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Frontiers in Physiology 2024Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multi...
Proximal tubule (PT) cells maintain a high-capacity apical endocytic pathway to recover essentially all proteins that escape the glomerular filtration barrier. The multi ligand receptors megalin and cubilin play pivotal roles in the endocytic uptake of normally filtered proteins in PT cells but also contribute to the uptake of nephrotoxic drugs, including aminoglycosides. We previously demonstrated that opossum kidney (OK) cells cultured under continuous fluid shear stress (FSS) are superior to cells cultured under static conditions in recapitulating essential functional properties of PT cells . To identify drivers of the high-capacity, efficient endocytic pathway in the PT, we compared FSS-cultured OK cells with less endocytically active static-cultured OK cells. Megalin and cubilin expression are increased, and endocytic uptake of albumin in FSS-cultured cells is > 5-fold higher compared with cells cultured under static conditions. To understand how differences in receptor expression, distribution, and trafficking rates contribute to increased uptake, we used biochemical, morphological, and mathematical modeling approaches to compare megalin traffic in FSS- versus static-cultured OK cells. Our model predicts that culturing cells under FSS increases the rates of all steps in megalin trafficking. Importantly, the model explains why, despite seemingly counterintuitive observations (a reduced fraction of megalin at the cell surface, higher colocalization with lysosomes, and a shorter half-life of surface-tagged megalin in FSS-cultured cells), uptake of albumin is dramatically increased compared with static-grown cells. We also show that FSS-cultured OK cells more accurately exhibit the mechanisms that mediate uptake of nephrotoxic drugs compared with static-grown cells. This culture model thus provides a useful platform to understand drug uptake mechanisms, with implications for developing interventions in nephrotoxic injury prevention.
PubMed: 38948083
DOI: 10.3389/fphys.2024.1404248 -
Theranostics 2024Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic... (Review)
Review
Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.
PubMed: 38948068
DOI: 10.7150/thno.95619 -
Theranostics 2024Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency....
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague. Sorafenib resistant HCC cells were established by continuous induction. UHPLC-MS/MS, proteomics, and flow cytometry were used to assess the lipid metabolism. ChIP and western blot were used to reflect the interaction of signal transducer and activator of transcription 3 (STAT3) with glycerol-3-phosphate acyltransferase 3 (GPAT3). Gain- and loss-of function studies were applied to explore the mechanism driving sorafenib resistance of HCC. Flow cytometry and CCK8 in and tumor size in were used to evaluate the sorafenib sensitivity of HCC cells. Our metabolome data revealed a significant enrichment of triglycerides in sorafenib-resistant HCC cells. Further analysis using proteomics and genomics techniques demonstrated a significant increase in the expression of GPAT3 in the sorafenib-resistant groups, which was found to be dependent on the activation of STAT3. The restoration of GPAT3 resensitized HCC cells to sorafenib, while overexpression of GPAT3 led to insensitivity to sorafenib. Mechanistically, GPAT3 upregulation increased triglyceride synthesis, which in turn stimulated the NF-κB/Bcl2 signaling pathway, resulting in apoptosis tolerance upon sorafenib treatment. Furthermore, our and studies revealed that pan-GPAT inhibitors effectively reversed sorafenib resistance in HCC cells. Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.
PubMed: 38948063
DOI: 10.7150/thno.92646 -
Theranostics 2024Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to...
Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC. In this study, we evaluated the therapeutic and immunological action of [Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling. Biodistribution studies showed high tumor uptake of [Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [Lu]Lu-DOTA-hG250 + a-PD1. analyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment. Subtherapeutic [Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.
PubMed: 38948062
DOI: 10.7150/thno.96944 -
Theranostics 2024This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival...
This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.
PubMed: 38948061
DOI: 10.7150/thno.98053 -
Theranostics 2024Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response...
Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.
PubMed: 38948055
DOI: 10.7150/thno.96738 -
Theranostics 2024Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different... (Review)
Review
Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different types of cancers. However, the current approaches to RPTs often follow a somewhat inflexible "one size fits all" paradigm, where patients are administered the same amount of radioactivity per cycle regardless of their individual characteristics and features. This approach fails to consider inter-patient variations in radiopharmacokinetics, radiation biology, and immunological factors, which can significantly impact treatment outcomes. To address this limitation, we propose the development of theranostic digital twins (TDTs) to personalize RPTs based on actual patient data. Our proposed roadmap outlines the steps needed to create and refine TDTs that can optimize radiation dose to tumors while minimizing toxicity to organs at risk. The TDT models incorporate physiologically-based radiopharmacokinetic (PBRPK) models, which are additionally linked to a radiobiological optimizer and an immunological modulator, taking into account factors that influence RPT response. By using TDT models, we envisage the ability to perform virtual clinical trials, selecting therapies towards improved treatment outcomes while minimizing risks associated with secondary effects. This framework could empower practitioners to ultimately develop tailored RPT solutions for subgroups and individual patients, thus improving the precision, accuracy, and efficacy of treatments while minimizing risks to patients. By incorporating TDT models into RPTs, we can pave the way for a new era of precision medicine in cancer treatment
PubMed: 38948052
DOI: 10.7150/thno.93973 -
Heliyon Jun 2024The GIMAP family genes play a key role in immune function. Increasing evidence suggests that GIMAP genes were implicated in the tumorigenesis of lung adenocarcinoma...
BACKGROUND
The GIMAP family genes play a key role in immune function. Increasing evidence suggests that GIMAP genes were implicated in the tumorigenesis of lung adenocarcinoma (LUAD). This study aimed to investigate the clinical significance of GIMAP family genes in LUAD.
METHODS
In this study, we explored the expression, mutation, prognostic value of GIMAP family genes and the correlation with immune microenvironment in LUAD. We further investigated the relationship between GIMAP family genes expression and immunotherapy response in GEO LUAD and melanoma cohorts.
RESULTS
Among the GIMAP family genes, the expression levels of GIMAP1, GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, and GIMAP8 were significantly lower in LUAD tumor tissues than normal tissues. Most GIMAP genes were closely related to age, tumor grade and T stage, but not significantly related to sex, N stage and M stage. In the overall population, patients with high expression of GIMAP family genes had a significant longer overall survival (OS). GO and KEGG enrichment analysis showed that GIMAP family genes were highly enriched in immune-related biological process. The expression of GIMAP family genes was positively correlated with immune cell infiltration and immune checkpoint molecules. Furthermore, high expression of GIMAP family genes were correlated with therapeutic response to immunotherapy in LUAD and melanoma patients.
CONCLUSION
In this study, we identified that GIMAP family genes were significantly associated with immune cell infiltration and immune checkpoint molecules. They potentially play a critical role in anti-tumor immunity and serve as immunotherapy biomarkers.
PubMed: 38948046
DOI: 10.1016/j.heliyon.2024.e33111 -
Heliyon Jun 2024Renal Cell Carcinoma (RCC) stands as a formidable challenge within the field of oncology, despite considerable research endeavors. The advanced stages of this malignancy... (Review)
Review
BACKGROUND
Renal Cell Carcinoma (RCC) stands as a formidable challenge within the field of oncology, despite considerable research endeavors. The advanced stages of this malignancy present formidable barriers to effective treatment and management.
OBJECTIVE
This review aims to explore the potential of exosomes in addressing the diagnostic and therapeutic challenges associated with RCC. Specifically, it investigates the role of exosomes as biomarkers and therapeutic vehicles in the context of RCC management.
METHODS
For this review article, a comprehensive literature search was conducted using databases such as PubMed, employing relevant keywords to identify research articles pertinent to the objectives of the review. Initially, 200 articles were identified, which underwent screening to remove duplicates and assess relevance based on titles and abstracts, followed by a detailed examination of full texts. From the selected articles, relevant data were extracted and synthesized to address the review's objectives. The conclusions were drawn based on a thorough analysis of the findings. The quality was ensured through independent review and resolution of discrepancies among multiple reviewers.
RESULTS
Exosomes demonstrate potential as diagnostic tools for early detection, prognosis, and treatment monitoring in RCC. Their ability to deliver various therapeutic agents, such as small interfering RNAs, lncRNAs, chemotherapeutic drugs, and immune-stimulating agents, allows for a personalized approach to RCC management. By leveraging exosome-based technologies, precision and efficacy in treatment strategies can be significantly enhanced.
CONCLUSION
Despite the promising advancements enabled by exosomes in the management of RCC, further research is necessary to refine exosome-based technologies and validate their efficacy, safety, and long-term benefits through rigorous clinical trials. Embracing exosomes as integral components of RCC diagnosis and treatment represents a significant step towards improving patient outcomes and addressing the persistent challenges posed by this malignancy in the field of oncology.
PubMed: 38948044
DOI: 10.1016/j.heliyon.2024.e32875 -
Oncology Research 2024Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated...
BACKGROUND
Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated with tumorigenesis. is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer. However, the mechanism underlying its function in cancer progression remains poorly understood.
METHODS
Here, the regulatory role of in lung adenocarcinoma was examined using lung cancer cell lines, clinical samples, and xenografts.
RESULTS
We found that high levels of expression were associated with shorter overall survival rate of patients, whereas knockdown of inhibited proliferation of cancer cell lines and tumor growth in xenografts. Western blot and flow cytometry analyses indicated that silencing of induced autophagy and apoptosis. Moreover, we showed that interacted with and stabilized the transcriptional co-repressor Switch-independent 3a (SIN3A), which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner. Silencing of SIN3A also reduced proliferation of lung cancer cells, which was correlated with the induction of autophagy. These observations raise the possibility that functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma.
CONCLUSIONS
Our findings thus identify SIN3A as a -associated protein and should help to understand the mechanism underlying -mediated oncogenesis.
PubMed: 38948024
DOI: 10.32604/or.2023.030771