Unfavorable Response Research Articles

Machine Learning-enhanced Signature of Metastasis-related T Cell Marker Genes for Predicting Overall Survival in Malignant Melanoma.

In this study, we aimed to investigate disparities in the tumor immune microenvironment (TME) between primary and metastatic malignant melanoma (MM) using single-cell RNA sequencing (scRNA-seq) and to identify metastasis-related T cell marker genes (MRTMGs) for predicting patient survival using machine learning techniques. We identified 6 distinct T cell clusters in 10×scRNA-seq data utilizing the Uniform Manifold Approximation and Projection (UMAP) algorithm. Four machine learning algorithms highlighted SRGN, PMEL, GPR143, EIF4A2, and DSP as pivotal MRTMGs, forming the foundation of the MRTMGs signature. A high MRTMGs signature was found to be correlated with poorer overall survival (OS) and suppression of antitumor immunity in MM patients. We developed a nomogram that combines the MRTMGs signature with the T stage and N stage, which accurately predicts 1-year, 3-year, and 5-year OS probabilities. Furthermore, in an immunotherapy cohort, a high MRTMG signature was associated with an unfavorable response to anti-programmed death 1 (PD-1) therapy. In conclusion, primary and metastatic MM display distinct TME landscapes with different T cell subsets playing crucial roles in metastasis. The MRTMGs signature, established through machine learning, holds potential as a valuable biomarker for predicting the survival of MM patients and their response to anti-PD-1 therapy.

Recent advances in mRNA-based cancer vaccines encoding immunostimulants and their delivery strategies

The high prevalence of drug resistance, relapse, and unfavorable response rate of conventional cancer therapies necessitate the development of more efficient treatment modalities. Immunotherapy represents a novel therapeutic approach to cancer treatment in which the immune system's potential is harnessed to recognize and eliminate tumor cells. mRNA cancer vaccines, as a burgeoning field of immunotherapy, have recently drawn particular attention, and among mRNAs encoding tumor-associated antigens, tumor-specific antigens, and immune stimulatory factors, the latter has been relatively less explored. These immunostimulatory mRNAs encode a range of proteins, including stimulatory ligands, receptors, enzymes, pro-inflammatory cytokines, and inhibitory binding proteins, which collectively augment the host immune system's ability against cancerous cells. In this review, we aimed to provide a comprehensive account of mRNA-based cancer vaccines encoding immune stimulants, encompassing their current status, mechanisms of action, delivery strategies employed, as well as recent advances in preclinical and clinical studies. The potential challenges, strategies and future perspectives have also been discussed.

Multi-modal response control with multiple suspension-type tuned vibration absorbers

Due to complicated excitations, engineering structures are often subjected to multi-modal responses. Considering the feasibility in practical installation on slender structures, multiple Suspension-type Tuned Vibration Absorbers (S-TVAs) are investigated for multi-modal response control. Firstly, parametric optimization of a single S-TVA for single-modal response control is investigated analytically. The issues regarding to the optimal tuning, static and dynamic performances, and installation location are addressed. Subsequently, an optimal design method for multi-modal response control with multiple S-TVAs is presented. Two aspects on the optimization strategy are discussed. Consequently, the optimization should be performed with an inverse modal order sequence. And, the modal information should be updated considering the S-TVA optimized in the previous step. Finally, the effectiveness of the presented optimal design method is validated through practical wind-induced response control on a slender chimney. The most unfavorable response can be suppressed up to 59.7 %, which is 47.8 % better than traditional single-modal control approach. Moreover, it is interesting to find that the practical overall control performance may not be achieved with more controlled modes intuitively. It is recommended to select from several practical cases determined by the presented optimal design method. Practical installation and feasibility are highly required to be considered in practice.

Combination of FDG PET/CT radiomics and clinical parameters for outcome prediction in patients with non-Hodgkin's lymphoma.

The purposes was to build model incorporating PET + computed tomography (CT) radiomics features from baseline PET/CT + clinical parameters to predict outcomes in patients with non-Hodgkin lymphomas. Cohort of 138 patients with complete clinical parameters and follow up times of 25.3 months recorded. Textural analysis of PET and manual correlating contouring in CT images analyzed using LIFE X software. Defined outcomes were overall survival (OS), disease free-survival, radiotherapy, and unfavorable response (defined as disease progression) assessed by end of therapy PET/CT or contrast CT. Univariable and multivariable analysis performed to assess association between PET, CT, and clinical. Male (P = 0.030), abnormal lymphocytes (P = 0.030), lower value of PET entropy (P = 0.030), higher value of SHAPE sphericity (P = 0.002) were significantly associated with worse OS. Advanced stage (III or IV, P = 0.013), abnormal lymphocytes (P = 0.032), higher value of CT gray-level run length matrix (GLRLM) LRLGE mean (P = 0.010), higher value of PET gray-level co-occurrence matrix energy angular second moment (P < 0.001), and neighborhood gray-level different matrix (NGLDM) busyness mean (P < 0.001) were significant predictors of shorter DFS. Abnormal lymphocyte (P = 0.033), lower value of CT NGLDM coarseness (P = 0.082), and higher value of PET GLRLM gray-level nonuniformity zone mean (P = 0.040) were significant predictors of unfavorable response to chemotherapy. Area under the curve for the three models (clinical alone, clinical + PET parameters, and clinical + PET + CT parameters) were 0.626, 0.716, and 0.759, respectively.

The Association Between Chronic Pain, Substance use, and Primary Care Experience Among Veterans with Ongoing or Recent Homelessness.

Chronic pain and problematic substance use are prevalent among Veterans with homeless experience (VHE) and may contribute to a challenging primary care experience. To examine the association of chronic pain and problematic substance use with unfavorable primary care experiences among VHE and to explore the association of pain treatment utilization and unfavorable care experiences in VHE with chronic pain. We surveyed VHE (n = 3039) engaged in homeless-tailored primary care at 29 Veterans Affairs Medical Centers (VAMCs). We assessed unfavorable primary care experiences with four validated Primary Care Quality-Homeless (PCQ-H) scales: multivariable logistic regressions explored associations between unfavorable care experiences for VHE with chronic pain and problematic substance use, chronic pain alone, problematic substance use alone, or neither. We then examined the association between receipt of pain treatments and unfavorable experiences among VHE with chronic pain. Last, we identified PCQ-H items that had the greatest difference in unfavorable response rates between VHE with and without chronic pain. The prevalence of unfavorable primary care experience was higher on all four scales for patients reporting chronic pain (with or without problematic substance use) (all p < 0.001), but not for problematic substance use alone, compared to VHE with neither pain nor problematic substance use. In analyses limited to VHE with chronic pain, those on long-term opioids were less likely to report an unfavorable experience (OR = 0.49, 95%CI 0.34-0.69). Receipt of occupational therapy was associated with lower odds of reporting an unfavorable experience (OR = 0.83, 95%CI 0707-0.98). PCQ-H items related to trust, relationships, and provider communication had the greatest differences in dissatisfaction ratings (all p < 0.001). Chronic pain is associated with unfavorable primary care experiences among VHE, potentially contributing to poor care outcomes. Strategies are needed to enhance patient-provider trust and communication and increase VHE's access to effective pain treatments.

8338 A Case Series of 3 Patients with Unusual Miliary Lung Metastases in Paraganglioma: Diagnostic Workup, Treatment Challenges and Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G&amp;gt;T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C&amp;gt;G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively.Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

8338 A Case Series Of 3 Patients With Unusual Miliary Lung Metastases In Paraganglioma: Diagnostic Workup, Treatment Challenges And Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G&amp;gt;T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C&amp;gt;G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively. Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

Perspectives of Healthcare Professionals and People with a Spinal Cord Injury on Resistance Exercise Intensity in Japan, Indonesia, Korea and Thailand

(1) Background: This study aims to investigate differences in the perspectives of healthcare professionals (HCPs) and adults with spinal cord injury (SCI) on resistance exercise intensity in Asian countries in association with knowledge translation (KT). Also, it verifies the appropriateness of the conventional indicators for resistance exercise intensity in an Asian context. (2) Methods: 121 certified HCPs and 107 adults with SCI participated in a survey conducted in Indonesian, Japanese, Korean and Thai languages. The survey asked what principles are important for prescribing resistance exercise, and if ‘moderate’ and ‘vigorous’ were appropriate terms for indicating an intensity level. Perspective differences were examined between both groups and, further, between countries from a psychosocial perspective. (3) Results: Of the HCPs, 92% perceived that resistance exercise intensity was far more important than frequency, time or type of exercise while frequency (61%) followed by intensity (58%) was perceived as important by respondents with SCI. Only Japanese respondents with SCI agreed with the HCPs’ perception of intensity. Both HCPs and respondents with SCI showed unfavorable responses to the usage of ‘moderate’ and ‘vigorous’ for describing resistance exercise intensity, especially Japanese HCPs and respondents with SCI from Indonesia. (4) Conclusions: Our findings suggest that non-HCPs must improve their perceptions of exercise intensity. Our findings also suggest the need for more explicit and user-friendly terms or expressions indicating the level of intensity in a local (Asian) context.

The Laws of Attraction: Chemokines as Critical Mediators in Cancer Progression and Immunotherapy Response in Bladder Cancer.

Bladder cancer (BCa) is a prevalent urogenital malignancy, characterized by a myriad of genetic and environmental risk factors that drive its progression. Approximately 75% of bladder tumors are non-muscle-invasive at diagnosis. For such cases, bladder preservation is often feasible with intravesical chemotherapy or immunotherapy. However, the high recurrence rates associated with these tumors necessitate multiple cystoscopic examinations and biopsies, leading to significant financial burden and morbidity. Despite bladder tumors exhibiting one of the highest cancer mutational loads, which typically correlates with improved responses to immunotherapy, challenges persist. The tumor microenvironment serves as a nexus for interactions between tumor cells and the immune system, wherein chemokines and chemokine receptors orchestrate the recruitment of immune cells. This review addresses existing gaps in our understanding of chemokine dynamics in BCa by elucidating the specific roles of key chemokines in shaping the immune landscape of the tumor microenvironment (TME). We explore how dysregulation of chemokine signaling pathways contributes to the recruitment of immunosuppressive cell populations, such as Tregs and monocytes, leading to an unfavorable immune response. Additionally, we highlight the potential of these chemokines as predictive biomarkers for tumor progression and treatment outcomes, emphasizing their role in informing personalized immunotherapeutic strategies. By integrating insights into chemokine networks and their implications for immune cell dynamics, this review seeks to provide a comprehensive understanding of the interplay between chemokines and the immune microenvironment in BCa. Furthermore, we discuss the potential of targeting these chemokine pathways as innovative immunotherapeutic strategies, paving the way for enhanced treatment responses and improved patient outcomes.

Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma

Novel neoadjuvant immunotherapy combined with chemotherapy (neoICT) has improved outcomes for patients with esophageal squamous-cell carcinoma (ESCC), but challenges persist in low response rates and therapy resistance. Little is known about the intra-tumoral heterogeneity in the ESCC tumor microenvironment (TME) that underlies differential responses to neoadjuvant therapy. We applied single-cell RNA sequencing (scRNA-seq) profiling and multiplexed immunofluorescence staining to thoroughly decipher the TME in ESCC specimens from a neoadjuvant anti-PD1 combination therapy clinical trial. The cancer-associated fibroblasts (CAFs) population showed the significant alteration in abundance following neoadjuvant therapy. Specifically, IL6 + CCL2 + immunomodulatory CAFs and a novel CD248 + mechanoresponsive CAFs subset exhibited increasing infiltration. Mechanistically, CD248 + mechanoresponsive CAFs approached and lined the tumor nest to physically block the infiltration of CD8 + T cells and drug delivery, while IL6 + CCL2 + immunomodulatory CAFs induced therapeutic resistance with distinct IL-6 expression. Among patients treated with neoICT, we observed prominent CAF-T cell interactions. In particular, the NECTIN2-TIGIT ligand-receptor pair was enriched in treated samples, and TIGIT was identified as the major inhibitory checkpoint of T cells. Our findings demonstrate distinct alterations in TME constituent responses to neoadjuvant immunotherapy and identify functional phenotypes of CAFs associated with unfavorable therapeutic responses in patients. This provides potential targets to enhance responses to neoadjuvant therapy in ESCC.

Rapid progression of CD8 and CD4 T cells to cellular exhaustion and senescence during SARS-CoV2 infection

Abstract Risk factors for the development of severe COVID-19 include several comorbidities, but age was the most striking one since elderly people were disproportionately affected by SARS-CoV-2 infection. Among the reasons for this markedly unfavorable response in the elderly, immunosenescence and inflammaging appear as major drivers of this outcome. A finding that was also notable was that hospitalized patients with severe COVID-19 have an accumulation of senescent T cells, suggesting that immunosenescence may be aggravated by SARS-CoV-2 infection. The present work was designed to examine whether these immunosenescence changes are characteristic of COVID-19 and whether it is dependent on disease severity using cross-sectional and longitudinal studies. Our cross-sectional data show that COVID-19, but not other respiratory infections, rapidly increased cellular senescence and exhaustion in CD4 and CD8 T cells during early infection. In addition, longitudinal analyses with patients from Brazil and Portugal provided evidence of increased frequencies of senescent and exhausted T cells over a 7-d period in patients with mild/moderate and severe COVID-19. Altogether, the study suggests that accelerated immunosenescence in CD4 and especially CD8 T-cell compartments may represent a common and unique outcome of SARS-CoV2 infection.

A Behavior-Based Model to Validate Electronic Systems Designed to Collect Patient-Reported Outcomes: Model Development and Application.

The merits of technology have been adopted in capturing patient-reported outcomes (PROs) by incorporating PROs into electronic systems. Following the development of an electronic system, evaluation of system performance is crucial to ensuring the collection of meaningful data. In contemporary PRO literature, electronic system validation is overlooked, and evidence on validation methods is lacking. This study aims to introduce a generalized concept to guide electronic patient-reported outcome (ePRO) providers in planning for system-specific validation methods. Since electronic systems are essentially products of software engineering endeavors, electronic systems used to collect PRO should be viewed from a computer science perspective with consideration to the health care environment. On this basis, a testing model was blueprinted and applied to a newly developed ePRO system designed for clinical use in pediatric dentistry (electronic Personal Assessment Questionnaire-Paediatric Dentistry) to investigate its thoroughness. A behavior-based model of ePRO system validation was developed based on the principles of user acceptance testing and patient-centered care. The model allows systematic inspection of system specifications and identification of technical errors through simulated positive and negative usage pathways in open and closed environments. The model was able to detect 15 positive errors with 1 unfavorable response when applied to electronic Personal Assessment Questionnaire-Paediatric Dentistry system testing. The application of the behavior-based model to a newly developed ePRO system showed a high ability for technical error detection in a systematic fashion. The proposed model will increase confidence in the validity of ePRO systems as data collection tools in future research and clinical practice.

Hematological biomarkers of systemic inflammation in predicting long-term treatment response of temporomandibular disorders

BackgroundChronic systemic inflammation has been proposed as the underlying mechanism of pain chronicity in several pain conditions. In spite of the growing evidence supporting the role of systemic inflammatory markers as a diagnostic tool, their role has not been analyzed in a well-defined group of temporomandibular disorders (TMD) patients until now. This study aimed to investigate the association between various clinical features and comorbidity levels of TMD in relation to hematological markers and seek its association with long-term treatment response.MethodsClinical features and hematological indices including those for systemic inflammation were assessed in TMD patients (n = 154). Examinations were re-done after 6 months of conservative treatment. Patients were divided into pain improved and unimproved groups based on ≥ 2 numeric rating scale improvement in pain intensity at 6 months for final analysis.ResultsThe portion of patients with low lymphocyte-to-monocyte ratio (p = 0.026), total protein (p = 0.014), hemoglobin (p = 0.040), and mean corpuscular hemoglobin concentration (p = 0.042) values showed significant differences according to prognosis groups. Low hemoglobin levels were significantly associated with unfavorable response to long-term treatment (β = 1.706, p = 0.018). High pre-treatment pain intensity (β=-0.682, p < 0.001) and low Graded Chronic Pain Scale (β = 1.620, p = 0.002) could predict significant pain improvement with long-term treatment.ConclusionsHematologic assessment could be considered in addition to clinical examination to better determine long-term prognosis in TMD patients.

Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance

Neonatal intensive care unit (NICU), particularly in treating developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep understanding of their complex etiologies and treatment responses. After excluding treatable cases such as infectious or autoimmune encephalitis, our focus shifted to a more challenging subgroup of 59 patients for in-depth genetic analysis using exome sequencing (ES). The ES analysis identified 40 genetic abnormalities, significantly including de novo variants. Notably, we found structural variation as duplications in regions 2q24.3, including SCN1A and SCN2A were observed in 7 cases. These genetic variants, impacting ion channels, glucose transport, transcription regulation, and kinases, play a crucial role in determining medication efficacy. More than one-third (34.2%) of patients with DEE had an unfavorable response to anti-seizure medications (ASMs) in the chronic phase. However, since the ketogenic supplementary diet showed a positive effect, more than three-quarters (80%) of these drug-resistant patients improved during a 3-month follow-up. In contrast, the ME had a lower adverse reaction rate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and 10 cases with unidentified genetic etiologies. This study suggests the potential of categorizing drug-resistant variants and that a ketogenic diet could be beneficial in managing DEE and ME. It also opens new perspectives on the mechanisms of the ketogenic diet on the discovered genetic variants.

Comparing the Immune Response to PEEK as an Implant Material with and without P-15 Peptide as Bone Graft Material in a Rabbit Long Bone Model.

P-15 is a 15-amino-acid-long biomimetic peptide widely demonstrated to enhance osteogenesis in vivo. Despite the prevalence of polyether-ether-ketone (PEEK) in interbody device manufacturing, a growing body of evidence suggests it may produce an unfavorable immune response. The purpose of this preliminary study was to characterize the immune response and new bone growth surrounding PEEK implants with and without a P-15 peptide-based osteobiologic. A bilateral femoral defect model was conducted using New Zealand white rabbits. A total of 17 test subjects received one implant in each distal femur, either with or without bone graft material. Animals were allowed to survive to 4 or 8 weeks, at which time the femurs were collected and subjected to micro-computer tomography (microCT) or cytokine analysis. MicroCT analysis included the quantification of bone growth and density surrounding each implant. The cytokine analysis of periprosthetic tissue homogenates included the quantification of interleukins (ILs) and TNF-α expression via ELISA kits. Improvements in bone volume were observed in the P-15 cohort for the regions of interest, 500-136 and 136-0 µm from the implant surface, at 8 weeks post-op. Concentrations of IL-1β, IL-4, and IL-6 cytokines were significantly higher in the P-15 cohort compared to the PEEK cohort at the 4-week timepoint. Significant reductions in the concentrations of IL-4 and IL-6 cytokines from the 4- to 8-week cohort were observed in the P-15 cohort only. The P-15 peptide has the potential to modulate the immune response to implanted materials. We observed improvements in bone growth and a more active micro-environment in the P-15 cohort relative to the PEEK control. This may indicate an earlier transition from the inflammatory to remodeling phase of healing.

H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response

Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ Tcells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ Tcell dysfunction invivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ Tcell exhaustion, and cholesterol-modified siIL11 restores CD8+ Tcell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.

CD19+CD73+ B cells infiltration indicates poor prognosis and unfavorable responses to immunotherapy in gastric cancer

ObjectivesCluster of Differentiation 73 (CD73) is expressed on immune cells and plays a significant role in tumor inhibition by suppressing antitumor immunity. The objectives of this study were to explore the expression and functional mechanisms of CD73 on B cells in patients with gastric cancer (GC). MethodsThe prognostic significance of CD19+CD73+ B cells was evaluated in 390 GC patients through dual immunohistochemistry staining. Flow cytometry was employed to analyze the phenotype of the CD19 subpopulation using fresh tumor and non-tumor tissue samples from 8 GC patients. A bioinformatics analysis of CD19+CD73+ B cells was also performed within the scRNA-seq cohort, and the CD19+ B cell subtype was assessed using multiple immunofluorescence staining. ResultsThe infiltration of CD19+CD73+ B cells was observed to be elevated in gastric cancer (GC) tissue compared to normal tissues. A strong correlation was observed between high CD19+CD73+ B cell infiltration, poor overall survival, and diminished responsiveness to neoadjuvant immunotherapy in GC. These cells emerged as a novel subset of regulatory B cells (Bregs) linked to adenosine metabolism and the exhaustion of CD8+ T cells. The CD19+CD73+ B cells also correlated with the production of immunosuppressive cytokines IL-10 and TGFB1. Further analysis indicated an association between CD19+CD73+ B cells and advanced-stage GC. ConclusionsThe presence of CD19+CD73+ B cells in GC may serve as a prognostic indicator for clinical outcomes and a predictive marker for poor responsiveness to neoadjuvant immunotherapy. The correlation between the presence of CD19+CD73+ B cells and CD8+ T cell exhaustion, along with immunosuppression, highlights the tumor-promoting function of these cells.

[68 Ga]Ga-CXCR4 PET/CT imaging in high-grade glioma for assessment of CXCR4 receptor expression

PurposeGliomas account for 75 % of primary malignant CNS tumors. High-grade glioma (CNS WHO grades 3 and 4) have an unfavorable treatment response and poor outcome. CXCR4 is a G protein-coupled receptor that plays an important part in the signaling pathway between cancer cells and tumor microenvironment. CXCR4 overexpression has been shown in a variety of cancers. In this study, we evaluate the potential value of [68Ga]Ga-Pentixafor as a PET/CT CXCR4-probe for in vivo assessment of CXCR4 expression in patients with high-grade glioma and its correlation with tumor grade. Materials and Methods[68Ga]Ga-CXCR4 PET/CT was performed in the prospective single-center study in treatment-naïve biopsy-proven patients with high-grade glioma. The acquired images were analyzed qualitatively and semi-quantitatively. ResultA total of 26 patients (mean age: 53.3±14.4 years, 11 women, 15 men) were enrolled. CNS WHO grade 3 pathology was seen in 19 % (5/26) of the sample. The patient-based sensitivity of 68Ga-CXCR4 was 96.2 %. Overall, 28 pathologic lesions were detected, leading to a lesion-based sensitivity of 96.4 %. The median (IQR) SUVmax of grade 4 lesions was substantially greater than the grade 3(3.03(2.5–3.7) vs. 1.51(1.2–1.8), p = 0.0145).). The highest tracer activity of organs −beside bladder as the main excretion reservoir-was in lymphoid tissue of Waldeyer’s ring (mean SUVmax: 7.41), and spleen (mean SUVmax: 6.62). ConclusionIn conclusion, this new application for [68Ga]Ga-Pentixafor PET tracer exhibits excellent visual and semi-quantitative diagnostic properties. Further studies are warranted.

C-Myc Inhibition Induces an Additive Effect with Cyclophosphamide in Acute Lymphoblastic Leukemia

Background: Cellular-myelocytomatosis (c-Myc), an oncoprotein and a transcription factor, is involved in several essential cellular processes. The c-Myc expression level is highly regulated in normal cells. It has been proved that c-Myc expression is deregulated in malignant cells due to rearrangements and mutations. The overexpression of this molecule is also reported to be present in acute lymphoblastic leukemia (ALL) as well, which is correlated with an unfavorable response to treatment, poor prognosis, and decreased overall survival. The upregulation of c-Myc results in increased proliferation, cell growth, and survival of ALL cells. Hence, making it an ideal target for leukemia treatment. This study evaluates the effect of c-Myc silencing combined with cyclophosphamide treatment, an FDA-approved chemotherapeutic. Methods: Peripheral blood and bone marrow samples (mononuclear cells) were derived from eleven ALL patients. To silence c-Myc, small interfering-RNA (siRNA)-lipofectamine was used. The efficacy of gene silencing was assessed by the qRT-PCR test. Next, the effect of c-Myc silencing combined with cyclophosphamide treatment in ALL primary cells was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) test. Results: ALL cells were successfully transfected with c-Myc-siRNA. Also, treating cells with cyclophosphamide exerted a slight fall in the c-Myc mRNA level. The MTT test revealed that following the inhibition of c-Myc by siRNA, the viability of primary ALL cells decreased in response to cyclophosphamide treatment. Also, it was discovered that silencing c-Myc with siRNA combined with cyclophosphamide treatment significantly inhibits the growth of primary ALL cells compared to cyclophosphamide monotherapy. Conclusion: c-Myc possesses high potential in the treatment of several cancers. Our findings add ALL to this category as well. Silencing c-Myc sensitizes ALL cells to cyclophosphamide treatment and can help with the better treatment of the afflicted individuals.

Response of Prospective Mathematics Teacher Students To Learning Difficulties In Calculus Course

This study was motivated by the learning difficulties faced by prospective mathematics teacher students in calculus courses, while calculus courses studied at the college level equip prospective teacher students to teach mathematics subjects at the secondary school level. This study aims to determine students' responses to learning difficulties in calculus courses. This research used descriptive quantitative method by involving 25 students of Tadris Mathematics IAIN Kerinci as the research sample. The sampling technique used in this study was convenience sampling, which is when a researcher chooses his sample only by including people who are available. This study uses a closed questionnaire as a data collection tool that is reviewed from 7 aspects of difficulty, namely interest, motivation, talent, intelligence, facilities and infrastructure, quality, and teaching methods. The results of descriptive analysis showed that students have a high level of difficulty in learning calculus. The conclusion of this study shows that students' learning difficulties, especially in calculus courses, are strongly influenced by external factors, especially related to learning facilities and infrastructure. The results also show that prospective math teacher students at IAIN Kerinci have an unfavorable response to learning difficulties in calculus courses.