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CNS Neuroscience & Therapeutics Jul 2024This study aimed to explore the mechanisms of transient receptor potential (TRP) channels on the immune microenvironment and develop a TRP-related signature for...
Multicenter integration analysis of TRP channels revealed potential mechanisms of immunosuppressive microenvironment activation and identified a machine learning-derived signature for improving outcomes in gliomas.
AIM
This study aimed to explore the mechanisms of transient receptor potential (TRP) channels on the immune microenvironment and develop a TRP-related signature for predicting prognosis, immunotherapy response, and drug sensitivity in gliomas.
METHODS
Based on the unsupervised clustering algorithm, we identified novel TRP channel clusters and investigated their biological function, immune microenvironment, and genomic heterogeneity. In vitro and in vivo experiments revealed the association between TRPV2 and macrophages. Subsequently, based on 96 machine learning algorithms and six independent glioma cohorts, we constructed a machine learning-based TRP channel signature (MLTS). The performance of the MLTS in predicting prognosis, immunotherapy response, and drug sensitivity was evaluated.
RESULTS
Patients with high expression levels of TRP channel genes had worse prognoses, higher tumor mutation burden, and more activated immunosuppressive microenvironment. Meanwhile, TRPV2 was identified as the most essential regulator in TRP channels. TRPV2 activation could promote macrophages migration toward malignant cells and alleviate glioma prognosis. Furthermore, MLTS could work independently of common clinical features and present stable and superior prediction performance.
CONCLUSION
This study investigated the comprehensive effect of TRP channel genes in gliomas and provided a promising tool for designing effective, precise treatment strategies.
Topics: Glioma; Machine Learning; Tumor Microenvironment; Humans; Brain Neoplasms; Animals; Transient Receptor Potential Channels; TRPV Cation Channels; Mice; Male; Female
PubMed: 38948951
DOI: 10.1111/cns.14816 -
CNS Neuroscience & Therapeutics Jul 2024To investigate the alterations of the optic nerve and visual cortex in dysthyroid optic neuropathy (DON), a subgroup of thyroid eye disease (TED).
AIMS
To investigate the alterations of the optic nerve and visual cortex in dysthyroid optic neuropathy (DON), a subgroup of thyroid eye disease (TED).
METHODS
Multiple orbital imaging biomarkers related to optic nerve compression and the amplitude of low-frequency fluctuations (ALFF) of the brain were obtained from 47 patients with DON, 56 TED patients without DON (nDON), and 37 healthy controls (HC). Correlation analyses and diagnostic tests were implemented.
RESULTS
Compared with HC, the nDON group showed alterations in orbital imaging biomarkers related to optic nerve compression in posterior segments, as well as ALFF of the right inferior temporal gyrus and left fusiform gyrus. DON differed from nDON group mainly in the modified muscle index of the posterior segment of optic nerve, and ALFF of orbital part of right superior frontal gyrus, right hippocampus, and right superior temporal gyrus. Orbital and brain imaging biomarkers were significantly correlated with each other. Diagnostic models attained an area under a curve of 0.80 for the detection of DON.
CONCLUSION
The combined orbital and brain imaging study revealed alterations of the visual pathway in patients with TED and DON as well as provided diagnostic value. The initiation of alterations in the visual cortex in TED may precede the onset of DON.
Topics: Humans; Male; Female; Middle Aged; Graves Ophthalmopathy; Visual Cortex; Adult; Magnetic Resonance Imaging; Optic Nerve Diseases; Orbit; Optic Nerve; Aged
PubMed: 38948947
DOI: 10.1111/cns.14820 -
ANZ Journal of Surgery Jul 2024Colonoscopy is a key component of surveillance after colorectal cancer (CRC) resection. Surveillance intervals for colonoscopy vary across the world, with a limited...
BACKGROUND
Colonoscopy is a key component of surveillance after colorectal cancer (CRC) resection. Surveillance intervals for colonoscopy vary across the world, with a limited evidence-base to support guidelines.
OBJECTIVE
To evaluate the timing and outcome of colonoscopies after CRC resection.
METHODS
Retrospective cohort study on prospectively collected data. Included adult patients under surveillance following CRC resection. Patients with organ transplant, inflammatory bowel disease or colon cancer syndromes were excluded. The outcomes of the first (up to) three follow-up colonoscopies were audited and classified for presence of advanced neoplasia (advanced adenoma or adenocarcinoma).
RESULTS
980 patients underwent at least one follow-up colonoscopy with a median time to first colonoscopy of 12.4 months. The findings included 2.7% CRC and 13.2% advanced adenoma. Older age, stage IV disease, and synchronous cancers at surgery were significantly associated with a finding of advanced neoplasia at first colonoscopy. 562 patients underwent a second colonoscopy (median of 35 months after the first surveillance colonoscopy) with findings of 1.8% CRC and 11.4% advanced adenoma. Advanced adenoma on prior colonoscopy was associated with finding advanced neoplasia at the second colonoscopy. 288 patients underwent a third colonoscopy (median of 37 months from the preceding colonoscopy), with similar outcomes of advanced neoplasia being associated with advanced adenoma at the previous colonoscopy. 43 (4.4%) patients developed CRC whilst on surveillance.
CONCLUSIONS
Timely surveillance after CRC resection is important for detecting advanced neoplasia, and prolonged intervals between colonoscopies in the early years after surgery should be avoided.
PubMed: 38948942
DOI: 10.1111/ans.19132 -
American Journal of Clinical Oncology Jul 2024
PubMed: 38948937
DOI: 10.1097/COC.0000000000001130 -
Oncoimmunology 2024Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic...
Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.
Topics: Animals; Male; Prostatic Neoplasms; Antigens, Neoplasm; Mice; Dendritic Cells; Adjuvants, Immunologic; RNA, Messenger; Cancer Vaccines; Humans; Mice, Inbred C57BL; Cell Line, Tumor; mRNA Vaccines; CD8-Positive T-Lymphocytes; T-Lymphocytes; Immunotherapy; Lymphocyte Activation
PubMed: 38948931
DOI: 10.1080/2162402X.2024.2373526 -
Oncoimmunology 2024Deregulation or loss of the human leukocyte antigen class I (HLA-I) molecules on tumor cells leading to inhibition of CD8 T cell recognition is an important tumor immune...
Deregulation or loss of the human leukocyte antigen class I (HLA-I) molecules on tumor cells leading to inhibition of CD8 T cell recognition is an important tumor immune escape strategy, which could be caused by a posttranscriptional control of molecules in the HLA-I pathway mediated by RNA-binding proteins (RBPs). So far, there exists only limited information about the interaction of RBPs with HLA-I-associated molecules, but own work demonstrated a binding of the heterogeneous ribonucleoprotein C (hnRNP C) to the 3' untranslated region (UTR) of the TAP-associated glycoprotein tapasin (tpn). In this study, analysis of pan-cancer TCGA datasets revealed that hnRNP C is higher expressed in tumor specimens compared to corresponding normal tissues, which is negatively correlated to tpn expression, T cell infiltration and the overall survival of tumor patients. Functional analysis demonstrated an upregulation of tpn expression upon siRNA-mediated downregulation of hnRNP C, which is accompanied by an increased HLA-I surface expression. Thus, hnRNP C has been identified to target tpn and its inhibition could improve the HLA-I surface expression on melanoma cells suggesting its use as a possible biomarker for T-cell-based tumor immunotherapies.
Topics: Humans; Melanoma; Heterogeneous-Nuclear Ribonucleoprotein Group C; 3' Untranslated Regions; Membrane Transport Proteins; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38948930
DOI: 10.1080/2162402X.2024.2370928 -
HemaSphere Jul 2024Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk...
Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.
PubMed: 38948925
DOI: 10.1002/hem3.117 -
HemaSphere Jul 2024Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T...
Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine-containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR-T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre-apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi-cel and tisa-cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non-benda group (62% vs. 45%, = 0.02). Concerning CAR-T efficacy, complete responses were comparable for benda versus non-benda BT cohorts with axi-cel (70% vs. 53%, = 0.12) and tisa-cel (44% vs. 36%, = 0.70). Also, 12-month progression-free and overall survival were not significantly different between BT groups with axi-cel (56% vs. 43% and 71% vs. 63%) and tisa-cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T-cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, = 0.79), ICANS G ≥3 (15% vs. 17%, = 0.68), severe infections, and neutropenia post-infusion were comparable among BT regimens. BT with bendamustine-containing regimens is safe for patients requiring disease control during CAR T-cell manufacturing.
PubMed: 38948924
DOI: 10.1002/hem3.86 -
Advances in Radiation Oncology Jul 2024For lung stereotactic body radiation therapy, 4-dimensional computed tomography is often used to delineate target volumes, whereas organs at risk (OARs) are typically...
PURPOSE
For lung stereotactic body radiation therapy, 4-dimensional computed tomography is often used to delineate target volumes, whereas organs at risk (OARs) are typically outlined on either average intensity projection (AIP) or midventilation (MidV = 30% phase) images. AIP has been widely adopted as it represents a true average, but image blurring often precludes accurate contouring of critical structures such as central airways. Here, we compare AIP versus MidV planning for centrally located tumors via respiratory motion-inclusive (RMI) plans to better evaluate dose delivered throughout the breathing cycle.
METHODS AND MATERIALS
Independently contoured and optimized AIP and MidV plans were created for 16 treatments and rigidly copied to each of the 10 breathing phase-specific computed tomography image sets. Resulting dose distributions were deformably registered back to the MidV image set (used as reference because of clearer depiction of anatomy compared with motion-blurred AIP) and averaged to create RMI plans. Doses to central OARs were compared between plans.
RESULTS
Mean absolute dose differences were low for all comparisons (range, 0.01-2.87 Gy); however, individual plans exhibited differences >20 Gy. Dose differences >5 Gy were observed most often for plan comparisons involving AIP-based plans (MidV vs AIP 23, AIP RMI vs AIP 12, MidV RMI vs AIP RMI 7, and MidV RMI vs MidV 8 times). Inclusion of respiratory motion reduced large dose differences. Standard OAR thresholds were exceeded up to 5 times for each plan comparison scenario and always involved proximal bronchial tree D4 cc tolerance dose. AIP-based contours were larger by, on average, 3% to 15%.
CONCLUSIONS
Large dose differences were observed when plans with AIP-based contours were compared with MidV-based contours, indicating that observed dose differences were likely due to contoured volume differences rather than the effect of motion. Because of blurring with AIP images, MidV RMI-based planning may offer a more accurate method to determine dose to critical OARs in the presence of respiratory motion.
PubMed: 38948918
DOI: 10.1016/j.adro.2024.101525 -
Advances in Radiation Oncology Jul 2024The attack by Hamas on Israeli civilians (October 7, 2023) triggered the ongoing war, which could be detrimental to cancer care in general and radiation therapy (RT) in...
PURPOSE
The attack by Hamas on Israeli civilians (October 7, 2023) triggered the ongoing war, which could be detrimental to cancer care in general and radiation therapy (RT) in particular. To assure continuity of care within the Radiation Oncology Department of Samson Assuta Ashdod University Hospital (SAAUH), which borders on Gaza, patient-centric measures were redoubled by our institution. This study describes the impact of these measures on patients' perception and their willingness to continue RT, despite fear of war.
METHODS AND MATERIALS
A survey questionnaire was designed to detect changes in attitude and treatment adherence during war. It was offered to the patients undergoing RT at SAAUH. A Pearson correlation between the items relating to desire to continue the therapy was calculated. Smallest space analysis was conducted to illustrate the association between the variables.
RESULTS
Forty-seven patients enrolled in this study reported a significantly lower feeling of personal safety during wartime in comparison with the confidence in the professionalism of the staff (paired samples test, t(43) = 4.61; < .001). Simultaneously, patients perceived that the impact of the national situation on their health was very low (mean of 1.59 on a scale of 1-6). Both the Pearson correlation test and smallest space analysis revealed that the desire to continue treatment in general and to continue treatment at the same department were significantly related to trust in the staff's professionalism.
CONCLUSIONS
Fear of war can pose a major pitfall in providing daily RT care. This obstacle may be potentially overridden by creating deep, trusting relationships between the patients and the medical staff.
PubMed: 38948917
DOI: 10.1016/j.adro.2024.101514