Therapy Response Research Articles

Imaging Mutant Huntingtin Aggregates using [18F]CHDI-650 PET in a preclinical model of Huntington’s disease

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT) that encodes pathogenic mutant huntingtin (mHTT) protein. Therapeutic strategies aimed at lowering mHTT would benefit from non-invasive PET-based methods to evaluate treatment response. The CHDI foundation developed the first-generation PET ligands labelled with 11C, which advanced to clinical evaluation. Further optimization generated an 18F radioligand with improved metabolic stability, brain exposure and specificity, shown by PET imaging in wild-type mice and autoradiography in HD brain samples1,2. Here, we characterised the PET radioligand [18F]CHDI-650 in the R6/1 mouse model of HD to assess its sensitivity for monitoring treatment response of mHTT lowering therapies. [18F]CHDI-650 was produced according to an established method3 using a TRACERlab system. Radiochemical purity/molar activity of the final [18F]CHDI-650 product was detected by reverse-phase HPLC analysis. Dynamic PET imaging was conducted using R6/1 mice and wild-type littermates at various disease stages. Image processing and kinetic modelling (2TCM) analysis were performed using PMOD software. Ex vivo brain radioactivity was measured using gamma counting. Brains were cryo-sectioned and processed for immunofluorescence to identify HTT load. [18F]CHDI-650 was produced (1.3 ± 0.2 GBq) with an average radiochemical purity of 99.9 ± 0.1 % and a molar activity of 32.4 ± 5.2 GBq/µmol (n = 9). The radioligand was able to discriminate R6/1 HET from WT mice at an early presymptomatic age for both dynamic PET imaging (striatal) and ex vivo whole brain gamma. A well-defined age associated increase was also evident using both measures. Dual immunofluorescence spatially defined the level of aggregated HTT in striatal and hippocampal regions across the age groups. [18F]CHDI-650 PET shows great potential as a non-invasive tool for visualising the development of mHTT pathology and as a biomarker for preclinical efficacy studies. Please click on the 'PDF' for the full abstract!

Increased CD14+HLA-DR-/low myeloid-derived suppressor cells can be regarded as a biomarker on disease severity and response to therapy in acute coronary syndrome.

This study aimed to investigate the dynamic changes in monocytic myeloid-derived suppressor cells (M-MDSCs) and their implications in the pathogenesis of acute coronary syndrome (ACS), shedding light on potential therapeutic targets. Peripheral blood samples were collected from 68 ACS patients, 35 stable angina pectoris (SAP) patients, and 30 healthy controls (HC). Multi-parameter flow cytometry was employed for analysis of M-MDSCs, explored with disease characteristics and progression. ACS patients exhibited an increased frequency of circulating M-MDSCs compared to SAP patients and HC. M-MDSCs levels demonstrated associations with ACS type, coronary artery lesions, multi-vessel disease, and cardiac dysfunction severity. Higher M-MDSCs levels were found in obese patients. Notably, therapy led to a significant decrease in M-MDSCs frequency. Furthermore, ACS patients exhibited elevated levels of interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) in the cytokine profile associated with M-MDSCs. Increased expression of arginase-1(Arg-1) was observed in ACS patients, with positive correlations between M-MDSCs levels and IL-6, GM-CSF, and Arg-1 expression. The diagnostic performance of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and M-MDSCs levels varied in predicting the severity of coronary artery stenosis, with TG showing higher specificity, HDL-C displaying higher sensitivity, and M-MDSCs levels demonstrating balanced sensitivity and specificity. Assessment of M-MDSCs frequency holds promise as a predictive marker for disease progression and therapy response of coronary artery stenosis. The elevated presence of M-MDSCs suggests their potential role in modulating ACS-related inflammation.

Regulation of autophagy by non-coding RNAs in human glioblastoma.

Glioblastoma, a lethal form of brain cancer, poses substantial challenges in treatment due to its aggressive nature and resistance to standard therapies like radiation and chemotherapy. Autophagy has a crucial role in glioblastoma progression by supporting cellular homeostasis and promoting survival under stressful conditions. Non-coding RNAs (ncRNAs) play diverse biological roles including, gene regulation, chromatin remodeling, and the maintenance of cellular homeostasis. Emerging evidence reveals the intricate regulatory mechanisms of autophagy orchestrated by non-coding RNAs (ncRNAs) in glioblastoma. The diverse roles of these ncRNAs in regulating crucial autophagy-related pathways, including AMPK/mTOR signaling, the PI3K/AKT pathway, Beclin1, and other autophagy-triggering system regulation, sheds light on ncRNAs biological mechanisms in the proliferation, invasion, and therapy response of glioblastoma cells. Furthermore, the clinical implications of targeting ncRNA-regulated autophagy as a promising therapeutic strategy for glioblastoma treatment are in the spotlight of ongoing studies. In this review, we delve into our current understanding of how ncRNAs regulate autophagy in glioblastoma, with a specific focus on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), and their intricate interplay with therapy response.

Impact of low HER2 expression on response to CDK4/6 inhibitor treatment in advanced HR + /HER2- breast cancer: a multicenter real-world data analysis.

CDK4/6 inhibitors (CDK4/6i) represent the first-line therapy approach of choice for patients with hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER-ABC). Approximately 50% of HR + /HER2-ABC displays low HER2 expression (HER2 low). Recent data emerging from the DESTINY-Breast04 trial demonstrated practice-changing efficacy of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in patients with low HER2 expression. Here, we aimed to analyze the impact of low HER2 expression on CDK4/6i therapy response in a well-characterized multicenter HR + /HER-ABC cohort. Patients diagnosed with HR + /HER2-ABC who were treated with CDK4/6i in clinical routine between November 2016 and December 2020 at four certified German Breast Cancer Centers were retrospectively identified. The cohort was stratified according to graduation of positivity in HER2 immunohistochemistry (IHC; HER2 zero = IHC score 0 and HER2 low = IHC score 1 + , 2 + /fluorescence in situ hybridization negative). Subgroups were analyzed with regard to progression-free survival (PFS) following CDK4/6i initiation. The study cohort comprised n = 448 patients. For n = 311 patients, HER2 status from the metastatic site was available. n = 91 (29.3%) cases were HER2 zero and n = 220 cases (70.7%) were HER2 low. There was no significant difference in PFS between the two groups (PFS: 17months versus 18months, log-rank p = 0.42). Further, we examined the influence of HER2 expression changes between primary and metastatic tissue (n = 171; HER2 gain/HER2 loss/HER2 stable expression) on CDK4/6i treatment response. Again, there was no significant difference between these three groups, respectively (PFS: 16months versus 13months versus 17months, log-rank p = 0.86). In our analysis, HER2 status did not have a significant impact on treatment response to CDK4/6i.

Antiretroviral therapy combined with Shenling Guben Granules for the treatment of HIV infection with immune reconstitution deficiency: A randomized, double-blind, placebo-controlled study

Background: Even with long-term complete suppression of the virus through Antiretroviral therapy (ART), people infected with HIV cannot attain optimal immune reconstitution. This phenomenon is called immune reconstitution deficiency, there are no effective therapeutic interventions for immune reconstitution deficiency in modern medicine. Objective: To evaluate the efficacy and safety of ART with Shenling Guben Granules Traditional Chinese medicine in boosting immunological reconstitution compared with ART alone. Methods: This was a randomized, double-blind, placebo-controlled, multi-center clinical trial evaluating the efficacy and safety of ART combined with Chinese medicine. The individuals aged 18–65 years with poor immune reconstitution following ART were included in this trial. The primary outcome was a change in the absolute value of CD4+ T lymphocytes after 72 weeks of combined ART and Chinese medicine administration. Secondary outcomes included changes in CD4+ T lymphocyte functional subpopulations, activated T lymphocyte subpopulations, CD4+ T lymphocyte proliferation, and T lymphocyte apoptosis from baseline to after 72 weeks. We also evaluated efficacy at 24- and 48-week intervals to better understand the dynamics of the trial drug’s efficacy. Results: There was a significant increase in CD4+ cell counts in groups treated with the Shenling Guben Granules after 24 weeks, 48 weeks, and 72 weeks of treatment (P<0.05), and the difference in CD4+ cell counts at 24 weeks of treatment was statistically significant (P=0.010). After 48 and 72 weeks of therapy, the CD4+CD38+ cell counts in the Shenling Guben Granules group were significantly higher than in the control group (P<0.05). In the subgroup analysis of CD4+ cell counts ≥200 cells/mm3, the CD4+ cell counts in the treatment group were higher than the control group after treatment for 24, 48, and 72 weeks (P<0.05). Discussion: CD4 cell counts in HIV/AIDS patients with immunological reconstitution insufficiency can be improved to a certain extent using Shenling Guben Granules. The greater the CD4 cell count at the start, the better the therapy response. Furthermore, Shenling Guben Granules have the efficacy and safety to prevent aberrant immunological activation. A large sample size, long-term follow-up, and multiple efficacy indicators were employed to assess the therapy’s safety. Our findings will lead to new therapeutic alternatives for HIV/AIDS patients suffering from immune reconstitution deficiency. Clinical Trial Registry: Name of the registry: Sundy on promote the reconstruction of Inadequate responders in HIV/AIDS patients after combined antiretroviral therapy by Shen Ling Gu Ben Granules;Chictr.org.cn Identifier: ChiCTR1800015290, registered on March 21, 2018( http://www.chictr.org.cn/registry.aspx).

Prognostic Impact of Thoracic Duct Resection in Patients Who Underwent Transthoracic Esophagectomy Following Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma: Exploratory Analysis of JCOG1109.

Although several studies have investigated whether thoracic duct (TD) resection improves prognosis, the conclusion remains controversial. JCOG1109 is a three-arm randomized phase III trial to confirm the survival advantage of docetaxel, cisplatin, 5-fluorouracil (DCF), and cisplatin plus 5-fluorouracil (CF) combined with radiotherapy (CF-RT) over CF as neoadjuvant treatment. The study aimed to evaluate the survival impact of TD resection and its association with neoadjuvant treatment and pathological response in patients enrolled in JCOG1109. Clinicopathological factors, surgical results, and prognosis were compared between TD preserved and resected groups. The survival impact of TD resection was also evaluated in the subgroups on the basis of combinations of preoperative therapy and pathological response. Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200) in JCOG1109. Of them, 541 patients underwent esophagectomy (183/181/177), and TD was resected in 265 patients (93/91/81). For the entire cohort, TD resection was not a significant prognostic factor for overall survival in the multivariable analysis (HR 1.20, 95% CI 0.91-1.57). In the subgroup analyses by combinations of neoadjuvant treatment and pathological response, TD resected group had a significantly better overall survival compared with TD preserved group in patients who received DCF and achieved pathological response (HR 0.20, 95% CI 0.07-0.61). The survival benefit of TD resection was not demonstrated in patients with surgically resectable esophageal squamous cell carcinoma enrolled in JCOG1109. The residual tumor burden after neoadjuvant treatment might be linked to the survival impact of TD resection.

Single-cell RNA sequencing identifies a subtype of FN1 + tumor-associated macrophages associated with glioma recurrence and as a biomarker for immunotherapy

BackgroundGlioma is the most common primary malignant tumor in the brain, and even with standard treatments including surgical resection, radiotherapy, and chemotherapy, the long-term survival rate of patients remains unsatisfactory. Recurrence is one of the leading causes of death in glioma patients. The molecular mechanisms underlying glioma recurrence remain unclear.MethodsOur study utilized single-cell sequencing, spatial transcriptomics, and RNA-seq data to identify a subtype of FN1 + tumor-associated macrophages (FN1 + TAMs) associated with glioma recurrence.ResultsThis study revealed an increased abundance of FN1 + TAMs in recurrent gliomas, indicating their potential involvement as a critical factor in glioma recurrence. A negative correlation was observed between the abundance of FN1 + TAMs in primary gliomas and the interval time to recurrence, suggesting poor prognosis for glioma patients with high levels of FN1 + TAMs. Further investigation showed that FN1 + TAMs were enriched in hypoxic tumor regions, implying that metabolic changes in tumors drive the production and recruitment of FN1 + TAMs. Additionally, FN1 + TAMs were found to contribute to the regulation of an immunosuppressive microenvironment in gliomas, and their abundance might serve as an indicator of patients’ sensitivity to immunotherapy. Finally, we developed a user-friendly website, PRIMEG (http://www.szflab.site/PRIMEG/), for exploring the immune microenvironment of primary and recurrent gliomas.ConclusionOur findings highlight a subtype of FN1 + TAMs associated with glioma recurrence, providing new insights into potential therapeutic targets. Moreover, the abundance of FN1 + TAMs hold promise for predicting immune therapy response and aiding in more precise risk stratification of recurrent glioma patients.

Imaging in malignant peritoneal neoplasms.

Peritoneal malignancies encompass a diverse range of tumors originating within the peritoneum, including primary tumors such as mesothelioma and primary serous peritoneal carcinoma or secondary tumors resulting from the spread of cancers from gastrointestinal, gynecological, and extra-abdominal sources. The traditional approach of palliative care for these malignancies is being replaced by a multimodal strategies that integrates surgery with systemic or intraperitoneal chemotherapy. Notably, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has shown significant improvements in survival rates. Imaging is crucial in the multidisciplinary management of these tumors, aiding in diagnosis, staging, restaging, and monitoring therapy response. It is also vital for appropriate patient selection, using the acronym "PAUSE", which involves assessing tumor burden via the peritoneal carcinomatosis index, evaluating patients pre- and post-therapy, detecting complications following therapy, and predicting treatment outcomes. This review explores the imaging manifestations of peritoneal malignancies, distinguishing them from various mimics, and underscores the importance of imaging modalities such as CT, MRI, PET/CT, and PET/MRI in effective decision-making and management.

12423 Pre-treatment Blood Transcriptome Accurately Predicts Growth Response To Daily And Weekly GH Treatment In Children Born Small For Gestational Age

Abstract Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. R. Ard: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Predicting GH therapy response from gene expression has the potential to improve clinical management of short stature. Treatment in children born small for gestational age (SGA) requires daily GH injections. Although no long-acting GHs (LAGHs) are currently approved for SGA, results from REAL5 (randomised, multinational, open-label, controlled, phase 2 trial; NCT03878446) indicate that the LAGH somapacitan has an efficacy, safety, and tolerability profile similar to daily GH (1). Here, we investigate growth response prediction based on the baseline blood transcriptome with and without clinical variables in daily GH- or somapacitan-treated children in REAL5. Methods: REAL5 tested three somapacitan doses (0.16, 0.20, & 0.24 mg/kg/week; n=12, n=13, & n=12, respectively) versus two daily GH doses (0.035 & 0.067 mg/kg/day; n=12 & n=13, respectively). GH response was explored using four metrics calculated over 52-weeks: height velocity (HV; cm/year), HV standard deviation score (SDS), change in height SDS, and change in IGF-I SDS. Due to small sample sizes, dose groups were combined. Participants were split into tertiles to define fastest/slowest responders to each treatment which were compared to remaining tertiles. Differentially expressed genes (DEGs) were defined to distinguish one tertile from the remaining two. Random forest (RF) models were generated using the top 100 DEGs as well as in combination with a set of clinical variables. Area under the curve (AUC) describes RF prediction accuracy: for somapacitan sufficient samples were available for both training and validation while for daily growth hormone samples were only sufficient for training generating out of bag (OOB) AUCs, accompanied by error rates (ER). Accuracies were calculated for both fast & slow responders across all response metrics in each treatment. Results: We demonstrate excellent predictive ability of the transcriptome to identify SGA children who respond slowest in HV following treatment with either daily GH or somapacitan (OOB AUC (ER)= 1.0 (5.0%) & 0.99 (6.9%), respectively; validation AUC=0.812 for somapacitan), while prediction of other response measures was highly variable, particularly in validation (AUCs=0.56-1.0). The clinical variables combined with the transcriptomic data resulted in reduced accuracies and increased error rates (OOBs AUC(ER)=0.93(25%) [daily] & 0.90(19%) [somapacitan]). Conclusions: In the first use of transcriptomics for growth response prediction in children born SGA we show good performance for those treated with both daily and weekly GH. However, when the transcriptome is combined with clinical data performance is reduced, indicating the importance of gene expression signatures for GH-response prediction. These findings may be promising for personalizing dose in GH-treated SGA patients. (1) Juul et al. EJE 2023:188,19-30. Presentation: 6/3/2024

8744 Genomic Variant Landscape In Aggressive & Treatment Resistant Prolactin-Secreting Tumors

Abstract Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. E. Peña-Martinez: None. S. Vela-Patiño: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R. Chavez-Santoscoy: None. E. Sosa-Eroza: None. P.E. Espinosa Cardenas: None. M. Mercado: None. Pituitary tumors (PT) represent the second most frequent intracranial tumor and this neoplasm arises from adenohypophyseal cells. Prolactin-secreting tumor (PRL-tumors) are the most commonly neoplasm of the pituitary gland and arises from lactotrophs, and account for 50% of all pituitary tumors. Pituitary tumors are highly heterogeneous lesions and many of them are invasive in up to 45%, with up to 15% being clinically aggressive. Aggressive PRL-tumors are defined as invasive tumors with unusually rapid growth rate despite maximal tolerated dopamine agonist dose and requiring additional therapy and presenting multirecurrent potential. Predicting pituitary tumor behavior remains a challenge, therefore we performed whole exome sequencing to identify genomic variant landscape from aggressive and treatment-resistant prolactin-secreting pituitary tumors. Interestingly one tumor showed one hotspot mutation in splicing factor gene SF3B1 (c.C1873T:p.R625C), a second tumor showed an stop codon in SF3B1 (c.C496T:p.R166*). We then evaluated known hereditary-related pituitary tumor genes, identifying three patients with two different GNAS allelic variants the first one showed c.A3059G:p.N1020S and two tumors with c.C1307A:p.A436D variants. PRKAR1A gene did not showed any allelic variants in our cohort, while all tumors presented c.A1636G:p.T546A variant in MEN1 gene, in AIP gene allelic variant c.C682A:p.Q228K was present in all tumors. PAX6 gene is related to pituitary gland development and function, we found a deletion (c.980delA:p.K327Rfs*29) causing frameshift present in all tumors. The target coding-gene for cabergoline, first line of treatment, DRD2 di not showed any allelic variant. Also XRCC1 and ABCB1 genes, which are related to drug and therapy response showed c.A1196G:p.Q399R and c.T2887G:p.S963A allelic variants in 100% and 88% of tumors, respectively. Together this genomic landscape could represent higher risk to harbor aggressive non-responsive PRL secreting tumor. Presentation: 6/1/2024

Multipoint pacing is associated with improved prognosis and cardiac resynchronization therapy response: MORE-CRT MPP randomized study secondary analyses.

Cardiac resynchronization therapy (CRT) via biventricular (BIV) pacing is indicated in patients with heart failure (HF), reduced ejection fraction, and prolonged QRS duration. Quadripolar leads and multipoint pacing (MPP) allow multiple left ventricle (LV) sites pacing. We aimed to assess the clinical benefit of MPP in patients who do not respond to standard BIV pacing. Overall, 3724 patients were treated with standard BIV pacing. After 6 months, 1639 patients were considered as CRT non-responders (echo-measured relative reduction in LV end-systolic volume (LVESV) < 15%) and randomized to MPP or BIV. We analysed 593 randomized patients (291 MPP, 302 BIV), who had BIV pacing >97% of the time before randomization and complete 12 months of clinical and echocardiographic data. The endpoint composed of freedom from cardiac death and HF hospitalizations and by LVESV relative reduction ≥15% between randomization and 12 months occurred more frequently in MPP [96/291 (33.0%)] vs. BIV [71/302 (23.5%), P = 0.0103], which was also confirmed at multivariate analysis (hazard ratio = 1.55, 95% confidence interval = 1.02-2.34, P = 0.0402 vs. BIV). HF hospitalizations occurred less frequently in MPP [14/291 (4.81%)] vs. BIV [29/302 (9.60%), incidence rate ratio = 50%, P = 0.0245]. Selecting patients with a large (>30 ms) dispersion of interventricular electrical delay among the four LV lead dipoles, reverse remodelling was more frequent in MPP [18/51 (35.3%)] vs. BIV [11/62 (17.7%), P = 0.0335]. In patients who do not respond to standard CRT despite the high BIV pacing percentage, MPP is associated with lower occurrence of HF hospitalizations and higher probability of reverse LV remodelling compared with BIV pacing.

Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response.

Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serialNGS-based monitoring into prospective MDS clinical trials.

Prognostic value of a lactate metabolism gene signature in lung adenocarcinoma and its associations with immune checkpoint blockade therapy response.

Lung adenocarcinoma (LUAD) is a study that examines the prognostic value of lactate metabolism genes in tumor cells, which are associated with clinical prognosis. We analyzed the expression and clinical data for LUAD from The Cancer Genome Atlas database, using the GSE68465 dataset from the Gene Expression Omnibus and the MSigDB database. LASSO Cox regression and stepwise Cox regression were used to identify the optimal lactate metabolism gene signature. Differences in immune infiltration, tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB) therapy were evaluated between groups. LASSO and Cox regression analyses showed an eight-lactate metabolism gene signature for model construction in both TCGA cohort and GSE68465 data, with higher survival outcomes in high-risk groups. The lactate metabolism risk score had an independent prognostic value (hazard ratio: 2.279 [1.652-3.146], P < .001). Immune cell infiltration differed between the risk groups, such as CD8+ T cells, macrophages, dendritic cells, mast cells, and neutrophils. The high-risk group had higher tumor purity, lower immune and stromal scores, and higher TMB. High-risk samples had high tumor immune dysfunction and exclusion (TIDE) scores and low cytolytic activity (CYT) scores, indicating a poor response to ICB therapy. Similarly, most immune checkpoint molecules, immune inhibitors/stimulators, and major histocompatibility complex (MHC) molecules were highly expressed in the high-risk group. The 8-lactate metabolism gene-based prognostic model predicts patient survival, immune infiltration, and ICB response in patients with LUAD, driving the development of therapeutic strategies to target lactate metabolism.

Identification of Disulfidptosis-Related LncRNA Subtypes, Establishment of a Prognostic Signature, and Characterization of Immune Infiltration in Ovarian Cancer.

Ovarian Cancer (OC) is a lethal malignant tumor with a poor prognosis. Disulfidptosis is a newly identified form of cell death caused by disulfide stress. Targeting disulfidptosis is a new metabolic therapeutic strategy in cancer treatment. We aimed to establish a disulfidptosis- related lncRNA signature for prognosis prediction and explore its treatment values in OC patients. Data from the TCGA and GTEx databases and a disulfidptosis gene set were used to establish a disulfidptosis-related lncRNA signature for prognosis prediction in OC patients. Then, we internally and externally (PCR) validated our model. We also built a nomogram to improve our model's predictive power. Afterward, GSEA was employed to explore our model's potential functions. The ESTIMATE, CIBERSORT, TIMER, and ssGSEA were applied to estimate the immune landscape. Finally, the drug sensitivity of certain drugs for OC patients was analyzed. We built a prognosis model based on seven drlncRNAs, including AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1. Our model performed well by internal validation. PCR data also confirmed the same trend in the lncRNA levels. Furthermore, the nomogram-integrated age, grade, stage, and risk score could accurately predict the survival outcomes of OC patients. Subsequently, GSEA unveiled that our model genes enriched the Hedgehog signaling pathway, a key regulator in OC tumorigenesis. Our predictive signature was associated with immune checkpoints, such as PD-1(P < 0.01), PD-L1(P < 0.001), and CTLA4 (P < 0.01), which might help screen out OC patients who are sensitive to immunotherapy. Small molecule drugs, such as AZD-2281, GDC-0449, imatinib, and nilotinib, might benefit OC patients with different risk scores. Our disulfidptosis-related lncRNA signature comprised of AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1 could serve as a prognostic biomarker and guidance to therapy response for OC patients.

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.

The baseline hemoglobin level is a positive biomarker for immunotherapy response and can improve the predictability of tumor mutation burden for immunotherapy response in cancer.

Because only a subset of cancer patients can benefit from immunotherapy, identifying predictive biomarkers of ICI therapy response is of utmost importance. We analyzed the association between hemoglobin (HGB) levels and clinical outcomes in 1,479 ICIs-treated patients across 16 cancer types. We explored the dose-dependent associations between HGB levels and survival and immunotherapy response using the spline-based cox regression analysis. Furthermore, we investigated the associations across subgroups of patients with different clinicopathological characteristics, treatment programs and cancer types using the bootstrap resampling method. HGB levels correlated positively with clinical outcomes in cancer patients receiving immunotherapy but not in those without immunotherapy. Moreover, this association was independent of other clinicopathological characteristics (such as sex, age, tumor stage and tumor mutation burden (TMB)), treatment program and cancer type. Also, this association was independent of the established biomarkers of immunotherapy response, including TMB, PD-L1 expression and microsatellite instability. The combination of TMB and HGB level are more powerful in predicting immunotherapy response than TMB alone. Multi-omics analysis showed that HGB levels correlated positively with antitumor immune signatures and negatively with tumor properties directing antitumor immunosuppression, such as homologous recombination defect, stemness and intratumor heterogeneity. The HGB measure has the potential clinical value as a novel biomarker of immunotherapy response that is easily accessible from clinically routine examination. The combination of TMB and HGB measures have better predictive performance for immunotherapy response than TMB.

Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma

Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment.

Using nonlinear dynamics analysis to evaluate time response of cupping therapy with different intervention timings on reducing muscle fatigue.

Cupping therapy has been indicated effective in reducing muscle fatigue after 24h based on the spectral analyses of surface electromyography (sEMG). However, there is no sufficient evidence showing changes of sEMG nonlinear indexes at more time points after cupping therapy. Furthermore, it is unclear whether the intervention timings of cupping therapy affect the recovery from muscle fatigue. The purpose of this study was to use the sEMG nonlinear analysis to assess the difference of time response of cupping therapy between different intervention timings after muscle fatigue. This randomized controlled trial recruited 26 healthy volunteers. Cupping therapy (-300mmHg pressure for 5min by the 45mm-diameter cup) was applied before (i.e., pre-condition) or after (i.e., post-condition) muscle fatigue induced by performing repeated biceps curls at 75% of the 10 repetitions of maximum (RM) on the non-dominant upper extremity. Subjects were randomly allocated to the pre-condition group or the post-condition group. The sEMG signals during the maximal voluntary isometric contractions (MVC) of the biceps were recorded at four time points (i.e., baseline; post 1: immediate after cupping-fatigue/fatigue-cupping interventions; post 2: 3h after cupping-fatigue/fatigue-cupping interventions; post 3: 6h after cupping-fatigue/fatigue-cupping interventions). Two nonlinear sEMG indexes (sample entropy, SampEn; and percent determinism based on recurrence quantification analysis, %DET) were used to evaluate the recovery from exercise-introduced muscle fatigue. The Friedman test followed by the Nemenyi test and the Mann-Whitney U test were applied in statistics. The SampEn and %DET change rate did not show any significant differences at four time points in the pre-condition group. However, there were significant delayed effects instead of immediate effects on improving muscle fatigue in the post-condition group (SampEn change rate: baseline 0.0000 ± 0.0000 vs. post 2 0.1105 ± 0.2253, p < 0.05; baseline 0.0000 ± 0.0000 vs. post 3 0.0627 ± 0.4665, p < 0.05; post 1-0.0321 ± 0.2668 vs. post 3 0.0627 ± 0.4665, p < 0.05; and %DET change rate: baseline 0.0000 ± 0.0000 vs. post 2-0.1240 ± 0.1357, p < 0.01; baseline 0.0000 ± 0.0000 vs. post 3 0.0704 ± 0.6495, p < 0.05; post 1 0.0700 ± 0.3819 vs. post 3 0.0704 ± 0.6495, p < 0.05). Moreover, the SampEn change rate of the post-condition group (0.1105 ± 0.2253) was significantly higher than that of the pre-condition group (0.0006 ± 0.0634, p < 0.05) at the post 2 time point. No more significant between-groups difference was found in this study. This is the first study demonstrating that both the pre-condition and post-condition of cupping therapy are useful for reducing muscle fatigue. The post-condition cupping therapy can e ffectively alleviate exercise-induced muscle fatigue and there is a significant delayed effect, especially 3h after the interventions. Although the pre-condition cupping therapy can not significantly enhance muscle manifestations, it can recover muscles into a non-fatigued state.

Spatial resolution of the head and neck cancer tumor microenvironment to identify tumor and stromal features associated with therapy response.

Head and neck cancer (HNC) is the seventh most common cancer globally, resulting in 440 000 deaths per year. While there have been advancements in chemoradiotherapy and surgery, relapse occurs in more than half of HNCs, and these patients have a median survival of 10 months and a 2-year survival of < 20%. Only a subset of patients displays durable benefits from immunotherapies in metastatic and recurrent HNC, making it critical to understand the tumor microenvironment (TME) underpinning therapy responses in HNC. To recognize biological differences within the TME that may be predictive of immunotherapy response, we applied cutting-edge geospatial whole-transcriptome profiling (NanoString GeoMx Digital Spatial Profiler) and spatial proteomics profiling (Akoya PhenoCycler-Fusion) on a tumor microarray consisting of 25 cores from 12 patients that included 4 immunotherapy-unresponsive (8 cores) and 2 immunotherapy-responsive patients (5 cores), as well as 6 immunotherapy naïve patients (12 cores). Through high-plex, regional-based transcriptomic mapping of the tumor and TME, pathways involved with the complement system and hypoxia were identified to be differentially expressed in patients who went on to experience a poor immunotherapy response. Single-cell, targeted proteomic analysis found that immune cell infiltration of the cancer cell mass and interactions of CD8 Tcells with tumor and other immune cells were associated with positive immunotherapy response. The relative abundance of specific tumor phenotypes and their interactions with various immune cells was identified to be different between response groups. This study demonstrates how spatial transcriptomics and proteomics can resolve novel alterations in the TME of HNC that may contribute to therapy sensitivity and resistance.