. We discuss the biological rationale underpinning these agents, the mechanisms of resistance that have informed their development, and the clinical opportunities they may create across both advanced and early-stage settings. By refining target specificity and addressing resistance-associated cell-cycle rewiring, next-generation CDK inhibitors may reduce toxicity, enhance treatment durability, and enable more effective combination and sequencing strategies. Collectively, these advances promise to move breast cancer treatment beyond current CDK4/6 inhibition toward more precise, adaptable, and durable cell-cycle–directed therapy.
Authors
Daria Seriak, Jun Yong Kim, Geoffrey I. Shapiro, Antonio Giordano
Total views: 4139
Abstract
Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as “magic bullets” that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair–targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.
Authors
Chenxu Guo, Leif W. Ellisen
Total views: 3795
Abstract
GLP-1 receptor agonist (GLP-1RA) medications have transformed the treatment of type 2 diabetes (T2D) and obesity, with robust evidence for cardiovascular and renal benefits. Nevertheless, GLP-1RA therapy is associated with a pattern of adverse events affecting their safety and tolerability. Here, we delineate mechanisms potentially leading to adverse responses to GLP-1RAs, describe the impact of side effects on treatment persistence, discuss potential mitigation strategies, and identify areas requiring further studies. Concerns that GLP-1RAs raise the risk for acute pancreatitis and pancreatic cancer have been dispelled by long-term clinical trials. However, GLP-1RAs may confer an increased risk for thyroid cancer. Sight-threatening eye complications resulting from rapid reductions in glycemia may be avoided by retinal screening and ophthalmologic treatment before GLP-1RA initiation. The slowing of gastric emptying with GLP-1RA treatment increases the propensity for retained gastric contents, which could increase the risk of aspiration during upper gastrointestinal endoscopy or general anesthesia. These risks may, however, be elevated in individuals with long-standing T2D even in the absence of GLP-1RA treatment. Improved pharmacovigilance and a more standardized, quantitative assessment of adverse events in clinical trials, particularly in the assessment of gastrointestinal symptoms, would facilitate definition of the benefit-risk relationship for individual medications and indications.
Authors
Ryan J. Jalleh, Nicholas J. Talley, Michael Horowitz, Michael A. Nauck
Total views: 3701
Abstract
Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflecting in part the limitations of existing preclinical systems to fully model the human genetic context of disease. Patient-derived induced pluripotent stem cells (iPSCs) have the potential to address this shortcoming by faithfully recapitulating human cell biology and preserving each patient’s complete genetic architecture. This Review examines iPSC-based models of neurodegeneration across three themes. First, we discuss mechanisms revealed by these models, from convergent pathways uncovered by familial mutations to early evidence that sporadic disease biology is accessible at sufficient cohort scale. Second, we evaluate culture systems from 2-dimensional monocultures to organoids, examining how increasing complexity expands addressable biological questions while introducing trade-offs. Third, we address the aging problem: reprogramming erases epigenetic signatures of donor aging, removing the cellular context in which late-onset sporadic neurodegeneration emerges. We discuss strategies approximating aging in iPSC-derived neurons and highlight direct conversion strategies that preserve native epigenetic age, enabling access to age-dependent phenotypes. We propose a framework matching model systems to biological questions, improving mechanistic understanding and therapeutic development.
Authors
Shijie Wang, Lisa Elia, Weiyi Liu, Steven Finkbeiner
Total views: 3337
Abstract
Somatic alterations in the phosphoinositide 3-kinase (PI3K) pathway are frequent oncogenic drivers in cancer and are particularly relevant in estrogen receptor–positive breast cancer, where PI3K signaling integrates hormonal, growth factor, and metabolic inputs. Therapeutic targeting of PI3K has been limited by toxicity, pathway crosstalk, and adaptive resistance. Recent advances in structural and functional characterization of PIK3CA mutations have enabled the development of more selective inhibitors, including PI3K isoform–selective and emerging allosteric PI3Ka mutant–targeted compounds. These approaches aim to improve the therapeutic index while maintaining pathway inhibition. In parallel, combination strategies with endocrine therapy and CDK4/6 inhibitors have demonstrated clinical benefit in selected patient populations. However, responses are often transient owing to compensatory signaling and pathway reactivation. Additional metabolic and transcriptional adaptations further contribute to sustaining tumor cell survival. Overall, PI3K-targeted therapy is evolving along two complementary paths: increased mutant-selective inhibition to improve therapeutic index and broader pathway-level strategies designed to overcome adaptive resistance and achieve more durable responses. Ongoing efforts focus on optimizing combination strategies, enhancing development of predictive biomarkers, and improving therapeutic sequencing to achieve durable responses while minimizing toxicity.
Authors
Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga
Total views: 3207
Abstract
Preclinical drug development has long relied on animal models to predict safety and efficacy before agents enter human trials, despite critical differences between human and animal model physiology. The withdrawal of rosiglitazone, rofecoxib, and terfenadine due to cardiovascular toxicity exemplifies the translational cost of this mismatch. Alternative, human-based systems enable more accurate modeling of cardiometabolic diseases in a dish; in 2025, the US FDA’s new approach methodologies (NAMs) roadmap authorized the submission of results from human-relevant models. The roadmap encourages utilizing biological and digital twins as part of an integrated, context-specific, fit-for-purpose strategy. A “biological twin” is a human-derived in vitro system that captures the physiology of a patient and can be used to assess potential cardiotoxicity by drug metabolites. A “digital twin” is the computational counterpart trained on clinical drug response results that can further interpret biological twin data at the patient scale and predict pharmacological parameters. NAMs are no longer experimental but are not yet fully validated as replacements for animal models; major challenges remain before they can be effectively incorporated into the cardiometabolic disease drug discovery pipeline. Addressing these challenges head-on is essential for improving drug development and prediction of their cardiovascular safety.
Authors
Debarun Patra, Ibrahim M. Sayed, Ravichandra Venkateshappa, Latha Palaniappan, Tracey McLaughlin, Joseph C. Wu
Total views: 3135
Abstract
Despite growing recognition of invasive lobular carcinoma (ILC) as a biologically and clinically distinct subtype of breast cancer, ILC remains understudied. Most contemporary therapeutic trials continue to enroll patients predominantly with invasive ductal carcinoma/invasive carcinoma of no special type and rarely stratify by histology. As a result, ILC’s unique disease biology, characteristic loss of E-cadherin function, diffuse growth pattern, and distinct metastatic tropism remain underrepresented in evidence that guides systemic therapy recommendations. In this Review, we examine key molecular alterations and emerging therapeutic targets in ILC, emphasizing recent preclinical discoveries that identify subtype-specific therapeutic vulnerabilities and guide the development of histology-specific treatment approaches for this unique disease. In combination with endocrine therapies, effective targeting in ILC may require a multilayered strategy that extends beyond genomic alterations to leverage ILC’s specific estrogen receptor–associated proteins, metabolism, and tumor microenvironment. Future clinical trial frameworks incorporating prespecified ILC cohorts, tailored endpoints, and coclinical approaches enabling parallel testing in patients and patient-derived models could help accelerate the development and evaluation of ILC-targeted therapeutics.
Authors
Kristina A. Fanucci, Shaymaa Bahnassy, Arya Mariam Roy, Anna Sokolova, Daniel G. Stover, Peter T. Simpson, Rebecca B. Riggins, Rinath Jeselsohn
Total views: 3092
Abstract
One in eight women will be diagnosed with breast cancer in their lifetime. Most breast cancers express estrogen receptor α (ERα) and depend on its signaling, which promotes tumor growth, survival, and metastatic spread through hormone-dependent transcriptional reprogramming. Selective estrogen receptor degraders/downregulators (SERDs), such as fulvestrant (faslodex), which was FDA approved in 2002, are second-line endocrine therapies for the treatment of advanced metastatic disease. Tumors containing activating hotspot mutations in ESR1 (the gene encoding ERα) retain some sensitivity to fulvestrant but require higher doses to achieve inhibition of the mutant receptor. Substantial efforts to develop next-generation SERDs with improved pharmacology over fulvestrant have led to the FDA approval of the first-in-class orally available SERD elacestrant (Orserdu), followed by imlunestrant (Inluriyo), and the anticipated approval of several more therapies. Excitingly, recent studies show that in addition to their previously described antitumoral mechanisms, SERDs also act by increasing antitumor immunity. In this Review, we detail the current SERD clinical landscape and our emerging understanding of the interplay among SERDs, breast cancer cells, and the tumor immune microenvironment.
Authors
Kristen S. Young, Sean W. Fanning
Total views: 2988
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)