An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

Lessons learnedTKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.BackgroundPolo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.MethodsA 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.ResultsThe study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.ConclusionTKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted

Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448

Relative expression of KDM5B, MALAT1, SNAIL, Vimentin and miR 448 normalized against GAPDH in MCF10A WT, MCF10A OE, MDA-MB-231 WT and MDA-MB-231 KD cells. Data are representative of 3 independent experiments and analyzed by student’s t-test. All data are shown as mean ± SEM. WT, wild type; OE, KDM5B overexpressed; KD, knockdown using shKDM5B clone II. (DOCX 519 kb

The Application of Borehole Hydrogeological Investigation for Assessing Landslide Susceptibility

On the basis of 49 borehole studies at the mid- and upper-stream of the Dajia and Jhuoshuei river basins, landslide occurrence was found to not only be related to subsurface geological composition and hydrogeological characteristics, but also to groundwater level dynamics, which have seldom been addressed in previous works. It is suggested that the interplay between hydrogeologic and landslide factors be given further consideration in future investigations. This would be a crucial step towards effective disaster prevention for mountainous regions in Taiwan.本研究主要係嘗試透過孔內水文地質調查結果，評估大甲溪與濁水溪流域地表下岩層的地質材料特性、水力特性、地下水與集水區山崩潛勢之關聯性。過去研究較少針對崩塌地進行現地水文地質調查與試驗，本研究根據49處試驗場址成果顯示，水文地質特性與山崩的潛勢、滑動深度，以及地下水位有一定程度之關聯性。本研究建議進行調查區域的水文地質特性，以及各促崩因子所造成的山崩的易損性，係各類型山崩災害分析與潛勢評估之重要的研究各題，亦可提供相關台灣災害防治之參考

Unsupervised Multilingual Dense Retrieval via Generative Pseudo Labeling

Dense retrieval methods have demonstrated promising performance in multilingual information retrieval, where queries and documents can be in different languages. However, dense retrievers typically require a substantial amount of paired data, which poses even greater challenges in multilingual scenarios. This paper introduces UMR, an Unsupervised Multilingual dense Retriever trained without any paired data. Our approach leverages the sequence likelihood estimation capabilities of multilingual language models to acquire pseudo labels for training dense retrievers. We propose a two-stage framework which iteratively improves the performance of multilingual dense retrievers. Experimental results on two benchmark datasets show that UMR outperforms supervised baselines, showcasing the potential of training multilingual retrievers without paired data, thereby enhancing their practicality. Our source code, data, and models are publicly available at https://github.com/MiuLab/UMRComment: Accepted to Findings of EACL 202

CONVERSER: Few-Shot Conversational Dense Retrieval with Synthetic Data Generation

Conversational search provides a natural interface for information retrieval (IR). Recent approaches have demonstrated promising results in applying dense retrieval to conversational IR. However, training dense retrievers requires large amounts of in-domain paired data. This hinders the development of conversational dense retrievers, as abundant in-domain conversations are expensive to collect. In this paper, we propose CONVERSER, a framework for training conversational dense retrievers with at most 6 examples of in-domain dialogues. Specifically, we utilize the in-context learning capability of large language models to generate conversational queries given a passage in the retrieval corpus. Experimental results on conversational retrieval benchmarks OR-QuAC and TREC CAsT 19 show that the proposed CONVERSER achieves comparable performance to fully-supervised models, demonstrating the effectiveness of our proposed framework in few-shot conversational dense retrieval. All source code and generated datasets are available at https://github.com/MiuLab/CONVERSERComment: Accepted to SIGDIAL 202

Novel microRNAs modulating ecto-5′-nucleotidase expression

IntroductionThe expression of immune checkpoint molecules (ICMs) by cancer cells is known to counteract tumor-reactive immune responses, thereby promoting tumor immune escape. For example, upregulated expression of ecto-5′-nucleotidase (NT5E), also designated as CD73, increases extracellular levels of immunosuppressive adenosine, which inhibits tumor attack by activated T cells. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Thus, the binding of miRNAs to the 3′-untranslated region of target mRNAs either blocks translation or induces degradation of the targeted mRNA. Cancer cells often exhibit aberrant miRNA expression profiles; hence, tumor-derived miRNAs have been used as biomarkers for early tumor detection.MethodsIn this study, we screened a human miRNA library and identified miRNAs affecting the expression of ICMs NT5E, ENTPD1, and CD274 in the human tumor cell lines SK-Mel-28 (melanoma) and MDA-MB-231 (breast cancer). Thereby, a set of potential tumor-suppressor miRNAs that decreased ICM expression in these cell lines was defined. Notably, this study also introduces a group of potential oncogenic miRNAs that cause increased ICM expression and presents the possible underlying mechanisms. The results of high-throughput screening of miRNAs affecting NT5E expression were validated in vitro in 12 cell lines of various tumor entities.ResultsAs result, miR-1285-5p, miR-155-5p, and miR-3134 were found to be the most potent inhibitors of NT5E expression, while miR-134-3p, miR-6859-3p, miR-6514-3p, and miR-224-3p were identified as miRNAs that strongly enhanced NT5E expression levels.DiscussionThe miRNAs identified might have clinical relevance as potential therapeutic agents and biomarkers or therapeutic targets, respectively

A 64-week, multicenter, open-label study of aripiprazole effectiveness in the management of patients with schizophrenia or schizoaffective disorder in a general psychiatric outpatient setting

<p>Abstract</p> <p>Objective</p> <p>To evaluate the overall long-term effectiveness of aripiprazole in patients with schizophrenia in a general psychiatric practice setting in Taiwan.</p> <p>Methods</p> <p>This was a prospective, open-label, multicenter, post-market surveillance study in Taiwanese patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled. Eligible patients were titrated to aripiprazole (5-30 mg/day) over a 12-week switching phase, during which their previous medication was discontinued. Patients could then enter a 52-week, long-term treatment phase. Aripiprazole was flexibly dosed (5-30 mg/day) at the discretion of the treating physicians. Efficacy was assessed using the Clinical Global Impression scale Improvement (CGI-I) score, the Clinical Global Impression scale Severity (CGI-S) score, The Brief Psychiatry Rating Scale (BPRS), and the Quality of Life (QOL) scale, as well as Preference of Medicine (POM) ratings by patients and caregivers. Safety and tolerability were also assessed.</p> <p>Results</p> <p>A total of 245 patients were enrolled and switched from their prior antipsychotic medications, and 153 patients entered the 52-week extension phase. In all, 79 patients (32.2%) completed the study. At week 64, the mean CGI-I score was 3.10 and 64.6% of patients who showed response. Compared to baseline, scores of CGI-S, QOL, and BPRS after 64 weeks of treatment also showed significant improvements. At week 12, 65.4% of subjects and 58.9% of caregivers rated aripiprazole as better than the prestudy medication on the POM. The most frequently reported adverse events (AEs) were headache, auditory hallucinations and insomnia. A total of 13 patients (5.3%) discontinued treatment due to AEs. No statistically significant changes were noted with respect to fasting plasma glucose, lipid profile, body weight, and body mass index after long-term treatment with aripiprazole.</p> <p>Conclusions</p> <p>Although the discontinuation rate was high, aripiprazole was found to be effective, safe and well tolerated in the long-term treatment of Taiwanese patients with schizophrenia who continued to receive treatment for 64 weeks.</p

The Classification of Sini

We investigated the syndromes of the Sini decoction pattern (SDP), a common ZHENG in traditional Chinese medicine (TCM). The syndromes of SDP were correlated with various severe Yang deficiency related symptoms. To obtain a common profile for SDP, we distributed questionnaires to 300 senior clinical TCM practitioners. According to the survey, we concluded 2 sets of symptoms for SDP: (1) pulse feels deep or faint and (2) reversal cold of the extremities. Twenty-four individuals from Taipei City Hospital, Linsen Chinese Medicine Branch, Taiwan, were recruited. We extracted the total mRNA of peripheral blood mononuclear cells from the 24 individuals for microarray experiments. Twelve individuals (including 6 SDP patients and 6 non-SDP individuals) were used as the training set to identify biomarkers for distinguishing the SDP and non-SDP groups. The remaining 12 individuals were used as the test set. The test results indicated that the gene expression profiles of the identified biomarkers could effectively distinguish the 2 groups by adopting a hierarchical clustering algorithm. Our results suggest the feasibility of using the identified biomarkers in facilitating the diagnosis of TCM ZHENGs. Furthermore, the gene expression profiles of biomarker genes could provide a molecular explanation corresponding to the ZHENG of TCM