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Cell Jun 2024Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi,...
Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.
Topics: Animals; Mice; Intestinal Mucosa; Extracellular Matrix; Myosin Type II; Mesoderm; Mesenchymal Stem Cells; Receptor, Platelet-Derived Growth Factor alpha; Morphogenesis; Matrix Metalloproteinases
PubMed: 38781967
DOI: 10.1016/j.cell.2024.04.039 -
The Journal of Clinical Investigation May 2024PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal...
PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.
PubMed: 38781024
DOI: 10.1172/JCI175949 -
Advances in Radiation Oncology Apr 2024Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/β, STS may be more responsive...
PURPOSE
Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/β, STS may be more responsive to hypofractionated radiation therapy (RT), which is often limited by long-term toxicity risk to surrounding normal tissue. An isotoxic approach using a hypofractionated accelerated radiation dose-painting (HARD) regimen allows for dosing based on clinical risk while sparing adjacent organs at risk.
METHODS AND MATERIALS
We retrospectively identified patients from 2019 to 2022 with unresected STS who received HARD with dose-painting to high, intermediate, and low-risk regions of 3.0 Gy, 2.5 Gy, and 2.0 to 2.3 Gy, respectively, in 20 to 22 fractions. Clinical endpoints included local control, locoregional control, progression free survival, overall survival, and toxicity outcomes.
RESULTS
Twenty-seven consecutive patients were identified and had a median age of 68 years and tumor size of 7.0 cm (range, 1.2-21.0 cm). Tumors were most often high-grade (70%), stage IV (70%), located in the extremities (59%), and locally recurrent (52%). With a median follow-up of 33.4 months, there was a 3-year locoregional control rate of 100%. The 3-year overall and progression-free survival were 44.9% and 23.3%, respectively. There were 5 (19%) acute and 2 (7%) late grade 3 toxicities, and there were no grade 4 or 5 toxicities at any point.
CONCLUSIONS
The HARD regimen is a safe method of dose-escalating STS, with durable 3-year locoregional control. This approach is a promising alternative for unresected STS, though further follow-up is required to determine long-term control and toxicity.
PubMed: 38778821
DOI: 10.1016/j.adro.2024.101447 -
EJNMMI Radiopharmacy and Chemistry May 2024A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach...
BACKGROUND
A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the "effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with At.
RESULTS
In vivo results favor the smaller polymer's biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.
CONCLUSIONS
Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.
PubMed: 38775973
DOI: 10.1186/s41181-024-00273-z -
Pharmacology Research & Perspectives Jun 2024The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of...
The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 μg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels in vivo and platelet aggregation in vitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.
Topics: Animals; Abietanes; Mice; Male; Vehicle Emissions; Thrombosis; Lung; Vascular System Injuries; Antioxidants; Particulate Matter; NF-E2-Related Factor 2; Air Pollutants; Oxidative Stress; Platelet Aggregation
PubMed: 38775298
DOI: 10.1002/prp2.1201 -
JU Open Plus Apr 2024Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have...
Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.
BACKGROUND
Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators.
RESULTS
This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non- mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies.
CONCLUSIONS
The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.
PubMed: 38774467
DOI: 10.1097/ju9.0000000000000138 -
JU Open Plus Apr 2024Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded...
PURPOSE
Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy.
RESULTS
The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC.
CONCLUSIONS
CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.
PubMed: 38774466
DOI: 10.1097/ju9.0000000000000137 -
Theranostics 2024Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting... (Review)
Review
Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with Ac in PCa are PSMA-targeted TAT agents, notably [Ac]Ac-PSMA-617, [Ac]Ac-PSMA-I&T and [Ac]Ac-J591. Ongoing investigations spotlight [Ac]Ac-hu11B6, [Ac]Ac-YS5, and [Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including Th, Ra, At, Bi, Pb or Tb, providing viable alternatives for TAT.
Topics: Humans; Male; Actinium; Prostatic Neoplasms; Alpha Particles; Radiopharmaceuticals; Animals
PubMed: 38773983
DOI: 10.7150/thno.96403 -
Ultrasonics Sonochemistry Jul 2024Ultrasound envelope statistics imaging, including ultrasound Nakagami imaging, homodyned-K imaging, and information entropy imaging, is an important group of...
Multimodality quantitative ultrasound envelope statistics imaging based support vector machines for characterizing tissue scatterer distribution patterns: Methods and application in detecting microwave-induced thermal lesions.
Ultrasound envelope statistics imaging, including ultrasound Nakagami imaging, homodyned-K imaging, and information entropy imaging, is an important group of quantitative ultrasound techniques for characterizing tissue scatterer distribution patterns, such as scatterer concentrations and arrangements. In this study, we proposed a machine learning approach to integrate the strength of multimodality quantitative ultrasound envelope statistics imaging techniques and applied it to detecting microwave ablation induced thermal lesions in porcine liver ex vivo. The quantitative ultrasound parameters included were homodyned-K α which is a scatterer clustering parameter related to the effective scatterer number per resolution cell, Nakagami m which is a shape parameter of the envelope probability density function, and Shannon entropy which is a measure of signal uncertainty or complexity. Specifically, the homodyned-K log(α), Nakagami-m, and horizontally normalized Shannon entropy parameters were combined as input features to train a support vector machine (SVM) model to classify thermal lesions with higher scatterer concentrations from normal tissues with lower scatterer concentrations. Through heterogeneous phantom simulations based on Field II, the proposed SVM model showed a classification accuracy above 0.90; the area accuracy and Dice score of higher-scatterer-concentration zone identification exceeded 83% and 0.86, respectively, with the Hausdorff distance <26. Microwave ablation experiments of porcine liver ex vivo at 60-80 W, 1-3 min showed that the SVM model achieved a classification accuracy of 0.85; compared with single log(α),m, or hNSE parametric imaging, the SVM model achieved the highest area accuracy (89.1%) and Dice score (0.77) as well as the smallest Hausdorff distance (46.38) of coagulation zone identification. We concluded that the proposed multimodality quantitative ultrasound envelope statistics imaging based SVM approach can enhance the capability to characterize tissue scatterer distribution patterns and has the potential to detect the thermal lesions induced by microwave ablation.
Topics: Microwaves; Support Vector Machine; Animals; Swine; Ultrasonography; Liver; Phantoms, Imaging; Image Processing, Computer-Assisted
PubMed: 38772312
DOI: 10.1016/j.ultsonch.2024.106910 -
Communications Biology May 2024Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be...
Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7; Nras; p53 (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.
Topics: Animals; Glutamine; Mice; Glutaminase; Sarcoma; Glucose; Disease Models, Animal; Radiation Tolerance
PubMed: 38769385
DOI: 10.1038/s42003-024-06262-x