Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor ...eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.
Breast cancer (BC) is the most frequent tumour in women. Triple negative tumours (TNBC)-which are associated with minor survival rates-lack markers predictive of response to anticancer drugs. Triple ...negative tumours frequently metastasise to the central nervous system (CNS).
The main objective of this study was to study differences in tumour protein expression between patients with CNS metastases and those without this kind of spread, and propose new biomarkers.
A retrospective study was performed. Targeted proteomics and statistical analyses were used to identify possible biomarkers.
Proteins were quantified by a targeted proteomics approach and protein expression data were successfully obtained from 51 triple negative formalin-fixed paraffin-embedded samples. ISG15, THBS1 and AP1M1 were identified as possible biomarkers related with CNS metastasis development.
Three possible biomarkers associated with CNS metastases in TNBC tumours were identified: ISG15, THBS1 and AP1M1. They may become markers predicting the appearance of CNS infiltration in triple negative BC.
Purpose
Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of ...integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research.
Methods
The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation.
Results
We identified 7 genes coding for integrin α and β subunits, i.e.,
ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL
and
ITGA8
, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (
IBSP, ITGB3BP, ITGB6, ITGB1
and
ITGAV
) were not associated with any of these parameters.
Conclusions
We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis.
There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several ...solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8
T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8
T cells, CD4
T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.
BackgroundPrognosis is poor for patients with recurrent/metastatic (R/M) human papillomavirus (HPV) 16+ head and neck squamous cell carcinoma (HNSCC) after first-line standard of care therapy. HB-200 ...is comprised of an alternating sequence of two replicating attenuated arenavirus vectors derived from LCMV (HB-201) and Pichinde virus (HB-202), respectively, expressing the same non-oncogenic HPV16 E7E6 fusion protein.1 In a Phase 1 study, HB-200 monotherapy induced strong and long-lasting HPV16 E6 and E7-specific CD8+ T cell responses and demonstrated a favorable safety profile and antitumor activity in previously treated patients with HPV16+ R/M HNSCC.2 Here, we report long-term circulating tumor specific immune responses and clinical benefit in these patients.MethodsPatients with HPV16+ HNSCC post at least 1 prior systemic R/M anti-cancer therapy were treated with HB-200 monotherapy (alternating intravenous administration of HB-202 and HB-201 every 3 weeks Q3W then Q6W) until disease progression or unacceptable toxicity. Four dose levels of HB-200 were explored. HPV16 specific T cell responses were evaluated in peripheral blood mononuclear cells (PBMCs) by both direct IFN-γ ELISpot and intracellular cytokine staining (ICS) performed without prior in vitro expansion. Tumor analyses including sequencing were performed for patients with available baseline and on-treatment biopsies. Antitumor activity was measured by RECIST v1.1 per investigator assessment.ResultsAs of March 31, 2023, 41 patients with HPV16+ R/M HNSCC (37 oropharynx, 1 larynx, 2 nasopharynx, 1 unknown primary) were treated with HB-200 monotherapy. HB-200 rapidly induced HPV16+ tumor-specific CD8+ T cells in more than 90% of patients analyzed. The E6/E7 T cell responses were maintained for more than 8 months and on-going as of data cut-off. Circulating tumor-specific T cells responses increased up to 1250-fold (median 174, range 93–1250) from baseline, with more than 57% of patients exhibiting ≥1% (maximum 48%) tumor specific CD8+ T cells out of total CD8+ T cells. Furthermore, tumor-specific CD8+ T cells increased in poly-functionality during treatment. Characterization of paired tumor biopsies revealed that HB-200 induced increased CD8+ T cell infiltration in tumors. Across all HB-200 doses, disease control rate was 48.5% in 33 heavily pre-treated patients with imaging evaluation (1 partial response, 15 stable disease), and overall survival is being assessed.ConclusionsHB-200 monotherapy induces promising HPV16+ tumor-specific T cell responses and tumor infiltration in heavily pre-treated patients. This immune response coupled with clinical benefit in monotherapy suggests that HB-200 may enhance and strengthen current immunotherapy approaches by targeting specific tumor antigens.AcknowledgementsThe authors would like to thank all the patients participating in this study, their caregivers and study personnel. The study is sponsored by Hookipa Pharma, Inc.Trial RegistrationClinicaltrials.gov NCT04180215ReferencesLauterbach H, Schmidt S, Katchar K, Qing X, Iacobucci C, Hwang A, Schlienger K, Berka U, Raguz J, Ahmadi-Erber S, Schippers T, Stemeseder F, Pinschewer DD, Matushansky I, Orlinger KK. Development and Characterization of a Novel Non-Lytic Cancer Immunotherapy Using a Recombinant Arenavirus Vector Platform. Front Oncol. 2021 Oct 14;11:732166. doi:10.3389/fonc.2021.732166Fu S, Nabell L, Pearson A, Leidner R, Adkins D, Posner M, Nieva JJ, Richardson DL, Pimentel A, Goel S, Wong SJ, Ho AL, Rosenberg A, Taylor MH, Abdul-Karim R, Iacobucci C, Qing X, Katchar K, Schlienger K, Pfister, DG. Recommended phase 2 dose (RP2D) of HB-200 arenavirus-based cancer immunotherapies in patients with HPV16+ cancers. ASCO 2022. Abstract 2517Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers:20–165A(5) (Memorial Sloan Kettering Cancer Center), IRB19–1294 (University of Chicago), 2019–0928 (University of Texas M. D. Anderson Cancer Center), HS# STUDY-19–01049 (Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute), 1275383 (Washington University School of Medicine), 1282128 (University of Alabama at Birmingham Heersink School of Medicine), 1266389 (Banner MD Anderson Cancer Center), H-200–001 (RM 662) (Stephenson Cancer Center at University of Oklahoma Health Sciences Center), STUDY2019000305 (Providence Cancer Institute), Pro00092499 (Greenville Hospital System University Medical Center), 202101073 (University of Iowa), HS-19–00931 (University of Southern California, Norris Cancer Center), PRO00036737 (Medical College of Wisconsin), CODIGO:EC/21/252/6495 (R) (Hospital Universitari Vall d’Hebron, Spain). All participants provided written informed consent.
Breast cancer (BC) is the most frequent tumour in women, representing 20-30% of all malignancies, and continues to be the leading cause of cancer deaths among European women. Triple-negative (TN) BC ...biological aggressiveness is associated with a higher dissemination rate, with central nervous system (CNS) metastases common. This study aims to elucidate the association between gene expression profiles of PTGS2, HBEGF and ST6GALNAC5 and the development of CNS metastases in TNBC.
This is a case-controlled retrospective study comparing patients (pts) with CNS metastases versus patients without them after adjuvant treatment. The selection of the samples was performed including 30 samples in both case and control groups. Formalin-fixed, paraffin-embedded samples were retrieved from the Hospital 12 de Octubre Biobank. Five 10 µm sections from each FFPE sample were deparaffinised with xylene and washed with ethanol, and the RNA was then extracted with the RecoverAll Kit (Ambion). Gene expression was assessed using TaqMan assays.
A total of 53 patients were included in the study. The average age was 55 years (range 25-85). About 47 patients (88.67%) had ductal histology and presented high grade (III) tumours (40 patients; 75.47%). Eight women in the case group presented first distant recurrence in the CNS (34.80%), local recurrence (three patients, 13.04%), lungs (two patients; 8.7%), bone (one patient; 4.34%) and other locations (seven patients; 30.38%). In the control group, first distant recurrence occurred locally (six patients; 46.1%), in bone (two patients; 15.4%), lungs (one patient; 7.7%) and other sites (four patients; 23.1%). RNA was successfully obtained from 53 out of 60 samples. PTGS2, HBEGF, and ST6GALNAC5 expression values were not related to metastasis location.
TN tumours frequently metastasise to the visceral organs, particularly lungs and brain, and are less common in bone. The literature suggests that expression of the three genes of interest (PTGS2, HBEGF, and ST6GALNAC5) could be different in TNBC patients with CNS metastasis when compared to patients without it. We did not find a differential expression pattern in PTGS2, HBEGF, and ST6GALNAC5 genes in primary TNBC showing CNS metastases. Further studies are needed to clarify the role of these genes in CNS metastases in TNBC patients.
Centrifugation is an alternative assisted technique to improve the efficiency of block freeze concentration. In this study reported the centrifugation to enhance the separation of concentrated ...solution from frozen fruit juices (blueberry and pineapple) in three cryoconcentration cycles. To force the separation of solutes from the frozen samples we used a centrifuge operated for 10min at 20°C and 4600rpm. This technique has good performance after the third cycle, reaching an increase of approximately 2.5 times the initial concentrations of solids, values close to 0.74kg solute per 1kg initial solute, and approximately 60% of the percentage of concentrate. The performance of block freeze concentration assisted by centrifugation applied to fruit juices was attributed to ice matrix acting as a porous solid through which the concentrated solution percolates through drainage channels of the ice improved by the centrifugal force.
The block freeze concentration allows producing food concentrates with high quality when thawed a frozen solution assisted or not by a technique to enhance the separation efficiency. In this work has applied centrifugation as an assisted technique to improve the efficiency of block freeze concentration applied to fruit juices, obtaining promissory results.
•We use the centrifugation for separating the concentrate from frozen juices.•This technique has high performance after the third cryoconcentration cycle.•The concentrated solution percolates through drainage channels of the ice.
This retrospective study determined features associated with brain metastasis (BM) in women with breast cancer.
A total of 215 initially early breast cancer cases were included. We reviewed files and ...CT scan images of BM.
Median age was 47 years and most of our cases were stage III (58.6%), grade III (62.8%), ER negative (62.3%) and nonluminal (59.1%). Median survival after BM was 4 months. Nonluminal, extracranial disease, time to CNS shorter than 15 months, >three brain lesions and poor breast-graded prognostic assessment and recursive partitioning analysis scores were associated with shorter survival. Adding extracranial disease to breast-graded prognostic assessment score also predicted survival after BM. Radiation response was assessed in 57 patients and response tended to be associated with nonluminal phenotype but not with survival.
Factors associated with both initial tumor and clinical features at BM time are associated with shorter survival in our Latinas population.
Introduction
Little is known about the association between Yerbamate (YMT) tea consumption and Parkinson disease (PD). We determined whether there was an association between YMT tea consumption and ...PD.
Methods
We conducted a multicenter case-control study in 3 countries (Argentina, Paraguay, and Uruguay). We applied a structured questionnaire about YMT tea consumption history. The survey also included information about factors previously associated with a decreased and increased risk of PD, apart from medical and demographic factors. Odds ratios and 95% confidence intervals were calculated using multivariate unconditional binary logistic regression analysis.
Results
We included 215 cases and 219 controls. The mean age of the cases was 65.6 ± 10.5 years and that of controls was 63.1 ± 10.5 years (
P
< 0.02). Years of YMT tea consumption, number of liters drunk per day, and amount of YMT used for preparing the infusion were similar between cases and controls (
P
> 0.05), but not the number of times the YMT was added into the container (
P
= 0.003) and the YMT tea concentration per serving (
P
= 0.02). The multivariate analysis showed that YMT tea concentration per serving lowered the risk for PD, independent of potential confounders (odds ratio, 0.62; 95% confidence interval, 0.47–0.84).
Conclusions
This multicenter study highlights the association between an environmental factor, the YMT tea drinking, and PD. Although more evidence from longitudinal studies is needed, the results obtained here points toward a protective effect of the YMT tea concentration per serving on PD.
Purpose To determine the frequency of PIK3CA mutations in a Peruvian cohort with HER2-amplified and triple negative breast cancers (TNBC). Methods We analyzed two cohorts of 134 primary ...non-metastatic breast cancer patients from Peru. Cohorts consisted of 51 hormone receptors (+)/HER2-amplified breast tumor patients surgically resected as first treatment included in the ALTTO trial (ALTTO cohort) and 81 TNBC patients with residual disease after neoadjuvant treatment (neoadjuvant cohort). Genomic DNA was extracted from paraffin-embedded tumor samples. Samples from the ALTTO and neoadjuvant cohorts were taken at biopsies and from residual tumors, respectively. PIK3CA mutations were detected by sequencing DNA fragments obtained by PCR amplification of exons and their flanking introns. All of the detected PIK3CA mutations were confirmed in a second independent run of sample testing. Results PIK3CA mutations were present in 21/134 cases (15.7%). Mutations in exon 9 and 20 were present in 10/134 (7.5%) and 11/134 (8.2%), respectively. No cases had mutations in both exons. Mutations in exon 9 consisted of E545A (seven cases), E545K (two cases) and E545Q (one case); while in exon 20, mutations consisted of H1047R (10 cases) and H1047L (one case). Compared to TNBC patients, HER2-amplified patients were more likely to have PIK3CA mutated (23% vs 9.6%; P = 0.034). There were no associations between mutational status of PIK3CA with estrogen receptor status ( P = 0.731), progesterone receptor status ( P = 0.921), age ( P = 0.646), nodal status ( P = 0.240) or histological grade ( P = 1.00). No significant associations were found between PIK3CA mutational status and clinicopathological features. Conclusions We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors.
PDF
