Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer ...cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8
tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT.
SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed ...replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
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•SLFN11 binds replication forks in response to replication stress•SLFN11 blocks replication regardless of ATR-CHK1 activity•SLFN11 opens chromatin in the near vicinity of replication initiation sites•By killing cells with defective replication, SLFN11 arises a guardian of the genome
SLFN11 is a dominant determinant of sensitivity to DNA-targeted therapies. Murai et al. show that SLFN11 is recruited to stressed replication forks, opens chromatin, and blocks replication when replication is perturbed by DNA damage or improperly activated by cell cycle checkpoint inhibition. SLFN11 emerges as a unique S-phase regulator.
The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy ...or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel‐Lindau gene (VHL) using a combination of digital PCR and multiplex PCR–based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell‐free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%‐4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%‐2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.
Somatic genome profiling of cell‐free DNA (cfDNA) and matched tumor tissues from patients with clear cell renal cell carcinoma focusing on VHL mutations was conducted. By combination of digital PCR and targeted sequencing, thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%‐4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%‐2.88%).
To elucidate the clinical characteristics of atypical retinal vascular proliferation in patients with von Hippel-Lindau (VHL) disease using OCT angiography (OCTA).
Prospective, observational study.
...Fifty-seven consecutive patients with a diagnosis of VHL disease who visited Kyoto University Hospital between January 2019 and March 2022.
Retinal hemangioblastomas (RHs) were assessed using multimodal imaging including OCTA. Retinal hemangioblastomas were classified into 2 phenotypes: nodular and flat. Nodular RHs were defined as typical RHs that were globular, well-circumscribed tumors, often accompanied with dilated feeder arterioles and draining venules. Flat RHs lacked a protruded red or colored mass, had variable and indistinct borders, and were not accompanied with feeder and draining vessels.
The prevalence, distribution, and description of atypical flat RHs.
Among 57 consecutive patients with VHL disease, 37 patients (64.9%) showed RHs in at least 1 eye. Bilateral RHs were seen in 23 patients (62.2%). Among 58 eyes of 37 patients with RHs, typical nodular RHs were detected in 54 eyes. Nodular RHs were seen mainly in the peripheral retina and occasionally in the peripapillary region, and they showed exudative changes in some cases. Flat RHs were detected in 7 eyes (12.1%). Four eyes showed only flat RHs, and 3 eyes showed both types in the same eye. Most flat RHs appeared as retinal hemorrhages or faint flat abnormal retinal vessels in the inner retina on the fundus examination, often within the macula area or peripapillary. In all eyes with flat RHs, OCTA showed abundant blood flow in the lesions. OCT revealed that flat RHs were seen mainly between the retinal nerve fiber layer and the ganglion cell layer, and occasionally within the inner nuclear layer. During a mean follow-up period of 20.4 ± 15.0 months, no flat RHs accompanied exudative change, tractional retinal detachment, or progression in size.
Patients with VHL disease can demonstrate 2 distinct types of RHs: the classic nodular type and an atypical flat type. OCT angiography can be useful in improving the detection of atypical flat RHs, which can be difficult to detect clinically.
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To elucidate the impact of genetic variations in breast cancer resistance protein (BCRP/ ABCG2) and P-glycoprotein (MDR1/ABCB1) on the pharmacokinetics of sunitinib, we carried out a pharmacogenetic ...study in a clinical setting and pharmacokinetic analysis using Abcg2−/−, Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice. Nineteen renal cell carcinoma patients were enrolled in this study. The plasma concentrations of sunitinib and its active metabolite were determined and the area under the concentration- time curve (AUC) was calculated. Genetic polymorphisms in ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A and 3435C>T) were examined. The dose-adjusted AUC0–24 of sunitinib was significantly higher in patients with a heterozygous variant for ABCG2 421C>A than in wild-type patients (p=0.02), and one homozygous patient showed the highest dose-adjusted AUC0–24. The ABCB1 polymorphisms were not associated with the dose-adjusted AUC0–24. The maximum concentration and AUC0–4 of sunitinib were significantly higher in Abcg2−/−, Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice than wild-type mice when sunitinib was given orally but not intraperitoneally. Incidence of thrombocytopenia and hypertension and poor compliance were associated with the systemic exposure to sunitinib and its active metabolite. These results suggest that the loss of protein expression of ABCG2 by genetic polymorphism is associated with an increase in the systemic exposure to sunitinib and sunitinib-induced toxicity.
Background
The prognostic factors of retroperitoneal soft tissue sarcoma (STS) have been explored but not yet certain. This study evaluated the prognostic impact of various preoperative clinical ...parameters and inflammatory indices in primary STS, with a particular focus on the transition of inflammatory index before and after tumor resection in de-differentiated liposarcoma (DD-LPS).
Methods
The clinical data of 113 patients with primary retroperitoneal STS receiving tumor resection were reviewed. Six variables (neutrophils, platelets, C-reactive protein (CRP), lymphocytes, albumin, and hemoglobin) in the blood samples were measured and nine inflammatory indices (neutrophil–lymphocyte ratio (NLR), CRP–lymphocyte ratio (CLR), platelet–lymphocyte ratio (PLR), neutrophil–albumin ratio (NAR), CRP–albumin ratio (CAR), platelet–albumin ratio (PAR), HALP (hemoglobin, albumin, lymphocyte and platelet), prognostic nutrition index (PNI), and modified Glasgow Prognostic Score (mGPS)) were calculated. The prognostic value of the indices was analyzed by univariate and multivariate analyses.
Results
Elevated NLR, CLR, PLR, NAR, CAR, PAR, and mGPS were associated with a worse overall survival (
p
= 0.0124, 0.0011, 0.049, 0.0047, 0.0085, 0.0332, and 0.0086, respectively) in univariate analysis. Multivariate analysis showed that elevated CLR and DD-LPS were associated with poor overall survival (
p
= 0.0267 and 0.0218, respectively) in all retroperitoneal STS. In DD-LPD, patients with preoperative high CLR, whose postoperative CLR was normalized, demonstrated a favorable survival rate similar to those with preoperative low CLR.
Conclusions
Elevated CLR before surgery as well as DD-LPS were poor prognostic markers for overall survival in primary retroperitoneal STS. Perioperative CLR normalization may be related to a favorable prognosis in DD-LPS.
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, ...which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here, we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth, while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore, the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.
•Copy number gains of chromosome 5q drive SQSTM1 overexpression•SQSTM1 gene product p62 activates NRF2 and promotes resistance to redox stress•mTOR acts downstream or parallel of p62 in renal cancer cells•p62 promotes renal cancer growth in vitro and in vivo
Introduction
Renal cell carcinoma with TFEB amplification is rare and reportedly aggressive. We herein report a case of renal cell carcinoma with TFEB translocation and amplification in which ...long‐term control was achieved by multimodal therapy including a vascular endothelial growth factor ‐receptor inhibitor.
Case presentation
A 70‐year‐old man was referred to our institution for the treatment of renal cell carcinoma with multinodal metastases. Open nephrectomy and lymph node dissection were performed. Immunohistochemistry for transcription factor EB was positive, and fluorescent in situ hybridization revealed TFEB rearrangement and amplification. The diagnosis was TFEB‐translocated and ‐amplified renal cell carcinoma. VEGFA amplification was also demonstrated by fluorescent in situ hybridization. The residual and recurrent tumors were treated and controlled for 52 months by vascular endothelial growth factor‐receptor target therapy, radiation therapy, and additional surgery.
Conclusion
A good long‐term response to anti‐vascular endothelial growth factor drug therapy may be due to VEGFA amplification and subsequent vascular endothelial growth factor overexpression.
Advances in next‐generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer‐related genes at once in daily clinical practice. In April 2015, ...we introduced clinical sequencing using an NGS‐based multiplex gene assay (OncoPrime) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy. A total of 85 patients underwent testing with multiplex gene assay between April 2015 and July 2016. The most common solid tumor types tested were pancreatic (n = 19; 22.4%), followed by biliary tract (n = 14; 16.5%), and tumors of unknown primary site (n = 13; 15.3%). Samples from 80 patients (94.1%) were successfully sequenced. The median turnaround time was 40 days (range, 18–70 days). Potentially actionable mutations were identified in 69 of 80 patients (86.3%) and were most commonly found in TP53 (46.3%), KRAS (23.8%), APC (18.8%), STK11 (7.5%), and ATR (7.5%). Nine patients (13.0%) received a subsequent therapy based on the NGS assay results. Implementation of clinical sequencing using an NGS‐based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients. Current challenges are to incorporate this genomic information into better therapeutic decision making.
In April 2015, we introduced clinical sequencing using a next‐generation sequencing (NGS)‐based multiplex gene assay certified by the Clinical Laboratory Improvement Amendment into daily clinical practice. Implementation of clinical sequencing using an NGS‐based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients with advanced solid tumors. Current challenges are to incorporate this genomic information into better therapeutic decision making.
Objectives
Radical cystectomy is the gold‐standard treatment for muscle‐invasive bladder cancer and aggressive non‐muscle‐invasive bladder cancer. To enhance clinical decision‐making regarding ...patients with bladder cancer who underwent radical cystectomy, a recurrence prediction biomarker with high accuracy is urgently needed. In this study, we developed a model for the prediction of bladder cancer recurrence after radical cystectomy by combining serum microRNA and a pathological factor.
Methods
We retrospectively analyzed the clinical records of 81 patients with bladder cancer who underwent radical cystectomy between 2008 and 2016. The dataset was divided into two, and Fisher linear discriminant analysis was used to construct a prognostic model for future recurrence in the training set (n = 41). The performance of the model was evaluated in the validation set (n = 40).
Results
Thirty patients had recurrence after having undergone radical cystectomy. A prognostic model for recurrence was constructed by combining a pathological factor (i.e. positive pathological lymph node status) and three microRNAs (miR‐23a‐3p, miR‐3679‐3p, and miR‐3195). The model showed a sensitivity of 0.87, a specificity of 0.80, and an area under the receiver operating characteristic curve of 0.88 (0.77–0.98) in the validation set. Furthermore, Kaplan–Meier analysis revealed that patients with a low prediction index have significantly longer overall survival than patients with a high prediction index (P = 0.041).
Conclusion
A combination of serum microRNA profiles and lymph node statuses is useful for the prediction of oncological outcomes after radical cystectomy in patients with bladder cancer.
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