bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic effect of porphyrin-induced photodynamic antimicrobial chemotherapy combined with Gentamicin against clinically important gram-positive and gram-negative bacteria
Authors: Murage Margaret W. , Amuhaya Edith K. , Mbatia Betty N. , Muge Edward K. , Derese Solomon
Published: December 2024

Infectious diseases remain a major cause of death globally, particularly in developing countries, with antibiotic resistance exacerbating the issue. To address this, alternative treatments like Photodynamic Antimicrobial Chemotherapy (PACT) using porphyrins as photosensitizers are gaining attention. This study investigates the antibacterial activity of a free base porphyrin and its zinc, indium, and gallium metal conjugates, both independently and in combination with gentamicin (GEN), against gram-positive (Staphylococcus aureus) and gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). The porphyrins and their conjugates were synthesized and characterized via UV-Vis spectroscopy, NMR, mass spectrometry, and FTIR. Photophysical properties, such as singlet oxygen and fluorescence quantum yields, were also determined. The indium metallated porphyrin showed the highest singlet oxygen yield ([Formula: see text]) (0.32) and excellent photodynamic activity, eradicating bacteria at sub-lethal light doses. The combination of PACT and GEN notably enhanced antibacterial efficacy, with the porphyrin P-InCl combined with GEN showing significant inhibition zones: 41.3 mm for S. aureus, 34.0 mm for E. coli, and 34.8 mm for P. aeruginosa, compared to GEN alone. This demonstrates the synergistic effect of combining PACT with antibiotics, significantly improving bacterial reduction compared to individual treatments. The study highlights the potential of this combination therapy as an effective strategy against antibiotic-resistant infections.
Palaeoenvironments and sedimentation in the southeastern margin of Lake Pannon (Western Smederevsko Podunavlje Area, Serbia)
Authors: Radivojević Dejan , Radonjić Miloš , Magyar Imre
Published: December 2024

The Late Miocene–Pliocene Lake Pannon gradually diminished as sediments sourced from the Alps and Carpathians filled its basin and pushed its northern shoreline southward. Sedimentary successions from the southern margin of the lake SE of Belgrade (Smederevsko Podunavlje area) were studied in several outcrops and interpreted together with literature data referring to the area. Three facies associations were distinguished: offshore lacustrine clays, delta front sands and delta plain sands with paludal huminitic clays. The facies associations are organized into at least four delta-scale (10–50 m thick) transgressive–regressive cycles. The age of the succession spans from the Sarmatian–Pannonian boundary (11.6 Ma) to the
Prosodacnomya dainellii
Zone (7.6–7.2 Ma), and most of the littoral and sublittoral mollusc biozones of that interval are represented by their characteristic fossils in the succession. These patterns suggest a very low subsidence rate, a low accommodation rate and a low rate of sedimentation. Although the investigated sections do not display any obvious stratigraphic gap, erosion must have been a major factor determining the apparently low average sedimentation rate. Persistent aggradation of lacustrine–deltaic sediments at the southern margin of the Pannonian Basin aligns with the general aggradational architecture of the basin fill in the high-supply endorheic Lake Pannon.
Learning About Development from Interventions
Authors: Bailey Drew H. , Watts Tyler W. , Hart Emma R. , Yu Mi Joung
Published: December 2024

In this review, we argue that the role of causally informative evaluations of interventions within developmental psychology should be elevated. Causally informative research on the effects of intervention inputs on medium- and long-term outcomes are sufficiently relevant to developmental psychology to inform or even constrain our theories and to inspire future developmental research. We review several examples of research that yielded developmental insights from such work and discuss a broad theoretical framework for using developmental theory to reason about the effects of interventions and vice versa. Finally, we discuss potential challenges that have inhibited the role of causally informative research on interventions in developmental psychology along with actionable steps researchers can take to integrate such work more deeply into the field.
Review—Understanding Thermal Runaway in Lithium-Ion Batteries: Trigger, Mechanism, and Early Warning Strategies
Authors: Liu Chenchen , Dai Hai , Wang Danyang , Ren Xiaobo , Lyu Siqi , Fan Jinbao , Lv Shiyin , Zhu Shengxin , Li Na , Wang Yana
Published: December 2024

Safety issues have hindered the rapid development of lithium-ion batteries for use in energy storage and vehicles, especially the frequent battery thermal runaway (TR) accidents. The TR of lithium-ion batteries can result in fire and explosion. Understanding the thermal runaway mechanisms and triggers is key to optimizing early warning strategies. Here, we provide a comprehensive review from three aspects: trigger, mechanism, and early warning strategy. By analyzing typical incidents, both external abuses and internal defects are identified as key triggers of TR. The energy release mechanisms during TR are explored through multi-physics coupling models, leading to the development of a TR safety-phase diagram. The primary exothermic reactions and heat generation pathways are summarized, with a focus on the contribution of side reactions in various material systems. Furthermore, early warning strategies are reviewed, including single-signal and multi-physics characteristic signal analysis, highlighting the technical challenges for future TR safety predictions. This review enhances the understanding of TR mechanisms and is crucial for advancing battery safety.
Efficacy of Clinical Tests in the Diagnosis of Meralgia Paresthetica: A Case Control Study
Authors: Paneyala Shasthara , S. Chandrashekhar Nemichandra , Sundaramurthy Harsha , Prashant Akila , Krishna Lakshmi
Published: December 2024

Background: Meralgia paresthetica (MP), a common entrapment syndrome, presents with paresthesias in the anterolateral aspect of the thigh. Clinical tests used to diagnose MP are the pelvic compression test, neurodynamic testing, and Tinel’s sign. The diagnostic accuracy of these three tests has not been analyzed to date. Hence, this study aims to analyze the sensitivity and specificity of these clinical tests.

Case Study: This study was a hospital‐based case‐control study that included 30 electrophysiologically proven patients with MP. The data were gathered over a period of 6 months after obtaining institutional ethics committee clearance. Demographics and risk factors among our cases are in keeping with the global scenario. The sensitivity and specificity of the pelvic compression test were 86.7% and 93.0%, the Tinsel sign was 85.1% and 87.5%, and neurodynamic testing was 86.7% and 93.0%, respectively.

Conclusion: Our study proves that these tests are a simple and accurate aid in the diagnosis of MP. These bedside clinical tests can be utilized to establish a diagnosis of MP in a setting of conflicting differentials such as lumbar canal stenosis or thoracolumbar junction disc pathologies and guide in choosing the next line of investigation.
Optimization of Instant Beverage Powder Containing Propolis Extract Nanoliposomes
Authors: Mirzazadeh Mehdi , Bagheri Hadiseh , Rasi Fatemeh , Mirzazadeh Nasim , Alam Zahra , Akhavan-Mahdavi Sahar
Published: December 2024

Propolis is a natural resinous complex mixture produced by honeybees that contain various bioactive compounds. However, these bioactive compounds are chemically unstable and their absorption in the gastrointestinal tract is influenced by their solubility and stability. Encapsulation technology has been employed to increase their bioavailability and protect them against hostile conditions. Nanoliposomes are nanoscale lipid‐based vesicles that can encapsulate various bioactive compounds, including propolis extracts. Therefore, in this study, propolis extract was encapsulated by nanoliposome technique and used in instant drink formulation. Nanoliposome characterization was done regarding particle size (255 ± 0.21 nm), zeta potential (−37.6 ± 1.14 mV), and encapsulation efficiency (73.71 ± 0.94). Response surface methodology (RSM) was employed to determine the effect of nanoliposome concentration (0%–5%) on the beverage characteristics including Brix, acidity, hygroscopicity, water solubility index, total phenol content, total microbial count, and sensory analyses. RSM predicted that a 3.19% nanoliposome would provide the overall optimum region for preparing the beverage with the best characteristics. Therefore, nanoliposome containing propolis can be successfully used in the enrichment of the beverage formulation by maintaining the sensory characteristics and improving its quality.
A Retrospective 8‐Year Single Institutional Study in Germany Regarding Diagnosis, Treatment, and Outcome of Malignant Parotid Tumors
Authors: Andrianopoulou S. , Fiedler L. S. , Lippert B. M. , Bulut O. C.
Published: December 2024

This study sought to comprehensively evaluate the diagnosis, therapeutic interventions, and outcomes of individuals afflicted with malignant parotid tumors at a tertiary care otolaryngology department in Heilbronn, Germany, spanning the years 2010–2018. The primary objective was to juxtapose this dataset with findings from analogous single and multicenter investigations. We conducted a meticulous analysis of electronic medical records pertaining to 45 patients subjected to primary parotid cancer treatment. The male‐to‐female ratio was 3:2, with an average age of 61 years. Predominant histological types included mucoepidermoid and squamous cell carcinomas, with ultrasound emerging as the predominant diagnostic modality (97.8% sensitivity). Intraoperative frozen sections exhibited a high level of sensitivity. Notably, lymph node metastasis was prevalent in T3 tumors, frequently located intraparotid and at Neck level II. Solely one patient exhibited distant metastases (pulmonary). All patients underwent parotidectomy, and 29% necessitated a secondary procedure due to positive resection margins. Postoperative complications encompassed facial nerve palsy, seromas, and salivary fistulas. Adjuvant radiotherapy (38%) was recommended for high‐grade tumors, T3/T4 stage, N+, perineural invasion (PNI), and positive or uncertain surgical margins. Neck dissection was executed in 67% of instances, with 20% revealing occult lymph node metastases. Recurrence manifested in 22% of patients, primarily as locoregional recurrence (80%) and distant metastases (20%). The 3‐year recurrence‐free survival (RFS), cancer‐specific survival (CSS), and overall survival (OS) rates stood at 72.1%, 91.9%, and 87.5%, respectively. Noteworthy factors influencing RFS included preoperative facial palsy, T stage, resection margins, and PNI. In summary, the management of parotid cancer involving surgical interventions, neck dissection, and radiotherapy in high‐risk patients yielded commendable outcomes with minimal complications, showcasing survival rates exceeding 70%. Timely diagnosis at an early stage is imperative for achieving tumor‐free margins and enhancing survival rates. More assertive therapeutic strategies are advocated for cases presenting with preoperative facial nerve palsy and PNI.
Effect of Thickening Additives and Heat Pump Drying Temperature on Probiotics (Lactobacillus casei) and Physicochemical Properties of Mango Powders
Authors: Thi Tran Nhi Yen , Dao Tan Phat , Nghia Nguyen Huu , Nhu Dang Be , Duc Vu Ngoc , Ngoc Nguyen Quy , Minh Nguyen Tien , Bao Huynh Long , Xuan Huynh Phong , Nguyen Tung Xuan Tan
Published: December 2024

Mango powders were supplemented with probiotics and then subjected to heat pump drying. The study evaluated the physicochemical, biochemical, and probiotic properties of the resulting mango powders. Through the effects of thickening additives type (sodium alginate and Arabic gum), concentration and drying temperature have been shown to have a direct effect on the objective functions of interest. The results showed that the foam stability increased approximately 2.14 times (MPD‐S), the solubility of powders tended to be similar to 67.65 ± 0.40%, while microbial density decreased and remained within the allowable limit of 6.9 × 106 CFU/mL (MPD‐G). Through heat pump drying, these values were drastically reduced. The mango powders were mixed for a second time to improve the organoleptic values and showed commercial viability with a score greater than 11.2.
Human iPSC–Derived Endothelial Cells Exhibit Reduced Immunogenicity in Comparison With Human Primary Endothelial Cells
Authors: Jia Haiyan , Moore Melanie , Wadhwa Meenu , Burns Chris
Published: December 2024

Human induced pluripotent stem cell (iPSC)–derived endothelial cells (ECs) have emerged as a promising source of autologous cells with great potential to produce novel cell therapy for ischemic vascular diseases. However, their clinical application still faces numerous challenges including safety concerns such as the potential aberrant immunogenicity derived from the reprogramming process. This study investigated immunological phenotypes of iPSC‐ECs by a side‐by‐side comparison with primary human umbilical vein ECs (HUVECs). Three types of human iPSC‐ECs, NIBSC8‐EC generated in house and two commercial iPSC‐ECs, alongside HUVECs, were examined for surface expression of proteins of immune relevance under resting conditions and after cytokine activation. All iPSC‐EC populations failed to express major histocompatibility complex (MHC) Class II on their surface following interferon‐gamma (IFN‐γ) treatment but showed similar basal and IFN‐γ‐stimulated expression levels of MHC Class I of HUVECs. Multiple iPSC‐ECs also retained constitutive and tumor necrosis factor‐alpha (TNF‐α)‐stimulated expression levels of intercellular adhesion molecule‐1 (ICAM‐1) like HUVECs. However, TNF‐α induced a differential expression of E‐selectin and vascular cell adhesion molecule‐1 (VCAM‐1) on iPSC‐ECs. Furthermore, real‐time monitoring of proliferation of human peripheral blood mononuclear cells (PBMCs) cocultured on an endothelial monolayer over 5 days showed that iPSC‐ECs provoked distinct dynamics of PBMC proliferation, which was generally decreased in alloreactivity and IFN‐γ‐stimulated proliferation of PBMCs compared with HUVECs. Consistently, in the conventional mixed lymphocyte reaction (MLR), the proliferation of total CD3+ and CD4+ T cells after 5‐day cocultures with multiple iPSC‐EC populations was largely reduced compared to HUVECs. Last, multiple iPSC‐EC cocultures secreted lower levels of proinflammatory cytokines than HUVEC cocultures. Collectively, iPSC‐ECs manifested many similarities, but also some disparities with a generally weaker inflammatory immune response than primary ECs, indicating that iPSC‐ECs may possibly exhibit hypoimmunogenicity corresponding with less risk of immune rejection in a transplant setting, which is important for safe and effective cell therapies.
Plasma Cell–Free DNA Chromatin Immunoprecipitation Profiling Depicts Phenotypic and Clinical Heterogeneity in Advanced Prostate Cancer
Authors: Sipola Joonatan , Munzur Aslı D. , Kwan Edmond M. , Seo Clara C.Y. , Hauk Benjamin J. , Parekh Karan , Liao Yi Jou (Ruby) , Bernales Cecily Q. , Donnellan Gráinne , Bloise Ingrid , Fung Emily , Ng Sarah W.S. , Wang Gang , Vandekerkhove Gillian , Nykter Matti , Annala Matti , Maurice-Dror Corinne , Chi Kim N. , Herberts Cameron , Wyatt Alexander W. , Takeda David Y.
Published: December 2024

Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell–free DNA (cfDNA) in humans may enable the capture of disparate prostate cancer phenotypes. In this study, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor–binding sites correlated strongly with ctDNA fraction—demonstrating capture of prostate cancer–specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinicogenomic features: bone- versus liver-predominant disease, serum PSA, biopsy-confirmed histopathologic subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential use for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insights into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.

Significance: Plasma cell–free chromatin immunoprecipitation sequencing enables phenotypic dissection of lethal prostate cancer and is a practical tool for biomarker discovery while overcoming prior limitations of access to relevant tissue and reliance on model systems.
Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant Non–Small Cell Lung Cancer
Authors: von Itzstein Mitchell S. , Burns Timothy F. , Dowell Jonathan E. , Horn Leora , Camidge D. Ross , York Sally J. , Eaton Keith D. , Kyle Kelly , Fattah Farjana , Liu Jialiang , Mu-Mosley Hong , Gupta Arjun , Nadeem Urooba , Gao Ang , Zhang Song , Gerber David E.
Published: December 2024

Purpose:

Patients with Kirsten rat sarcoma viral oncogene (KRAS)–mutant non–small cell lung cancer (NSCLC) have limited therapeutic options. Based on the activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated, advanced KRAS-mutant NSCLC.

Patients and Methods:

The primary outcomes of this multicenter phase I/II dose-escalation trial of selinexor plus docetaxel were safety and tolerability. Selinexor was started 1 week before docetaxel to permit monotherapy pharmacodynamic assessment.

Results:

Among 40 enrolled patients, the median age was 66 years, 55% were female, and 85% were White. The MTD was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every 3 weeks. The most common adverse events were nausea (73%, 8% grade ≥3), fatigue (70%, 5% grade ≥3), neutropenia (65%, 60% grade ≥3), and diarrhea (58%, 10% grade ≥3). Of 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild-type TP53 (42%), including response and disease control rates (27% and 80% vs. 9% and 27%, respectively; P = 0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% confidence interval, 0.07–0.67; P = 0.003). After selinexor initiation and prior to docetaxel administration, serum lactate dehydrogenase levels increased an average of 51 U/L in TP53-altered cases and decreased an average of 48 U/L in TP53 wild-type cases (P = 0.06).

Conclusions:

Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS-mutant NSCLC. The regimen has promising efficacy in TP53 wild-type cases, in which selinexor monotherapy may also have activity.
KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Authors: Chutake Yogesh K. , Mayo Michele F. , Dumont Nancy , Filiatrault Jessica , Breitkopf Susanne B. , Cho Patricia , Chen Dapeng , Dixit Vaishali S. , Proctor William R. , Kuhn Eric W. , Bollinger Martinez Sarah , McDonald Alice A. , Qi Jianfeng , Hu Kan-Nian , Karnik Rahul , Growney Joseph D. , Sharma Kirti , Schalm Stefanie S. , Gollerkeri Ashwin M. , Mainolfi Nello , Williams Juliet A. , Weiss Matthew M.
Published: December 2024

Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT-253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with small-molecule MDM2/p53 interaction inhibitors and induces apoptosis in a range of hematologic and solid tumor lines. A single intravenous dose of KT-253 triggered rapid apoptosis and sustained tumor regression in p53 wild-type acute myeloid leukemia and acute lymphoblastic leukemia xenograft models. Additionally, a single intravenous dose of KT-253 in combination with standard-of-care venetoclax overcame venetoclax resistance in an acute myeloid leukemia xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type malignancies, as a monotherapy and in combination with standard-of-care agents.
Abstract A014: OICR41103: a chemical probe for investigating DCAF1 function and therapeutic potential
Authors: Noureldin Mahmoud , Kimani Serah , Wilson Brian , Halabelian Levon , Al-awar Rima
Published: December 2024

DCAF1 is a multifunctional protein that plays an important role in cellular processes, including protein degradation, cell cycle regulation, and immune function, by serving as a substrate receptor for RING-type CRL4 and the HECT family EDVP E3 ubiquitin ligases. Due to its involvement in various biological pathways and diseases, such as cancer and viral infections, there is a growing need for tools to study and regulate DCAF1 functions. Building upon our previous discovery of OICR-38268, a small-molecule binder of the DCAF1 WD40 domain, we have developed an improved chemical probe, OICR-41103. This compound exhibits enhanced binding affinity and selectivity for the WD40 domain of DCAF1. We successfully crystallized OICR-41103 with the WD40 domain, revealing its binding mode. Our probe binds to the WD40 domain of DCAF1 with a low nanomolar affinity in biophysical assays, and engages this domain in cells at nanomolar concentrations. This work presents a valuable chemical probe for studying DCAF1 function and provides a foundation for future drug discovery efforts, either by directly targeting DCAF1 or leveraging it for PROTAC-based strategies

Citation Format: Mahmoud Noureldin, Serah Kimani, Brian Wilson, Levon Halabelian, Rima Al-awar. OICR41103: a chemical probe for investigating DCAF1 function and therapeutic potential. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A014
Abstract A019: Discovery of a potent and brain-penetrable tubulin inhibitor SB-216 that shows efficacy in primary tumor growth and brain metastasis
Authors: Adeleye Kelli L. , Pochampally Satyanarayana , Krutilina Raisa , Wang Rui , Yue Junming , Seagroves Tiffany , Duane Miller D. , Li Wei
Published: December 2024

A major clinical challenge in cancer treatment is to prevent and treat metastatic disease. Despite the significant advancements in targeted therapy and immunotherapy, chemotherapeutic drugs, including taxanes, remain one of the mainline systemic treatment options for several major cancer types. However, the prolonged use of taxanes has been associated with the development of multidrug resistance, dose-limiting hematopoietic toxicity, and neurotoxicity, frequently presenting as persistent peripheral neuropathy. In addition, these drugs have limited blood-brain barrier penetration, and thus they are not effective in treating brain tumors or brain metastases from other cancer types, particularly breast cancer metastases. We have developed a new generation of tubulin inhibitors, termed colchicine binding site inhibitors (CBSIs). Unlike taxanes, these compounds bind to the colchicine site in tubulin, structurally less complex than taxanes which enables fine-tuning of physical-chemical properties, and shows the ability to overcome acquired drug resistance to existing taxane drugs. One of the best inhibitors in this class of compounds is SB-216. We have solved the high-resolution crystal structure of SB-216 in a complex with tubulin protein (PDB: 6X1F) and confirmed its mode of action. Extensive preclinical evaluations of SB-216 in a number of tumor models, including taxane-resistant prostate cancer, melanoma, ovarian cancer, and triple-negative breast cancer, indicated that SB-216 is highly potent in suppressing both primary tumor growth and tumor metastases. Importantly, SB-216 shows high brain penetration and shows efficacy in suppressing brain metastases from triple-negative breast cancer. SB-216 also has good drug-like properties and shows strong promise as a new generation of tubulin inhibitor for systemic cancer treatments, not only in brain metastasis from non-CNS tumors but also potentially be useful for brain tumors such as glioma. The work is supported by NIH/NCI grants R01CA14876 and R01CA276152 and the DoD grant HT9425-23-1-0216.

Citation Format: Kelli L. Adeleye, Satyanarayana Pochampally, Raisa Krutilina, Rui Wang, Junming Yue, Tiffany Seagroves, Duane D.Miller, Wei Li. Discovery of a potent and brain-penetrable tubulin inhibitor SB-216 that shows efficacy in primary tumor growth and brain metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A019.
Abstract A020: Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors
Authors: Mangoli Avani , Kim Sarah , Blethen Kathryn , Everhart Angela , Nikiforov Sasha , Grant Gerry , Avigliano Luke
Published: December 2024

The blood-brain barrier (BBB) remains a significant obstacle in delivering effective chemotherapeutics to treat pediatric brain tumors, limiting drug penetration and reducing therapeutic outcomes. To overcome this challenge, we investigated the use of liposomal topotecan (TPT), encapsulated in a sonosensitive formulation, designed for controlled release triggered by low-intensity focused ultrasound (LIFU). In this study, we evaluated the in vitro efficacy of a sonosensitive liposomal topotecan formulation. The liposomal topotecan was created using remote loading with an ammonium sulfate gradient. TPT was loaded at a drug-to-lipid ratio of 1:10. The liposome was composed of hydrogenated soy PC, cholesterol, and DSPE-PEG2000. IC50 assay comparing free topotecan to the liposomal topotecan indicated that the cytoxicity of free TPT is lower than liposomal TPT indicating a sustained release of drug which would decrease long term toxicity. In addition, pharmcokinetic fluorescent quantification of liposomal topotecan showed linear increase in free drug (ug/uL) as liposomal TPT concentration is increased in brain homogenates. We hypothesize that tumor growth inhibition and overall survival would be significantly improved in mice receiving LIFU-mediated liposomal topotecan delivery. Our future work includes additional pharmokinetics with survival analysis in vivo with and without low intensity focused ultrasound. These results highlight the potential of combining liposomal drug formulations with focused ultrasound to overcome the challenges of BBB permeability, offering a promising therapeutic strategy for improving drug accumulation and survival outcomes in pediatric brain tumor models.

Citation Format: Avani Mangoli, Sarah Kim, Kathryn Blethen, Angela Everhart, Sasha Nikiforov, Gerry Grant, Luke Avigliano. Liposomal topotecan with low-intensity focused ultrasound utilization to improve drug penetration with brain parenchyma in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A020.
Abstract IA003: Synthetic lethality: Pathways to therapeutic discovery
Authors: Durocher Daniel
Published: December 2024

The orchestration of DNA repair is of fundamental importance to the maintenance of genomic integrity and tumor suppression. DNA damage must be detected in the context of the varied chromatin landscape, its presence must be communicated throughout the cell to alter many ongoing processes, and the machinery that will mend the lesion must be recruited to the damage site. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells. I will highlight how these screens can be used to identify new genome stability factors, characterize drug responses and provide new insights into the genetic architecture of the genome stability network. I will finally present how these screens can also identify potentially actionable synthetic lethal genetic interactions that could form the basis of new oncology drug discovery efforts.

Citation Format: Daniel Durocher. Synthetic lethality: Pathways to therapeutic discovery. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA003
Abstract IA004: Overcoming traditional design limitations with AI-based discovery
Authors: Hallett David J.
Published: December 2024

The properties of a new drug are set at the point of design, including any potential design flaws. Many small molecules that make it to human trials fail to progress beyond Phase 1 due to these flaws, which manifest as unacceptable side effects (either alone or in combination), meaning the drug (and therefore the pathway it is modulating) can never be adequately evaluated. This presentation will highlight how, through the thoughtful generation of a precise target candidate profile (TCP) and the subsequent use of GenAI, clinical candidates can now be precision designed to more exacting standards. Such molecules have the potential to have improved therapeutic indices, even against protein targets that are usually associated with mechanism-based adverse events.

Citation Format: David J. Hallett. Overcoming traditional design limitations with AI-based discovery. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA004
Abstract IA007: Preclinical Approaches to Discovery and Development of Novel Combination Therapies
Authors: Mettetal Jerome T.
Published: December 2024

Drug combinations provide an important tool to address the complexity of tumor biology, and the ability to drive deeper and more durable responses has led to many successful combination regimens in clinical use today. There are more possible novel combination regimens than can be feasibly explored clinically, and preclinical studies have become a common tool to identify and prioritize combinations partners for clinical investigation. Historically, these approaches have focused heavily on identification of synergy, however, a growing body of research is beginning to indicate that synergy may not be a key predictor of clinical utility. To better understand the role of synergy in combinations, we experimentally explored acquired resistance to combination therapies in preclinical models, and counterintuitively, find that combinations which derive activity through synergy rather than additivity can lead to less undesirable outcomes. Specifically, we find that the combinations which rely on synergy are more likely to develop resistance as well as demonstrate greater loss of combination activity upon acquisition of resistance than an equally active additive combination. We propose that instead of relying on synergy for combinations discovery, that a framework based on the 5Rs can be employed which emphasizes a more holistic view of combination rationale, development, and proposed clinical utility. We demonstrate the application of these principles to discovery of novel therapeutic agents in analysis of a large-scale pan-tumor screen, and how these factors can be used to identify novel rational combination partners linked to specific disease segments which drive activity in vivo. As more agents with novel mechanisms enter clinical development, preclinical studies will play an increasingly important role in designing combination regimens which can attack the tumor from multiple angles, leading to better activity, and present a more favorable therapeutic index.

Citation Format: Jerome T. Mettetal Preclinical Approaches to Discovery and Development of Novel Combination Therapies. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA007
Abstract IA010: Bioengineering cell-based therapeutics
Authors: Veiseh Omid
Published: December 2024

Cell-based therapeutics are an emerging modality that can potentially treat many currently intractable diseases through uniquely powerful modes of action. Our group is innovating new biomaterials and cellular constructs for medicine and biology by combining chemical biology, cellular engineering, and multi-scale fabrication. We have pioneered innovative approaches to synthesizing and in vivo screening of large libraries of biomaterial formulations for tailored applications in immunology and medicine. In my talk, I will describe our advances in discovering immunomodulatory biomaterials that can interact appropriately with the host immune system for localized immunomodulation. I will highlight our efforts to develop “cytokine factories” locally activating the innate and adaptive immune response to generate systemic immunotherapy and eradicate metastatic cancer. This approach has advanced to phase I/II human clinical trials for treating recurrent, refractory ovarian cancer.

Citation Format: Omid Veiseh. Bioengineering cell-based therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA010.
Abstract IA017: Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer
Authors: Zhou Xin
Published: December 2024

The membrane and extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor overexpressed in a broad spectrum of cancers, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, we show that TransTACs enabled the targeting of drug-resistant epidermal growth factor receptor (EGFR)-driven lung cancer and the reversible control of primary Chimeric Antigen Receptor (CAR)-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and for targeted cancer therapy.

Citation Format: Xin Zhou. Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA017.
Abstract IA022: DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma
Authors: Wk Josephzore , D'Alessio Joseph A. , Yerramilli-Rao Padmaja , Blankenship John , Buntin Kathrin , Burger Matthew , Chen Zhuoliang , Cho Young Shin , Davis John , Ebel Nicolas , Eisfeld Jochen , Haberkorn Anne , Hainzl Dominik , Hoffmaster Keith , Napp Matthias , Pistorius Dominik , Rauniyar Vivek , Reynolds Aimee , Romanet Vincent , Schnell Christian , Seiss Katherine , Tschantz William R. , Wieland-Berghausen Susanne , Wimmer Laurin , Wuersch Kuno , Zhang Alan , Manchado Eusebio
Published: December 2024

Activating mutations in GNAQ/GNA11, encoding the G protein α subunits Gq and G11, are the most frequent genetic alterations in uveal melanoma (UVM) and considered to be critical for the initiation and maintenance of this malignancy. Despite inhibitors of Gq and G11 exhibiting promising preclinical anti-uveal melanoma activity, their therapeutic potential is limited by on-target toxicities associated with the ubiquitous expression and critical biological processes mediated by these G proteins. Here we report the discovery of a novel Gq/11 inhibitor-based antibody-drug-conjugate (ADC), DYP688, that selectively targets UVM cells, while sparing normal Gq/11-dependent cells. This conjugate consists of the highly potent and selective Gq/11 inhibitor SDZ475 (FR900359) conjugated to an antibody targeting PMEL17, a lineage gene having significant differential expression in melanoma. DYP688 potently inhibits Gq/11 oncogenic signaling, resulting in selective antiproliferative activity and apoptosis in PMEL17-positive, GNAQ/11-mutant UVM cells. In vivo, DYP688 exhibits marked and durable tumor regression in GNAQ/11-mutant UVM models, including patient-derived xenograft and liver metastasis models. Finally, we show that DYP688 features favorable preclinical pharmacokinetic and safety profiles, supportive of clinical evaluation. A phase 1 clinical trial with DYP688 is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with metastatic UVM and other GNAQ/11-mutant melanomas (clinicaltrials.gov identifier NCT05415072).

Citation Format: Josephzore Wk, Joseph A. D'Alessio, Padmaja Yerramilli-Rao, John Blankenship, Kathrin Buntin, Matthew Burger, Zhuoliang Chen, Young Shin Cho, John Davis, Nicolas Ebel, Jochen Eisfeld, Anne Haberkorn, Dominik Hainzl, Keith Hoffmaster, Matthias Napp, Dominik Pistorius, Vivek Rauniyar, Aimee Reynolds, Vincent Romanet, Christian Schnell, Katherine Seiss, William R. Tschantz, Susanne Wieland-Berghausen, Laurin Wimmer, Kuno Wuersch, Alan Zhang, Eusebio Manchado. DYP688, a first-in-class PMEL17-targeted antibody drug conjugate delivering a Gq/11-specific inhibitor for the treatment of metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA022.
Abstract PR002: EP300 loss of function is a pan-cancer sensitizer to BET inhibition
Authors: Babak Tomas , Truesdell Peter , Vontz Greg , Heinecke Peter , Villa Doris Coto , Dai Meiou
Published: December 2024

Genetically targeted therapies have proven to be a successful approach to treating cancer because they inhibit the causal (driver) biology of tumors that is absent in healthy cells. While targeted therapies exist for most oncogenes, only a small fraction of loss-of-function (LoF) tumor suppressor genes (TSGs) have been drugged to date, despite TSG mutations causing 2/3 of all cancer. Here we report a novel 1st-in-class genetically targeted opportunity using BET inhibitors to treat EP300 LoF cancers. Among the hundreds of pharmacogenetic screens that we have conducted, this interaction is similar to PARP-BRCA1/HRD in significance, and among the strongest we have discovered. It is cancer-type agnostic and holds up with all potent BET inhibitors in various pre-clinical models, including PDXs. Mechanistically, we demonstrate that apoptosis induced by DNA catastrophe arising from pre-mature entry into S phase plays a significant role. BET inhibition blocks timely assembly of DNA replication factors, which leads to G1 arrest in healthy cells; cancer cells that lack p300, a key regulator of CDK2, and CDK7, proceed through G1-S before replication deficiencies can be resolved. EP300 loss of function is a causal driver in more than 25,000 new cancer cases per year in the US and there currently are no genetically targeted options for these patients. This presentation will focus on the discovery, characterization, and clinical re-entry plan for our BET inhibitor LFB-190, to treat EP300 LoF solid tumors.

Citation Format: Tomas Babak, Peter Truesdell, Greg Vontz, Peter Heinecke, Doris Coto Villa, Meiou Dai. EP300 loss of function is a pan-cancer sensitizer to BET inhibition. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR002
Abstract PR004: Brain penetrant allosteric EGFR inhibitors for NSCLC
Authors: Scott David , Cullis Courtney , Beyett Tyler , Feru Frederic , Gero Thomas , Gipson Krista , Gokhalle Praful , Gray Nathanael , Heppner David , Huang Sampson , Jänne Pasi , Pusalkar Sandeepraj , Eck Michael
Published: December 2024

Approximately 30-50% of Non-Small Cell Lung Cancer (NSCLC) patients already have CNS disease at time of diagnosis or else develop it during treatment, and there remains a need for better outcomes in these patients. The 3rd-generation covalent EGFR inhibitor osimertinib is an effective therapy for NSCLC patients, improving upon 1st-generation inhibitors gefitinib and erlotinib, and achieving enhanced brain penetration relative to those agents. However, the survival benefit relative to the 1st-generation inhibitors is observed primarily in patients with exon19 deletions rather than the L858R mutation. We developed a series of mutant-selective allosteric EGFR inhibitors that specifically target the L858R mutation (and subsequent resistance mutations), with high selectivity over wt EGFR and across the kinome. Early compounds including the isoindolinone JBJ-09-063 demonstrated good in vivo efficacy in mouse tumor models, despite limited bioavailability. Diversification and optimization of the chemistry, involving a scaffold hopping approach and the replacement of the thiazole amide with benzimidazole, delivered a set of compounds with promising potency and rodent PK. A subset of these achieved good brain exposure in mice and efficacy in an intracranial H1975 brain metastasis model. The mutant-selectivity and ability to co-bind with osimertinib makes an allosteric EGFR inhibitor an ideal partner for combination therapy, with the potential to deliver enhanced outcomes in L858R-driven NSCLC, especially for patients with CNS disease.

Citation Format: David Scott, Courtney Cullis, Tyler Beyett, Frederic Feru, Thomas Gero, Krista Gipson, Praful Gokhalle, Nathanael Gray, David Heppner, Sampson Huang, Pasi Jänne, Sandeepraj Pusalkar, Michael Eck. Brain penetrant allosteric EGFR inhibitors for NSCLC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR004
Long-Term Evaluation of Ocular Surface and Meibomian Gland Function after Laser-Assisted in situ Keratomileusis Surgery
Authors: Hei Lai Kenneth Ka , Hu Zhichao , Chiu Jamie Tsun , Aljufairi Fatema Mohamed Ali Abdulla , Sebastian Jake Uy , Cheng George Pak Man , Yip Wilson Wai Kuen , Young Alvin Lerrmann , Chee Yung Tham Clement , Chi Pui Pang Calvin , Chong Kelvin Kam Lung
Published: December 2024

Introduction: Laser-assisted in situ keratomileusis (LASIK) is a common refractive surgery. But it may lead to temporary dry eye due to reversible damage to the corneal subbasal nerve plexus. However, evidence on chronic ocular surface changes are unclear. This study reports the ocular surface changes, partial blinking rates, and meibomian gland statuses in eyes that underwent LASIK for at least 48 months. Methods: Cross-sectional, matched case-control comparison study, including 48 post-LASIK patients and 48 sex-, age-, smoking-, and axial length-matched healthy controls, recruited from a community eye screening program. Outcome measures include anterior segment clinical findings, keratographic and meibographic imaging. Results: Totally, 48 right eyes of 48 post-LASIK Chinese patients (39 females, 2 smokers) were analyzed with 48 right eyes of 48 matched healthy controls. The mean age at the time of ocular surface examination was 50 ± 11 years, and the axial length 26±1 mm. Post-LASIK eyes had a lower quality of meibum (p = 0.008) compared to healthy controls. Post-LASIK eyes were associated with a shorter Schirmer's test (p = 0.03). The ocular surface disease index (OSDI) score was higher in post-LASIK patients (p = 0.00001). Other anterior segment examination parameters, partial blinking rate, meibomian gland dropout, lipid layer thickness, noninvasive tear break-up time, and tear meniscus height were comparable between the 2 groups. Conclusions: Up to 75% of post-LASIK patients complained of on-going, chronic dry eye symptoms. Post-LASIK eyes were associated with a reduced aqueous tear production. Post-LASIK patients with chronic dry eye symptoms are advised to have periodic ocular surface evaluation. Treatments might be considered in patients with poor tear film stability.