Abstract Clustering algorithms for data with varying densities have been investigated in the past and there are some data situations and clustering needs that are not handled well by these algorithms. We present here an algorithm for such situations in which multiple, possibly overlapping, clusters exist and need to be identified by their density as the defining characteristic. In this paper, we define the idea of mutual K‐nearest neighbors (MKNN) relationship based on inter‐point affinities and use it as a basis for discovering the above‐mentioned types of clusters. With a synthetic and two real‐world datasets we show that our algorithm delivers the type of clustering results and robustness that we seek to achieve, and the performance is better than what is achievable by other algorithms. Statistical Analysis and Data Mining 2012
1084 Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. Here we report the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DDR gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/suspected pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with gBRCA1/2, gPALB2, gCHEK2) and the exploration cohort (MBC patients with gDDR gene mutations and brain metastases). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg qd combined with HX008 200 mg q3w, while HER2-positive patients received additional anti-HER2 TKI pyrotinib 400mg qd if having brain metastases, until disease progression. The primary endpoint was ORR. NGS of tissue and ctDNA were performed for exploratory biomarker analyses. Results: As of January 12, 2024, 37 patients were enrolled. In the main cohort with gBRCA1/2 mutations (n = 28), ORR was 78.6% (22/28), with 3 patients having complete response. DCR was 96.4% (27/28). Median PFS was 7.3 months (95%CI 4.2 to 10.4). According to Simon's Two-Stage design, since two patients with gCHEK2 mutations in the first stage had only stable disease, the recruitment was terminated. One patient with gPALB2 mutation had stable disease and the remaining one is in the screening process. In the patients having brain metastases (exploration cohort), ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. In the biomarker analysis, NGS of 700 genes was performed on 24 patients with gBRCA1/2 mutations in the main cohort. No significant difference was found in ORR or PFS between gBRCA1 and gBRCA2 mutations. Somatic mutations in XPO1 (16 patients (73%), 15/18 PR+CR, 1/4 SD+PD) showed significant correlation with response. Somatic TP53 mutations are significantly correlated with shorter PFS, while ASXL1 mutations are significantly correlated with longer PFS. Four somatic mutations (AR_c.1418_1420del, AR_c.231_239dup, 2 DUSP22 mutations) showed a consistent trend of decreasing in PD samples, while NF1_c.3198-4dup showed a consistent trend of increasing in PD samples. Conclusions: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline BRCA1/2 mutations, even in patients with brain metastases. Clinical trial information: NCT04508803 .
The aim of this study was to explore the feasibility and clinical value of ultrasound combined with a warm bath test in assessing the differences in reactivity of toe microcirculation between healthy adults and patients with type 2 diabetes mellitus (T2DM). A total of 56 T2DM patients were recruited as case group, whereas 50 healthy volunteers were enrolled as control group. Fasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol in T2DM group were significantly higher than in control group. Under stationary condition, peak systolic velocity (PSV), end-diastolic velocity (EDV), and mean velocity (MV) were lower, but pulsatility index (PI) and resistance index (RI) were higher in patients with T2DM than in controls both in dorsalis pedis artery (DPA) and plantar digital artery (PDA). On response to the warm test, PSV, EDV, and MV increased and PI and RI decreased both in DPA and PDA in these 2 groups. Moreover, the change rate in PSV, EDV, MV, PI, and RI of PDA was significantly lower in T2DM group than in control group. Color Doppler combined with a warm bath test may be used as a new method in evaluating the differences in reactivity of distal limb microvascular between healthy adults and patients with T2DM.
<div>Abstract<p>The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD<sup>+</sup>/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.</p>Significance:<p>Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-22-3350" target="_blank">See related commentary by Byrne and Bell, p.167</a></i></p></div>
<p>Regional counting of differential methylated probes in SK-N-BE(2) cells treated with NEN for 24hrs under nomoxia. Go enrichment pathways of the differential methylated probes of the CpG Island in the promoter (B) (C) and gene body (D) (E)</p>
Aortoesophageal fistula (AEF) induced by esophageal fishbones is a rare complication of esophageal foreign bodies and is very difficult to treat. Although the current view suggests that endovascular stent-graft treatment is useful for AEF, whether a subsequent thoracic operation is necessary remains controversial. The purpose of this report is to describe our experience using endovascular stent-graft treatment without combined thoracic operations for the treatment of AEF in two specific cases.We presented two cases of patients complaining of retrosternal discomfort treated in our department for an aortoesophageal fistula caused by the accidental ingestion of a fishbone. The two patients were effectively managed with combined means of endoscopic, medical (broad-spectrum antibiotic therapy, fasting, gastrointestinal decompression, etc.) and endovascular stent-graft treatment. The main difference in treatment was that the first patient presented with hematemesis after endoscopic removal of the fishbone. Subsequently, the patient underwent endovascular stent-graft treatment. The second case was managed with endoscopic removal of the fishbone with simultaneous endovascular stent-graft treatment, without any signs of hematemesis or melena. Both patients had successful postoperative management and were discharged home. Long-term follow-up is ongoing.The treatment decision-making process should depend on the patients' specific situations. Our practice indicates that endovascular stent-graft treatment without combined thoracic operations could be a valuable alternative in selected patients.
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