Munkholmpereira6708
Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[
F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([
F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.
[
F]DASA-23 was synthesized with a molar activity of 100.47 plus minus 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [
F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [
F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.
In mouse imaging studies, [
F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue aaging therapy-induced normalization of aberrant cancer metabolism.
Abnormal notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting γ-secretase, a pivotal regulator in the Notch pathway, has yielded numerous GSIs for clinical investigation in the last two decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess γ-secretase activity and its inhibition
Experimental Design We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine labeled analogs [
I]- or [
I]-PN67 from corresponding trimethyl-tin precursors. Both membrane- and cell-based ligand binding assays were performed using [
I]-PN67 to determine the binding affinity and specificity for γ-secretase
Moreover, we evaluated [
I]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models.
The probe was synthesized through iodo-destannylation using chloramine-T as oxidant with high labeling yield and efficiency.
binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant (
less than 0.05) increased in the uptake of [
I]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 xenograft, MMTV-PyMT breast cancer, and U87 glioblastoma xenograft.
biodistribution and autoradiography corroborate these results, indicating γ-secretase specific tumor accumulation of [
I]-PN67.
[
I]-PN67 is a novel PET imaging agent that enables assessment of γ-secretase activity and target engagement of clinical GSIs.
[124I]-PN67 is a novel PET imaging agent that enables assessment of γ-secretase activity and target engagement of clinical GSIs.Type 2 diabetes (T2DM) and hypertension (HTN) are both relatively common systemic diseases and cause damage to the retina, such as inner retina reduction and microvascular impairment. The purpose of this study was to identify peripapillary retinal nerve fiber layer (pRNFL) damage by diabetic neurodegeneration (DRN) and the effects of HTN on the pRNFL thickness in T2DM patients without clinical diabetic retinopathy. Subjects were divided into 3 groups healthy control (group 1), patients with T2DM (group 2), and patients with both DM and HTN (group 3). The pRNFL thickness was measured using optical coherence tomography and was compared among each group. Linear regression analyses were performed to identify factors associated with pRNFL thickness. A total of 325 eyes were included; 143 eyes in the group 1, 126 eyes in group 2, and 56 eyes in group 3. The mean pRNFL thicknesses of each group were 96.1 ± 7.7, 94.4 ± 8.6, and 91.6 ± 9.6 μm, respectively (P = 0.003). In multivariate linear analyses, DM duration (B = -0.236, P = 0.018) and HTN (B = -3.766, P = 0.008) were significant factors affecting the pRNFL thickness in group 2 and group 3. Additionally, the HTN duration was significantly correlated with pRNFL thickness in group 3 (R2 = 0.121, P = 0.008). In conclusion, T2DM patients with HTN showed thinner pRNFL thickness than those with T2DM only. Additionally, the duration of HTN was significantly correlated with pRNFL thickness in patients with both DM and HTN.Activating transcription factor 3 (ATF3) has been shown to play an important role in HDL metabolism, yet the role of hepatocytic ATF3 in the development of steatohepatitis remains elusive. Here we show that adeno-associated virus-mediated over-expression of human ATF3 in hepatocytes prevents diet-induced steatohepatitis in C57BL/6 mice and reverses steatohepatitis in db/db mice. Conversely, global or hepatocyte-specific loss of ATF3 aggravates diet-induced steatohepatitis. Mechanistically, hepatocytic ATF3 induces hepatic lipolysis and fatty acid oxidation and inhibits inflammation and apoptosis. We further show that hepatocyte nuclear factor 4α (HNF4α) is required for ATF3 to improve steatohepatitis. Thus, the current study indicates that ATF3 protects against steatohepatitis through, at least in part, hepatic HNF4α. GSK-3 phosphorylation Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.
We evaluated the predictive value of candidate serum biomarkers for recurrence in stage II and III colorectal cancer (CRC) after curative surgery.
A total of 33 and 120 patients with CRC with or without recurrence at 5 years after curative surgery were included in the training set and the validation set, respectively. Possible serum biomarkers were examined for associations with CRC recurrence using receiver operating characteristics (ROC) curve analysis.
In the training set, the expression levels of the 14 biomarkers were compared according to recurrence. Among them, five biomarkers that had significantly different expression levels were validated in 60 patients with recurrence at 5 years after curative surgery and 60 patients without. Multivariate analysis showed that natural log-transformed values of carcinoembryonic antigen (CEA), cyclin-dependent kinase regulatory subunit 2 (CKS2), 2'-5'-oligoadenylate synthetase 2 (OAS2), and autophagy-related gene 5 (ATG5) in preoperative serum were significantly related to recurrence. ROC analysis showed that these biomarkers were able to discriminate patients with recurrence from those without (area under the curve=0.828, 95% confidence interval=0.755-0.990).
Preoperative serum levels of CEA, CKS2, OAS2 and ATG5 were independent risk factors for recurrence. A combination of serum CEA, CKS2, OAS2 and ATG5 predicted tumor recurrence well in patients with stage II and III CRC.
Preoperative serum levels of CEA, CKS2, OAS2 and ATG5 were independent risk factors for recurrence. A combination of serum CEA, CKS2, OAS2 and ATG5 predicted tumor recurrence well in patients with stage II and III CRC.
Previous reports have indicated that increased expression of Jagged-1 (JAG1) may predict chemotherapy response and poor prognosis for patients with recurrent or metastatic colorectal cancer (CRC). This study aimed to investigate the clinical impact of JAG1 expression level in patients with CRC, including recurrence, especially in those diagnosed with lymph node-positive stage III CRC who underwent complete resection and appropriate adjuvant chemotherapy.
All patients were enrolled through a retrospective chart review, and only those for whom the clinical course and all clinical information were adequately determined according to the inclusion criteria were selected for retrospective review through medical records. Immunohistochemical staining of JAG1 was performed using paraffin-embedded tissue. JAG1 expression was determined by scoring for staining intensity and percentage of positively stained cells; the final JAG1 score was determined as the sum of both scores.
Sixteen patients who experienced relapse and 15 without (for over 3 years) were selected. The protein expression level of JAG1 showed a tendency for being lower in the group without recurrence, although not statistically significantly (p=0.083); however, the mean JAG1 expression score was significantly lower in the group without recurrence (1.53 vs. 3.19; p=0.004). The patients were divided into two groups with low and high JAG1 expression. The results showed that high JAG1 expression was significantly associated with recurrence of stage III CRC (p=0.029).
The expression of JAG1 may be a potential novel biomarker for predicting CRC recurrence.
The expression of JAG1 may be a potential novel biomarker for predicting CRC recurrence.
The aim of this study was to investigate frailty as a prognostic factor in patients with colorectal liver metastasis undergoing hepatectomy.
Eighty-seven patients who underwent hepatectomy at our institution were enrolled. Frailty was defined as a score of ≥4 on a clinical frailty scale. Patients were divided into frailty (n=29) and non-frailty (n=58) groups.
Overall and cancer-specific survival rates were significantly worse in the frailty group compared with the non-frailty group, and multivariate analysis revealed frailty as an independent prognostic factor. Disease-free survival tended to be worse in the frailty group. Fifty-eight patients relapsed after the first hepatectomy. Twenty-one of 58 recurrent patients were allocated to the frailty group. After recurrence, chemotherapy was significantly more frequently performed in the non-frailty group compared with the frailty group.
Frailty can predict the prognosis of patients with colorectal liver metastasis undergoing hepatectomy.
Frailty can predict the prognosis of patients with colorectal liver metastasis undergoing hepatectomy.
We aimed to develop a novel recurrence prediction model for stage II-III colon cancer using simple auto-artificial intelligence (AI) with improved accuracy compared to conventional statistical models.
A total of 787 patients who had undergone curative surgery for stage II-III colon cancer between 2000 and 2018 were included. Binomial logistic regression analysis was used to calculate the effect of variables on recurrence. The auto-AI software 'Prediction One' (Sony Network Communications Inc.) was used to predict recurrence with the same dataset used for the conventional statical model. Predictive accuracy was assessed by the area under the receiver operating characteristic curve (AUC).
The AUC of the multivariate model was 0.719 (95%CI=0.655-0.784), whereas that of the AI model was 0.815, showing a significant improvement.
This auto-AI prediction model demonstrates improved accuracy compared to the conventional model. It could be constructed by clinical surgeons who are not familiar with AI.
This auto-AI prediction model demonstrates improved accuracy compared to the conventional model. It could be constructed by clinical surgeons who are not familiar with AI.
The real-world outcomes of patients with advanced invasive lobular carcinoma (ILC) of the breast are unclear because of its rarity.
We identified 435 patients with estrogen receptor-positive (ER
), HER2-negative (HER2
) advanced breast cancer treated at our Institute between 2002 and 2019, and analyzed their outcomes retrospectively.
We identified 29 patients with advanced ILC. At presentation, they had a lower rate of lung metastasis (p=0.0053) but a higher rate of stomach metastasis (p=0.0379) compared with other patients with advanced breast cancer. Median overall survival did not differ; however, multivariate analyses showed that ILC histopathology was a risk factor for poorer overall survival (hazard ratio=3.43, p=0.0038) in patients with de novo stage IV ER
HER2
breast cancer. Patients with ILC showed a markedly different patten of subsequent metastasis, such as less in the lung and more in the stomach, leptomeninges, and bone marrow.
According to our retrospective study, in patients with de novo stage IV ER
HER2
breast cancer, ILC histopathology was associated with increased risk of death.
