bluuebunny/crossref_metadata_2025_split huggingface dataset:
The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma
Authors: Zhu Dawei , Liu Yingting , Chen Junjun , Wang Qi , Li Yuan , Zhu Yulan , Feng Jun , Jiang Jingting 
Published: July 2022

Abstract
Background
As an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined.

Methods
Immunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model.

Results
We found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion.

Conclusion
Our study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.
Homoharringtonine is synergistically lethal with BCL-2 inhibitor APG-2575 in acute myeloid leukemia
Authors: Wei Wenwen , Huang Shujuan , Ling Qing , Mao Shihui , Qian Yu , Ye Wenle , Li Fenglin , Pan Jiajia , Lin Xiangjie , Huang Jiansong , Huang Xin , Zhai Yifan , Sun Jie , Jin Jie 
Published: July 2022

Abstract
Background
Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity.

Methods
The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins.

Results
APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway.

Conclusion
Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.
Extracellular vesicle miR-32 derived from macrophage promotes arterial calcification in mice with type 2 diabetes via inhibiting VSMC autophagy
Authors: Cao Jingsong , Chen Cong , Chen Qian , Gao Yan , Zhao Zhibo , Yuan Qing , Li Anqi , Yang Shiqi , He Yuqi , Zu Xuyu , Liu Jianghua 
Published: July 2022

Abstract
Background
The development of diabetes vascular calcification (VC) is tightly associated with the inhibition of vascular smooth muscle cell (VSMC) autophagy. Previously, our team found that miR-32-5p (miR-32) promotes macrophage activation, and miR-32 is expressed at higher level in the plasma of patients with coronary calcification. However, whether miR-32 mediates the function of macrophages in type 2 diabetes (T2D) VC is still unclear.

Methods
Wild-type (WT) and miR-32−/− mice were used in this study. qRT-PCR and western blotting were used to analyze gene expression. Flow cytometry was used to analyze the influence of glucose concentration on macrophage polarization. Nanoparticle tracking analysis (NTA), transmission electron microscopy, and confocal microscopy were used to identify macrophage extracellular vehicles (EVs). Immunofluorescence, in situ hybridization (ISH), immunohistochemistry, and alizarin red staining were used to analyze the influence of macrophage EVs on autophagy and calcification of the aorta of miR-32−/− mice. A luciferase assay was used to analyze the effect of miR-32 on myocyte enhancer factor 2D (Mef2d) expression. Co-IP combined with mass spectrometry (MS) and transcriptome sequencing was used to analyze the signalling pathway by which Mef2d acts in VSMC autophagy.

Results
We found that high glucose conditions upregulate miR-32 expression in macrophages and their EVs. Importantly, macrophages and their EVs promote VSMC osteogenic differentiation and upregulate miR-32 expression in VSMCs. Moreover, miR-32 mimics transfection promoted osteogenic differentiation and inhibited autophagy in VSMCs. In vitro and in vivo experiments showed that Mef2d is the key target gene of miR-32 that inhibits VSMC autophagy. Furthermore, MS and transcriptome sequencing found that cGMP-PKG is an important signalling pathway by which Mef2d regulates VSMC autophagy. In addition, after T2D miR-32−/− mice were injected with macrophage EVs via the caudal vein, miR-32 was detected in aortic VSMCs of miR-32−/− mice. Moreover, autophagy was significantly inhibited, and calcification was significantly enhanced in aorta cells.

Conclusions
These results reveal that EVs are the key pathway by which macrophages promote T2D VC, and that EVs miR-32 is a key cause of autophagy inhibition in VSMCs.
Missed opportunity for alcohol use disorder screening and management in primary health care facilities in northern rural Tanzania: a cross-sectional survey
Authors: Mushi Dorothy , Moshiro Candida , Hanlon Charlotte , Francis Joel M. , Teferra Solomon 
Published: July 2022

Abstract
Objective
The study aimed to identify the missed opportunity for detection and management of alcohol use disorder by primary health care workers.

Design
A cross-sectional survey

Setting
Outpatient services in the six governmental primary health care facilities in Moshi district council in Tanzania.

Participants
A total of 1604 adults were screened for alcohol use disorder (AUD) using the Alcohol Use Disorder Identification Test (AUDIT). Participants scoring 8 or above then provided details about their help-seeking behavior and barriers to seeking care. Participants’ records were reviewed to assess the screening and management of AUD.

Results
In the last 12 months, 60.7% reported alcohol use, and heavy episodic drinking (HED) was reported by 37.3%. AUD (AUDIT ≥ 8) was present in 23.9%. Males were more likely to have HED (aPR = 1.43;95% CI:1.3 to 1.4) or AUD (aPR = 2.9; 95% CI 1.9 to 4.2). Both HED and AUD increased with age. Only one participant (0.3%) had documented AUD screening and management. Only 5% of participants screening positive for AUD had sought help. Reasons for not seeking care were thinking that the problem would get better by itself (55.0%), wanting to handle the problem alone (42.0%), or not being bothered by the problem (40.0%).

Conclusion
While reported alcohol use, HED, and AUD are common among patients presenting to primary healthcare facilities in northern Tanzania, help-seeking behavior and detection are very low. Not screening for AUD in primary health care is a missed opportunity for early detection and management. There is an urgent need to develop interventions to increase the detection of AUD by health care providers, while also addressing help-seeking behavior and barriers to seeking care.
Efficacy of non-operative treatment of patients with knee arthrofibrosis using high-intensity home mechanical therapy: a retrospective review of 11,000+ patients
Authors: Stinton Shaun K. , Beckley Samantha J. , Branch Thomas P. 
Published: July 2022

Abstract
Background
Recovery from knee surgery or injury can be hindered by knee arthrofibrosis, which can lead to motion limitations, pain and delayed recovery. Surgery or prolonged physical therapy are often treatment options for arthrofibrosis, but they can result in increased costs and decreased quality of life. A treatment option that can regain lost motion without surgery would help minimize risks and costs for the patient. The purpose of this study was to determine treatment efficacy of high-intensity home mechanical stretch therapy in patients with knee arthrofibrosis.

Methods
Records were reviewed for 11,000+ patients who were prescribed a high-intensity stretch device to regain knee flexion. Initial and last recorded knee flexion and days between measurements were available for 9842 patients (Dataset 1). Dataset 2 was a subset of 966 patients from Dataset 1. These 966 patients had separate more rigorous measurements available from physical therapy notes (Dataset 3) in addition to data from the internal database (Dataset 2). Within and between dataset statistics were calculated using t tests for comparison of means and Cohen’s d for determination of effect size.

Results
All dataset showed significant gains in flexion (p < 0.01). Mean initial flexion, last recorded flexion and flexion gain were 79.5°, 108.4°, and 29.9°, respectively in Dataset 1. Differences between Datasets 2 and 3 had small effect sizes (Cohen’s d < 0.17). The were no significant differences when comparing workers’ compensation and non-workers’ compensation patients. The average last recorded flexion for all datasets was above the level required to perform activities of daily living. Motion gains were recorded in under 60 days from device delivery.

Conclusions
High-intensity home mechanical stretch therapy was effective in restoring knee flexion, generally in 2 months or less, and in avoiding additional surgery in severe motion loss patients regardless of sex, age, or workers’ compensation status. We believe high-intensity stretching should be considered in any patient who is at risk for a secondary motion loss surgery, because in over 90% of these patients, the complications and costs associated with surgery can be avoided.
Distal tibial tubercle osteotomy can lessen change in patellar height post medial opening wedge high tibial osteotomy? A systematic review and meta-analysis
Authors: Ren Yi-Ming , Tian Meng-Qiang , Duan Yuan-Hui , Sun Yun-Bo , Yang Tao , Hou Wei-Yu 
Published: July 2022

Abstract
Objective
Medial opening wedge high tibial osteotomy (MOWHTO) is a mainstream surgical method for treating early medial compartment knee osteoarthritis. Undesirable sequelae such as patella infera may happen following tuberosity osteotomy. We conducted this systematic review and meta-analysis to compare the change in patellar position after proximal tibial tubercle osteotomy (PTO) versus distal tibial tubercle osteotomy (DTO) intervention.

Methods
The 11 studies were acquired from PubMed, Medline, Embase and Cochrane Library. The data were extracted by two of the coauthors independently and were analyzed by RevMan5.3. Mean differences, odds ratios and 95% confidence intervals were calculated. Cochrane Collaboration’s Risk of Bias Tool and Newcastle–Ottawa Scale were used to assess risk of bias.

Results
Eleven observational studies were assessed. The methodological quality of the trials ranged from moderate to high. The pooled results of postoperative patellar height (Caton-Deschamps index and Blackburne-Peel index) and postoperative complications showed that the differences were statistically significant between PTO and DTO interventions. Patellar index ratios decreased significantly in the PTO groups, and 12 (9.2%) complications under DTO surgery and 2 (1.6%) complications under PTO surgery were reported. The differences of postoperative posterior tibial slope (angle) was not statistically significant, but postoperative posterior tibial slope of both groups increased. Sensitivity analysis proved the stability of the pooled results and the publication bias was not apparent.

Conclusions
DTO in MOWHTO maintained the postoperative patellar height, and clinically, for patients with serious patellofemoral osteoarthritis, DTO can be preferred. Postoperative complications are easily preventable with caution. In view of the heterogeneity and small sample size, whether these conclusions are applicable should be further determined in future studies.
Regional analgesia techniques for effective recovery from coronary artery bypass surgeries: a retrospective study involving the experience of a single center
Authors: Cosarcan Sami Kaan , Sezer Özer Ali , Gürkahraman Sami , Erçelen Ömür 
Published: July 2022

Abstract
Background
Pain after cardiac surgery is both multifocal and multifactorial. Sternotomy, sternal retraction, internal mammary dissection, posterior rib dislocation or fracture, potential brachial plexus injury, and mediastinal and pleural drains all contribute to pain experienced in the immediate postoperative period. Ineffective pain management can result in systemic and pulmonary complications and significant cardiac consequences.

Methods
This study compared the effectiveness of regional anesthesia techniques for perioperative pain management in cardiac surgery patients at our clinic. The effects of different analgesic methods, in terms of contributing to recovery, were examined.

Results
The records of 221 patients who had undergone coronary bypass surgery were evaluated retrospectively. The extubation rate in the operating room was 91%. No patient received balloon pump support, and 20 patients were transferred to the cardiovascular intensive care unit while intubated. Regional anesthesia was performed on two of these 20 patients, but not on the remaining 18. Examination of intraoperative and postoperative opioid consumption revealed significantly lower levels among patients receiving regional anesthesia. The most effective results among the regional anesthesia techniques applied were achieved with double injection erector spinae plane block.

Conclusion
Regional anesthesia techniques severely limit opioid consumption during cardiac surgery. Their importance will gradually increase in terms of rapid recovery criteria. Based on our study results, double injection of the erector spinae plane block seems to be the most effective technique in cardiac surgery. We therefore favor the use of fascial plane blocks during such procedures.
Trial Numbers The study is registered with ClinicalTrials (NCT05282303). Ethics committee registration and approval were Granted under Number 2021.464.IRB1.131.
Positive predictive value estimates for noninvasive prenatal testing from data of a prenatal diagnosis laboratory and literature review
Authors: Liu Siping , Yang Fang , Chang Qingxian , Jia Bei , Xu Yushuang , Wu Ruifeng , Li Liyan , Chen Weishan , Yin Ailan , Huang Fodi , Feng Suxin , Li Fenxia 
Published: July 2022

Abstract
Objective
Since 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion, with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool are lacking. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations in order to inform pre- and post-test counseling, pre/perinatal decision making, and medical risk assessment/management.

Methods
This retrospective study included women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing, including karyotyping, chromosomal microarray analysis (CMA) were performed. Positive predictive values (PPVs) were calculated.

Results
In total, 468 women were recruited. The PPVs for trisomies 21, 18, and 13 were 86.1%, 57.8%, and 25.0%, respectively. The PPVs for rare chromosomal abnormalities (RCAs) and copy number variants (CNVs) were 17.0% and 40.4%, respectively. The detection of sex chromosomal aneuploidies (SCAs) had a PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY, and 62.5% for 47,XYY. The high-risk groups had a significant increase in the number of true positive cases compared to the low- and moderate-risk groups.

Conclusions
T13, monosomy X, and RCA were associated with lower PPVs. The improvement of cell-free fetal DNA screening technology and continued monitoring of its performance are important.
Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)
Authors: Zhao Wan-Hong , Wang Bai-Yan , Chen Li-Juan , Fu Wei-Jun , Xu Jie , Liu Jie , Jin Shi-Wei , Chen Yin-Xia , Cao Xing-Mei , Yang Yun , Zhang Yi-Lin , Wang Fang-Xia , Zhang Peng-Yu , Lei Bo , Gu Liu-Fang , Wang Jian-Li , Zhang Hui , Bai Ju , Xu Yan , Zhu Han , Du Juan , Jiang Hua , Fan Xiao-Hu , Li Jian-Yong , Hou Jian , Chen Zhu , Zhang Wang-Gang , Mi Jian-Qing , Chen Sai-Juan , He Ai-Li 
Published: July 2022

Abstract
Background
LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years.

Methods
LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy.

Results
As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer.

Conclusions
The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM.
Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.
Randomized double-blind controlled trial to assess the efficacy of intravenous acetaminophen associated with strong opioids in the treatment of acute pain in adult cancer patients: study protocol
Authors: Leiva Ofelia , Castellano Joel , Letelier Luz M. , Rojas Luis , Viviani Paola , Gonzalez Antonio , Perez-Cruz Pedro 
Published: July 2022

Abstract
Background
Cancer pain is one of the most frequent and relevant symptoms in cancer patients and impacts on patient’s quality of life. International and local standards recommend as an initial strategy the use of an analgesic scheme composed of strong opioids associated with adjuvants such as acetaminophen, based upon the assumption that combining drugs could have a better analgesic effect, could allow lowering opioid dosing, and could prevent the occurrence of adverse effects of opioids. However, there is uncertainty about the impact of acetaminophen as an adjuvant in patients who use strong opioids for moderate to severe pain management in cancer patients. The aim of this study is to assess the efficacy and safety of intravenous acetaminophen associated with strong opioids in hospitalized adult cancer patients who have moderate to severe cancer-related pain.

Methods
We will perform a randomized double-blinded controlled study comparing intravenous acetaminophen 1 g 4 times a day versus placebo for 48 h as an adjuvant to strong opioids. We will assess pain intensity as a primary outcome, using the verbal numerical rating scale (VNRS, I0 to 10 scale with higher scores meaning higher pain intensity), and we will compare the mean difference in pain intensity between baseline and 48 h among the placebo and intervention groups. We estimate that a decrease of 1 point in the VNRS would be clinically significant. Assuming a standard deviation in pain intensity of 1.7 points, an alpha of 0.025, and a power of 0.8, we estimate a sample size of 112 patients, with 56 patients in each arm. Secondary outcomes include the difference in total opioid use between baseline and at 48 h among the groups, and adverse effects such as drowsiness, constipation, nausea, and vomiting would be evaluated.

Discussion
The randomized, double-blind, placebo-controlled design is the best strategy to assess the efficacy of acetaminophen as an adjuvant in adult cancer patients with moderate to severe pain who are receiving strong opioids. We expect to contribute to national and international guidelines with these results.

Trial registration
Clinicaltrials.gov NCT04779567. Registered on March 3, 2021. Retrospectively registered.