Immunotherapy is a practical therapeutic approach in breast cancer (BRCA), and the role of FLI1 in immune regulation has gradually been unveiled. However, the specific role of FLI1 in BRCA was ...conflicted; thus, additional convincing evidence is needed.
We explored the upstream regulation of FLI1 expression via summary data-based Mendelian randomization (SMR) analysis and ncRNA network construction centering on FLI1 using BRCA genome-wide association study (GWAS) summary data with expression quantitative trait loci (eQTLs) and DNA methylation quantitative trait loci (mQTLs) from the blood and a series of in silico analyses, respectively. We illuminated the downstream function of FLI1 in immune regulation by integrating a series of analyses of single-cell RNA sequence data (scRNA-seq).
We verified a causal pathway from FLI1 methylation to FLI1 gene expression to BRCA onset and demonstrated that FLI1 was downregulated in BRCA. FLI1, a transcription factor, served as myeloid and T cells' communication regulator by targeting immune-related ligands and receptor transcription in BRCA tissues. We constructed a ceRNA network centering on FLI1 that consisted of three LncRNAs (CKMT2-AS1, PSMA3-AS1, and DIO3OS) and a miRNA (hsa-miR-324-5p), and the expression of FLI1 was positively related to a series of immune-related markers, including immune cell infiltration, biomarkers of immune cells, and immune checkpoints.
Low-methylation-induced or ncRNA-mediated downregulation of FLI1 is associated with poor prognosis, and FLI1 might regulate the tumor immune microenvironment via a cell-type-specific target genes manner in BRCA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in ...the tumor microenvironment remains largely unexplored.
Methods
A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies—namely RNA-sequencing, western blotting, quantitative reverse transcription–polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay—were used to reveal the mechanisms of MYBL2 in the OVC microenvironment.
Results
We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance.
Conclusions
The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.
Abstract Objectives The behaviors of placental site trophoblastic tumor (PSTT), especially lymphatic spread, have not been completely understood. We aimed to investigate the nature of lymphatic ...spread in PSTT as well as the expression of several molecules on tumor. Methods The clinical data of 5 cases with PSTT were reviewed retrospectively. The expression of EGFR, VEGF, HER2/neu, and CD117 was analyzed by immunohistochemical staining. A MEDLINE search was performed to identify patients with PSTT. Results There were several special aspects in our 5 cases. One patient was postmenopausal and had a 33-year long interval from antecedent pregnancy; two patients had lymph node and ovarian involvement each; the postmenopausal patient had 4 relapses and survived 57 months after the first recurrence. Tumor cells in all cases were strongly positive for EGFR and VEGF and negative for HER2/neu and CD117. A total of 286 cases (281 from the literature and 5 from our data) were analyzed for lymphatic spread. Of them, 17 (5.9%) had lymph node metastases, including pelvic in 5 patients, para-aortic in 7, retroperitoneal but not specified in 2, and other sites in 6. Conclusions Lymph node metastasis is one way of spread in PSTT. Retroperitoneal node, especially para - aortic node, is the most common site of lymphatic spread. EGFR and VEGF may be commonly expressed in PSTT tumors.
Vascular endothelial growth factor (VEGF)-targeted therapy is effective in patients with ovarian cancer. Whether adipose tissue (AT) could predict the efficacy of VEGF receptor (VEGFR) inhibitors in ...ovarian cancer is unknown. We aimed to evaluate the ability of distinct AT depots to predict the efficacy of apatinib, a VEGFR inhibitor, in recurrent ovarian cancers included in the AEROC trial.
The AEROC was a single-arm phase 2 trial of apatinib and oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer. Apatinib was administered continuously, and oral etoposide was administered every 21 days for a maximum of six cycles. This was a post hoc study based on the AEROC trial. Areas of visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) were measured using computed tomography scan at baseline to assess their association with the objective response rate, progression-free survival, and overall survival.
Of the 35 treated patients, 31 patients with at least one post-baseline efficacy assessment by computed tomography scan were included in this study. After adjusting for apatinib exposure, high VAT (odds ratio OR, 0.16; 95% confidence interval CI, 0.03-0.90, P = 0.037) and SAT (OR, 0.16; 95% CI, 0.03-0.87, P = 0.034) were significantly associated with a higher objective response rate. Further, decreased risks of disease progression and death were associated with high VAT (hazard ratio HR, 0.39; 95% CI, 0.17-0.92, P = 0.031, and HR, 0.12; 95% CI, 0.04-0.40, P < 0.001, respectively), SAT (HR, 0.35; 95% CI, 0.15-0.83, P = 0.027, and HR, 0.24; 95% CI, 0.08-0.67, P = 0.007, respectively), and IMAT (HR, 0.20; 95% CI, 0.06-0.74, P = 0.016, and HR, 0.13; 95% CI, 0.03-0.62, P = 0.011, respectively).
High areas of VAT, SAT, and IMAT were significantly associated with better outcomes in patients with platinum-resistant or platinum-refractory ovarian cancer who received VEGFR inhibitors. AT assessments may be valuable as patient-specific imaging biomarkers for predicting response to VEGFR inhibitors.
ClinicalTrials.gov identifier: NCT02867956 .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundThe Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor ...camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy.MethodsGenomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS).ResultsA subset of 32 patients was included in this analysis. Top altered genes included PIK3CA (43.8%), STK11 (25%), FBXW7 (15.6%), and PTEN (15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients. PIK3CA (PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) and PTEN (PFS HR 3.71e-09, p=0.05; OS HR 3.64e-09, p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with either PIK3CA or PTEN alterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), while ERBB3 mutations (PFS HR 34.9, p<0.001; OS HR 19.8, p<0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p<0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showed ERBB3 mutations (PFS p=0.01, OS p<0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival.ConclusionsWe uncovered that genetic alterations in PIK3CA, PTEN, ERBB3, and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy.Trial registration numberNCT03816553.
Background
Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated ...long‐term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported.
Methods
In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4‐week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Results
Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2‐year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12‐month progression‐free survival (PFS) rate was 40.7% (95% confidence interval CI, 25.2‐55.6), with an 18‐month PFS rate of 37.8% (95% CI, 22.7‐52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3‐36.9), and the 24‐month OS rate was 47.8% (95% CI, 31.7‐62.3). Age > 50 years, programmed death‐ligand 1 (PD‐L1) combined positive score (CPS) ≥ 1 (versus vs. < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio HR < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study.
Conclusion
Long‐term survival follow‐up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first‐line platinum‐based chemotherapy. No new safety signals were noted with long‐term treatment.
Abstract Objectives Intraperitoneal (IP) chemotherapy has not been widely accepted in the treatment of ovarian cancer. One of the main reasons is the lack of a convenient and safe way to deliver IP ...therapy. The objective of this study was to investigate the feasibility of delivering IP chemotherapy via direct puncture using a peripheral venous needle, as well as evaluating the associated risk factors and complications in the primary treatment of ovarian, fallopian tube, and primary peritoneal cancer. Methods The clinical records of all patients with stage II–IV epithelial ovarian, fallopian tube, and primary peritoneal cancer at Sun Yat-sen University Cancer Center from 01/1995 to 11/2006 were reviewed retrospectively to identify patients who had received IP therapy via direct puncture after primary cytoreduction. Results We identified 194 patients, and 121 (62.4%) of them successfully completed six or more cycles of IP chemotherapy, whereas 73 (37.6%) failed. Two (1%) patients ceased IP therapy directly due to IP access related complications and 35 (18.1%) discontinued IP therapy for reasons unrelated to IP access. Old age might be a potential risk factor for IP therapy failure. The IP therapy failure rate in patients over 60 years old was higher than that in patients under or at 60 (57.1% versus 34.3%, P = 0.021). Body mass index were not associated with IP therapy failure. Conclusions IP access via direct puncture using a peripheral venous needle could be an alternative and safe way to deliver IP chemotherapy in the primary treatment of ovarian cancer.
Corynebacterium crenatum
SYPA 5-5 is an aerobic and industrial
l
-arginine producer. It was proved that the
Corynebacterium glutamicum
/
Escherichia coli
shuttle vector pJC1 could be extended in
C. ...crenatum
efficiently when using the chloramphenicol acetyltransferase gene (
cat
) as a reporter under the control of promoter
tac
. The expression system was applied to over-express the gene
vgb
coding
Vitreoscilla
hemoglobin (VHb) to further increase the dissolved oxygen in
C. crenatum
. As a result, the recombinant
C. crenatum
containing the pJC-
tac
-
vgb
plasmid expressed VHb at a level of 3.4 nmol g
−1
, and the oxygen uptake rates reached 0.25 mg A
562
−1
h
−1
which enhanced 38.8% compared to the wild-type strain. Thus, the final
l
-arginine concentration of the batch fermentation reached a high level of 35.9 g L
−1
, and the biomass was largely increased to 6.45 g L
−1
, which were 17.3% and 10.5% higher than those obtained by the wild-type strain, respectively. To our knowledge, this is the first report that the efficient expression system was constructed to introduce
vgb
gene increasing the oxygen and energy supply for
l
-arginine production in
C. crenatum
, which supplies a good strategy for the improvement of amino acid products.
Objective:
To evaluate the outcomes of adjuvant chemotherapy administered alone or with radiotherapy in a "sandwich" protocol in patients with advanced endometrial cancer.
Methods:
The authors ...retrospectively reviewed the clinical records of patients with staged III - IV disease who received adjuvant chemotherapy (docetaxel plus carboplatin) administered alone or interposed with radiotherapy between January 2004 and August 2010.
Results:
Of the 35 study patients, 10 (28.6%) had stage IIIA disease, 15 (42.9%) had IIIC1 disease, 7 (20.0%) had IIIC2 disease and 3 (8.6%) had IVB disease. Nine (90.0%) of the 10 patients with stage IIIA disease received four to six cycles of adjuvant docetaxel and carboplatin chemotherapy alone. All 25 patients with stage IIIC - IVB disease and 1 patient with stage IIIA disease received radiotherapy sandwiched between chemotherapy cycles (total, three to six cycles). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.0 and 87.0%, respectively, for all patients. For patients with stage IIIC - IVB disease, the 3-year PFS and OS rates were 62.4 and 81.8%, respectively.
Conclusion:
Combination chemotherapy with docetaxel and carboplatin interposed with radiotherapy is efficacious and well tolerated for stage IIIC - IVB endometrial cancer. Adjuvant chemotherapy alone with docetaxel and carboplatin might be sufficient for stage IIIA disease.
Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor ...receptor-2, in patients with advanced cervical cancer.
This multicenter, open-label, single-arm, phase II study enrolled patients with advanced cervical cancer who progressed after at least one line of systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once per day. The primary end point was objective response rate (ORR) assessed by investigators per RECIST version 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, and safety.
Forty-five patients were enrolled and received treatment. Median age was 51.0 years (range, 33-67 years), and 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease. Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months (range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months to not estimable). Median duration of response and median OS were not reached. Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). The most common potential immune-related AEs included grade 1-2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%).
Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.
PDF
