Publications by authors named "Ming Yin"

258 Publications

Artificial intelligence (AI) for medical imaging to combat coronavirus disease (COVID-19): a detailed review with direction for future research.

Artif Intell Rev 2021 Apr 15:1-31. Epub 2021 Apr 15.

Discipline of Business Analytics in Business School, The University of Sydney, Sydney, Australia.

Since early 2020, the whole world has been facing the deadly and highly contagious disease named coronavirus disease (COVID-19) and the World Health Organization declared the pandemic on 11 March 2020. Over 23 million positive cases of COVID-19 have been reported till late August 2020. Medical images such as chest X-rays and Computed Tomography scans are becoming one of the main leading clinical diagnosis tools in fighting against COVID-19, underpinned by Artificial Intelligence based techniques, resulting in rapid decision-making in saving lives. This article provides an extensive review of AI-based methods to assist medical practitioners with comprehensive knowledge of the efficient AI-based methods for efficient COVID-19 diagnosis. Nearly all the reported methods so far along with their pros and cons as well as recommendations for improvements are discussed, including image acquisition, segmentation, classification, and follow-up diagnosis phases developed between 2019 and 2020. AI and machine learning technologies have boosted the accuracy of Covid-19 diagnosis, and most of the widely used deep learning methods have been implemented and worked well with a small amount of data for COVID-19 diagnosis. This review presents a detailed mythological analysis for the evaluation of AI-based methods used in the process of detecting COVID-19 from medical images. However, due to the quick outbreak of Covid-19, there are not many ground-truth datasets available for the communities. It is necessary to combine clinical experts' observations and information from images to have a reliable and efficient COVID-19 diagnosis. This paper suggests that future research may focus on multi-modality based models as well as how to select the best model architecture where AI can introduce more intelligence to medical systems to capture the characteristics of diseases by learning from multi-modality data to obtain reliable results for COVID-19 diagnosis for timely treatment .
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http://dx.doi.org/10.1007/s10462-021-09985-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047522PMC
April 2021

RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK-Parkin-Mitophagy in Cardiac Remodelling after Myocardial Infarction.

Oxid Med Cell Longev 2021 27;2021:6635955. Epub 2021 Mar 27.

Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.

Receptor-interacting protein 3- (RIPK3-) modulated necroptosis plays a critical role in cardiac remodelling after myocardial infarction (MI). However, the precise regulatory mechanism is not fully elucidated yet. In the present study, we showed that RIPK3 expression was upregulated in myocardial tissue after MI in a mouse model by coronary artery ligation, as well as in the cardiomyocytes following hypoxic injury . The increase of RIPK3 expression was found to be accompanied by severe cardiac remodelling, cardiac dysfunction, and higher mortality. Elevated RIPK3 expression subsequently abrogated the AMPK pathway that was accompanied by inhibition of Parkin-mediated mitophagy. Loss of mitophagy increased the opening of mitochondrial permeability transition pore (mPTP), which ultimately induced the cardiomyocyte necroptosis. In contrast, genetic ablation of induced the AMPK/Parkin-mitophagy pathway, favouring a prosurvival state that eventually inhibited mPTP opening and induced the necroptosis of cardiomyocytes in the post-MI cardiac remodelling. In conclusion, our results revealed a key mechanism by which necroptosis could be mediated by RIPK3 via the AMPK/Parkin-mitophagy/mPTP opening axis, which provides a potential therapeutic target in the management of heart failure after MI.
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http://dx.doi.org/10.1155/2021/6635955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019651PMC
March 2021

Calcitriol-mediated hypercalcemia as an immune-related adverse event in a patient receiving nivolumab and ipilimumab for metastatic renal cell carcinoma, case report.

BMC Urol 2021 Apr 1;21(1):51. Epub 2021 Apr 1.

Medical Oncology, Ohio State University James Cancer Hospital, Suite 1335 Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA.

Background: Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors.

Case Presentation: We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia.

Conclusion: This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.
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http://dx.doi.org/10.1186/s12894-021-00825-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017871PMC
April 2021

Genome-wide identification, expression, and sequence analysis of CONSTANS-like gene family in cannabis reveals a potential role in plant flowering time regulation.

BMC Plant Biol 2021 Mar 17;21(1):142. Epub 2021 Mar 17.

Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, 410205, China.

Background: Cannabis, an important industrial crop, has a high sensitivity to photoperiods. The flowering time of cannabis is one of its important agronomic traits, and has a significant effect on its yield and quality. The CONSTANS-like (COL) gene plays a key role in the regulation of flowering in this plant. However, the specific roles of the COL gene family in cannabis are still unknown.

Results: In this study, 13 CsCOL genes were identified in the cannabis genome. Phylogenetic analysis implied that the CsCOL proteins were divided into three subgroups, and each subgroup included conserved intron/exon structures and motifs. Chromosome distribution analysis showed that 13 CsCOL genes were unevenly distributed on 7 chromosomes, with chromosome 10 having the most CsCOL members. Collinearity analysis showed that two syntenic gene pairs of CsCOL4 and CsCOL11 were found in both rice and Gossypium raimondii. Of the 13 CsCOL genes, CsCOL6 and CsCOL12 were a pair of tandem duplicated genes, whereas CsCOL8 and CsCOL11 may have resulted from segmental duplication. Furthermore, tissue-specific expression showed that 10 CsCOL genes were preferentially expressed in the leaves, 1 CsCOL in the stem, and 2 CsCOL in the female flower. Most CsCOL exhibited a diurnal oscillation pattern under different light treatment. Additionally, sequence analysis showed that CsCOL3 and CsCOL7 exhibited amino acid differences among the early-flowering and late flowering cultivars.

Conclusion: This study provided insight into the potential functions of CsCOL genes, and highlighted their roles in the regulation of flowering time in cannabis. Our results laid a foundation for the further elucidation of the functions of COL genes in cannabis.
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http://dx.doi.org/10.1186/s12870-021-02913-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972231PMC
March 2021

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

Lancet 2021 Mar;397(10277):892-901

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.

Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.

Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.

Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.

Funding: Loxo Oncology.
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http://dx.doi.org/10.1016/S0140-6736(21)00224-5DOI Listing
March 2021

HBV induces liver fibrosis via the TGF-β1/miR-21-5p pathway.

Exp Ther Med 2021 Feb 25;21(2):169. Epub 2020 Dec 25.

Department of Hepatology, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu 215131, P.R. China.

MicroRNA (miR)-21-5p is a newly discovered factor that mediates TGF-β1 signaling. The present study was designed to investigate the role of TGF-β1/miR-21-5p in hepatitis B virus (HBV)-induced liver fibrosis. HBV-infected sodium taurocholate co-transporting polypeptide (NTCP)-transfected Huh7.5.1 cells were co-cultured with LX2 cells to simulate HBV infection in the present study. A total of 29 patients with chronic HBV infection were enrolled. Cells were transfected with miR-21-5p mimic or inhibitor with or without TGF-β1 stimulation. The demographic, biochemical and virological data from the 29 patients were analyzed and liver tissues were collected. miR-21-5p levels and the mRNA and protein expression of α-smooth muscle actin (SMA), collagen type 1 α 1 (CoL1A1), tissue inhibitor of metalloproteinase (TIMP)-1 and Smad from liver cells or tissues were detected by quantitative PCR analysis and western blotting, respectively. Cell viability was observed, and the liver fibrosis score was evaluated. The association between miR-21-5p and liver fibrosis was evaluated by correlation analysis. HBV infection upregulated TGF-β1/miR-21-5p mRNA expression in NTCP-Huh7.5.1 cells compared with mock infection (P<0.05). TGF-β1 incubation significantly increased miR-21-5p levels, as well as the mRNA and protein expression of α-SMA, CoL1A1 and TIMP-1, and reduced Smad7 expression in LX2 cells compared with the normal group, and these effects were counteracted by miR-21-5p inhibitor (P<0.05). miR-21-5p overexpression also contributed to TGF-β1-induced α-SMA, CoL1A1 and TIMP-1 expression in LX2 cells (P<0.05). Co-culture with HBV-infected NTCP-Huh7.5.1 cells upregulated TGF-β1/miR-21-5p activity and CoL1A1 expression in LX2 cells compared with normal control, which were significantly reduced by miR-21-5p inhibitor (P<0.05). miR-21-5p levels were significantly correlated with the liver fibrosis score (r=0.888; P<0.05). These data demonstrated that HBV induced liver fibrosis via the TGF-β1/miR-21-5p pathway and suggested that miR-21-5p may be an effective anti-fibrosis target.
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http://dx.doi.org/10.3892/etm.2020.9600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792493PMC
February 2021

Neoadjuvant chemotherapy in bladder cancer: Clinical benefit observed in prospective trials computed with restricted mean survival times.

Urol Oncol 2021 Jan 9. Epub 2021 Jan 9.

The Ohio State University, Department of Urology, Columbus, OH. Electronic address:

Purpose: Neoadjuvant chemotherapy (NAC) is the standard of care for eligible patients with cT2-4a N0 M0 bladder cancer undergoing surgical resection. The extent to which (and if) NAC increases patient survival is not clear as clinical trials and meta-analyses have generated both negative and "borderline" positive results. The novel method of calculating restricted mean survival times (RMST) may provide a more meaningful way to quantify treatment efficacy due to inherent statistical limitations of conventional hazard ratios. In this study we analyzed the survival benefit attributable to NAC in bladder cancer by calculating RMST of previously published clinical trials.

Materials And Methods: All published randomized controlled clinical trials of bladder cancer with available survival data comparing NAC plus radical cystectomy with cystectomy alone were included. RMSTs were calculated for each cohort at the 5-year and total follow-up time periods, comparing the NAC and radical cystectomy groups. Fixed effect meta-analysis of the 5-year RMSTs was then performed to calculate the net impact of NAC on overall survival.

Results: For 2 among 7 included trails, RMST analysis changed the statistical significance. The SWOG 8,710 trial that had previously suggested a survival benefit associated with NAC (P = 0.06) was found to have a clearer beneficial association by 5-year RMST (6.5 month benefit; P = 0.01) and total follow-up RMST (13.6 month benefit over 168 months; P = 0.04). The International Collaboration of Trialists trial that had previously suggested a survival benefit with NAC (P = 0.04) was found to have a beneficial association by total follow-up RMST (6.7 months benefit over 120 months; P = 0.04) but not 5-year RMST (P = 0.10). The interpretation of other trials did not change.  Fixed effect meta-analysis suggested a clinically significant overall survival benefit associated with NAC (3.2 months benefit over 60 months; P < 0.01).

Conclusions: Evaluation of published randomized controlled trials using RMSTs strengthens the association of neoadjuvant chemotherapy with survival benefit in bladder cancer. As RMST may enable improved detection of clinical benefit when compared to conventional statistical methods, consideration should be given to RMST-based endpoints in future clinical trial design.
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http://dx.doi.org/10.1016/j.urolonc.2020.12.012DOI Listing
January 2021

Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.

Am J Clin Oncol 2021 03;44(3):114-120

Tisch Cancer Institute, Division of Hematology/Oncology.

Objectives: Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown.

Methods: We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment.

Results: Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003).

Conclusions: Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.
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http://dx.doi.org/10.1097/COC.0000000000000793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902456PMC
March 2021

The relevant resting-state brain activity of ecological microexpression recognition test (EMERT).

PLoS One 2020 22;15(12):e0241681. Epub 2020 Dec 22.

School of Education, Soochow University, Soochow, China.

Zhang, et al. (2017) established the ecological microexpression recognition test (EMERT), but it only used white models' expressions as microexpressions and backgrounds, and there was no research detecting its relevant brain activity. The current study used white, black and yellow models' expressions as microexpressions and backgrounds to improve the materials ecological validity of EMERT, and it used eyes-closed and eyes-open resting-state fMRI to detect relevant brain activity of EMERT for the first time. The results showed: (1) Two new recapitulative indexes of EMERT were adopted, such as microexpression M and microexpression SD. The participants could effectively identify almost all the microexpressions, and each microexpression type had a significantly background effect. The EMERT had good retest reliability and calibration validity. (2) ALFFs (Amplitude of Low-Frequency Fluctuations) in both eyes-closed and eyes-open resting-states and ALFFs-difference could predict microexpression M. The relevant brain areas of microexpression M were some frontal lobes, insula, cingulate cortex, hippocampus, parietal lobe, caudate nucleus, thalamus, amygdala, occipital lobe, fusiform, temporal lobe, cerebellum and vermis. (3) ALFFs in both eyes-closed and eyes-open resting-states and ALFFs-difference could predict microexpression SD, and the ALFFs-difference was more predictive. The relevant brain areas of microexpression SD were some frontal lobes, insula, cingulate cortex, cuneus, amygdala, fusiform, occipital lobe, parietal lobe, precuneus, caudate lobe, putamen lobe, thalamus, temporal lobe, cerebellum and vermis. (4) There were many similarities and some differences in the relevant brain areas between microexpression M and SD. All these brain areas can be trained to enhance ecological microexpression recognition ability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241681PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755225PMC
January 2021

Increased bleeding risk associated with concurrent vascular endothelial growth factor receptor tyrosine kinase inhibitors and low-molecular-weight heparin.

Cancer 2021 Mar 20;127(6):938-945. Epub 2020 Nov 20.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio.

Background: Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized.

Methods: Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups.

Results: Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone.

Conclusions: Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.
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http://dx.doi.org/10.1002/cncr.33337DOI Listing
March 2021

Influence of Optimization Design Based on Artificial Intelligence and Internet of Things on the Electrocardiogram Monitoring System.

J Healthc Eng 2020 26;2020:8840910. Epub 2020 Oct 26.

Lenovo Research, Lenovo Group, Beijing 100094, China.

With the increasing emphasis on remote electrocardiogram (ECG) monitoring, a variety of wearable remote ECG monitoring systems have been developed. However, most of these systems need improvement in terms of efficiency, stability, and accuracy. In this study, the performance of an ECG monitoring system is optimized by improving various aspects of the system. These aspects include the following: the judgment, marking, and annotation of ECG reports using artificial intelligence (AI) technology; the use of Internet of Things (IoT) to connect all the devices of the system and transmit data and information; and the use of a cloud platform for the uploading, storage, calculation, and analysis of patient data. The use of AI improves the accuracy and efficiency of ECG reports and solves the problem of the shortage and uneven distribution of high-quality medical resources. IoT technology ensures the good performance of remote ECG monitoring systems in terms of instantaneity and rapidity and, thus, guarantees the maximum utilization efficiency of high-quality medical resources. Through the optimization of remote ECG monitoring systems with AI and IoT technology, the operating efficiency, accuracy of signal detection, and system stability have been greatly improved, thereby establishing an excellent health monitoring and auxiliary diagnostic platform for medical workers and patients.
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http://dx.doi.org/10.1155/2020/8840910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609146PMC
October 2020

Alterations of DNA damage response genes correlate with response and overall survival in anti-PD-1/PD-L1-treated advanced urothelial cancer.

Cancer Med 2020 12 23;9(24):9365-9372. Epub 2020 Oct 23.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti-PD-1/PD-L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti-PD-1/PD-L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum-based chemotherapy. DDR alterations (including ATM) were associated with a non-significantly higher ORR to PD-1/PD-L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non-significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20-1.38, p = 0.19). ATM alterations were associated with a non-significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65-19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD-1/PD-L1 blockade versus 24% ORR in patients with <3 DDR alterations. In summary, DDR alterations were associated with non-significantly higher ORR and longer OS for patients with advanced UC receiving anti-PD-1/PD-L1 agents. ATM alterations were associated with shorter OS.
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http://dx.doi.org/10.1002/cam4.3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774722PMC
December 2020

The predictive value of serum amyloid A and C-reactive protein levels for the severity of coronavirus disease 2019.

Am J Transl Res 2020 15;12(8):4569-4575. Epub 2020 Aug 15.

Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China Hefei 230001, Anhui Province, China.

This study was designed to assess the levels of human serum amyloid A (SAA) and C-reactive protein (CRP) in patients with coronavirus disease 2019 (COVID-19) to determine their prognostic value in predicting the severity of disease. Patients with COVID-19 who presented with acute respiratory distress syndrome (ARDS) shared distinct characteristics. For example, the patients were older, and had higher levels of inflammatory indicators [i.e., levels of CRP, SAA, procalcitonin (PCT), and interleukin-6; CRP-to-PCT ratio; SAA-to-CRP ratio; and neutrophil-to-lymphocyte ratio (NLR)], higher inflammatory cell counts (i.e., white blood cell count and neutrophil count), and lower lymphocyte counts compared with patients without ARDS. Patients without ARDS still exhibited mild illness and had elevated SAA levels but not CRP levels. In patients with elevated SAA and CRP levels, the NLR was statistically associated with disease severity. According to the receiver operating characteristic curve analysis, the combined predictive probability of CRP and SAA levels, along with white blood cell count, showed the highest area under the curve (AUC; 0.878), and was able to distinguish between patients with and without ARDS. The cut-off level for SAA to predict the severity of COVID-19 was 92.900, with a sensitivity of 95.8%, a specificity of 53.7%, and an AUC of 0.712. For patients with elevated levels of SAA but not CRP, a mild condition was predicted. For patients with elevated levels of both SAA and CRP, and a high NLR, a severe infection was predicted, requiring medical attention. Therefore, CRP and SAA levels demonstrate a prognostic value for predicting the severity of COVID-19.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476119PMC
August 2020

Pediatric tuina for the treatment of fever in children: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Aug;99(33):e21664

School of Basic Medicine.

Background: Infantile fever is a common symptom of the pediatric diseases, which is often caused by cold, food accumulation, or other pathogenic factors. Pediatric tuina is regarded as an acceptable non-pharmaceutical therapy for children with optimal effects, which has been widely used for infantile fever around China. But there is still a lack of systematic evaluation and research on its safety and effectiveness during the treatment of infantile fever. Thus the protocol is to collect clinical evidence and demonstrate the efficacy and safety of antipyretic manipulation by pediatric tuina.

Methods: The systematic electronic search will be executed in Cochrane Library (1991-2020.6), EMBASE (1980-2020.6), PubMed (1996-2020.6), WHOICTRP (2004-2020.6), Web of Science (1900-2020.6), CNKI (1994-2020.6), CBM (1994-2020.6), WANFANG (1980-2020.6), and VIP (2000-2020.6) Database. The Review Manager (V.5.3) will be use to assess the risk of bias and data analyses. The methodological quality will be assessed by using the online GRADEpro tool. If the quality of numeric data is favorable, a meta-analysis will be carried out.

Results: A high-quality evidence of pediatric tuina for the treatment of infantile fever.

Conclusion: The systematic review will provide a reliable basis for judging whether pediatric tuina is safe and effective in the treatment of pediatric fever.

Inplasy Registration Number: INPLASY202060032.
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http://dx.doi.org/10.1097/MD.0000000000021664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437734PMC
August 2020

Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma.

Eur Urol Focus 2020 Aug 26. Epub 2020 Aug 26.

Foundation Medicine, Inc., Cambridge, MA, USA.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms.

Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor.

Design, Setting, And Participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT).

Intervention: Hybrid-capture-based CGP.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between anatomic subgroups were reported.

Results And Limitations: In total, 39% of patients with UC harbored one or more tier 1-2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p=0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p<0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p=0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p<0.001).

Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

Patient Summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.
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http://dx.doi.org/10.1016/j.euf.2020.08.001DOI Listing
August 2020

The Establishment of Pseudorandom Ecological Microexpression Recognition Test (PREMERT) and Its Relevant Resting-State Brain Activity.

Front Hum Neurosci 2020 30;14:281. Epub 2020 Jul 30.

School of Education, Soochow University, Suzhou, China.

The EMERT (ecological microexpression recognition test) by Zhang et al. (2017) used between-subjects Latin square block design for backgrounds; therefore, participants could not get comparable scores. The current study used within-subject pseudorandom design for backgrounds to improve EMERT to PREMERT (pseudorandom EMERT) and used eyes-closed and eyes-open resting-state functional magnetic resonance imaging to detect relevant brain activity of PREMERT for the first time. The results showed (1) two new recapitulative indexes of PREMERT were adopted, such as microexpression M and microexpression SD. Using pseudorandom design, the participants could effectively identify almost all the microexpressions, and each microexpression type had significant background effect. The PREMERT had good split-half reliability, parallel-forms reliability, criterion validity, and ecological validity. Therefore, it could stably and efficiently detect the participants' microexpression recognition abilities. Because of its pseudorandom design, all participants did the same test; their scores could be compared with each other. (2) amplitude of low-frequency fluctuations (ALFF; 0.01-0.1 Hz) in both eyes-closed and eyes-open resting states and ALFF difference could predict microexpression M, and the ALFF difference was less predictive. The relevant resting-state brain areas of microexpression M were some frontal lobes, insula, cingulate cortex, hippocampus, amygdala, fusiform gyrus, parietal lobe, caudate nucleus, precuneus, thalamus, putamen, temporal lobe, and cerebellum. (3) ALFFs in both eyes-closed and eyes-open resting states and ALFF difference could predict microexpression SD, and the ALFF difference was more predictive. The relevant resting-state brain areas of microexpression SD were some frontal lobes, central anterior gyrus, supplementary motor area, insula, hippocampus, amygdala, cuneus, occipital lobe, fusiform gyrus, parietal lobe, caudate nucleus, pallidum, putamen, thalamus, temporal lobe, and cerebellum. (4) There were many similar relevant resting-state brain areas, such as brain areas of expression recognition, microexpressions consciousness and attention, and the change from expression backgrounds to microexpression, and some different relevant resting-state brain areas, such as precuneus, insula, and pallidum, between microexpression M and SD. The ALFF difference was more sensitive to PREMERT fluctuations.
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http://dx.doi.org/10.3389/fnhum.2020.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406786PMC
July 2020

Characterization of the Key Aroma Compounds in Dog Foods by Gas Chromatography-Mass Spectrometry, Acceptance Test, and Preference Test.

J Agric Food Chem 2020 Aug 15;68(34):9195-9204. Epub 2020 Aug 15.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China.

Gas chromatography-mass spectrometry (GC-MS) coupled with the acceptance test, partial least-squares regression (PLSR) analysis, validation experiment, and preference test was used to identify the key aroma compounds in dog foods (DFs). Six DFs were evaluated by spraying six palatability enhancers onto a basal DF. The differently flavored palatability enhancers were prepared by the Maillard reaction using different protein sources and reaction conditions. The intake ratios of the six DFs were tested by six adult beagle dogs and were classified into high, medium, and low levels. A total of 55 volatile compounds were identified using headspace solid-phase microextraction (HS-SPME) GC-MS. Correlation analysis of the volatile compounds associated with intake ratios using partial least-squares regression (PLSR) found nine significantly positive and three significantly negative compounds that made a significant contribution to the palatability of DFs. Validation tests undertaken by adding three significantly positive compounds, one significantly negative compound, and one nonsignificant compound into the odorless matrix successfully verified the accuracy prediction of the PLSR model. The nine significantly positive compounds were heptanal, nonanal, octanal, ()-2-hexenal, (,)-2,4-decadienal, 2-pentylfuran, 4-methyl-5-thiazoleethanol, 2-furfurylthiol, and ()-2-decenal. The contributions of nine key aroma compounds were further analyzed by the preference test. ()-2-decenal, 2-furfurylthiol, and 4-methyl-5-thiazoleethanol showed higher first choice, consumption ratio, and unit contribution rate and were vital to the overall preferred aroma of DFs.
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http://dx.doi.org/10.1021/acs.jafc.0c03088DOI Listing
August 2020

Analysis of Flavonoid Compounds by Terahertz Spectroscopy Combined with Chemometrics.

ACS Omega 2020 Jul 16;5(29):18134-18141. Epub 2020 Jul 16.

Synergetic Innovation Center of Quantum Information & Quantum Physics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230026, China.

Flavonoids are a large class of polyphenols widely distributed in plants in the free form or as glycosides, and they have antioxidation, antibacterial, antitumor growth, and other pharmacological effects. As an important active component of traditional Chinese medicine, they have high medicinal value and development prospects. In this work, the biomolecular properties of 10 common flavonoids, including baicalein, baicalin, apigenin, quercetin, naringenin, hesperetin, daidzein, genistein, puerarin, and gastrodin, are studied by terahertz time-domain spectroscopy (THz-TDS) in the range of 0.2-2.5 THz. The results reveal that these flavonoids have different characteristic absorption peaks in the terahertz band. Moreover, the terahertz absorption characteristics of samples in the temperature range of 78-320 K are studied. The results show that the characteristic absorption peaks gradually increase with the decrease in temperature, and the frequency position of the absorption peak has a slight blue shift. Furthermore, qualitative identification and quantitative analysis of flavonoids are carried out by terahertz spectra combined with chemometrics. Specifically, a series of mixtures of three flavonoids with similar molecular structures under various concentrations are analyzed. The partial least-squares regression (PLSR) model and the artificial neural network (ANN) model are applied to quantitatively analyze the ternary mixture. The results confirm that the ANN model obtains the best predicted value, with the root-mean-square errors in the prediction set (RMSEP) of 1.27% for daidzein. In summary, the biomolecular properties of flavonoids are studied by the THz-TDS technique, and a rapid, effective, and nondestructive method for qualitative identification and quantitative analysis of flavonoids is provided. The results demonstrate that this method has potential application value in the detection of Chinese herbal medicine and has better referential significance for the study of other biomolecules, especially for isomers or similar molecular structures.
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http://dx.doi.org/10.1021/acsomega.0c01706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391855PMC
July 2020

Different effects of total flavonoids from Arachniodes exilis on human umbilical cord mesenchymal stem cells in vitro.

Medicine (Baltimore) 2020 Jun;99(25):e20628

Medicine Graduate School of Nanchang University.

Traditional Chinese medicines are used in promotion of fractured bone healing and bone diseases. Some studies reported total flavonoids from plant can be used as an auxiliary source of exogenous.Use different methods to identify and verify effects of total flavonoids from Arachniodes exilis (TFAE) on human umbilical cord mesenchymal stem cells (HUCMSCs) in vitro.Concentrations of 1 and 5 μg/mL TFAE significantly increased ALPase activity in HUCMSCs compared to the other concentrations at days 3 and 7 (P < .05). RT-PCR showed that expression levels of osteogenic genes (Col1a1, OPN, Runx2 and Osx) were remarkably enhanced in HUCMSCs following treatment with different concentrations of TFAE for 9 days compared with 0 μg/mL TFAE group (control). The results showed that concentration < 5 μg/mL of TFAE induced osteogenic differentiation in HUCMSCs Alizarin red staining assays revealed that both TFAE and S1191 was significantly decreased (7.80 ± 0.66) compared with the TFAE group (16.00 ± 0.97) (P < .01). ALPase activity on days 3 and 7 was relatively lower in HUCMSCs grown in media supplemented with both S1191 and TFAE than that of in TFAE group only. The results indicated that osteogenic markers (Col1a1, OPN, Runx2 and Osx) were significantly downregulated in the TFAE + S1191 group in comparison to the control group. The expressions of Col1a and OPN in the TFAE + S1191 group decreased significantly (P < .01) by Western blotting.TFAE promotes the odonto/osteogenic differentiation of human UCMSCs via activation of ER.
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http://dx.doi.org/10.1097/MD.0000000000020628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310876PMC
June 2020

Low-Dose Enzalutamide in Late-Elderly Patients (≥ 75 Years Old) Presenting With Metastatic Castration-Resistant Prostate Cancer.

Clin Genitourin Cancer 2020 Dec 7;18(6):e660-e668. Epub 2020 Apr 7.

Ohio State University Comprehensive Cancer Center, Columbus, OH.

Background: Enzalutamide, a major antiandrogen indicated for metastatic castration-resistant prostate cancer, has worrisome toxicities in aging patients. Dose reduction might limit toxicity, but potential loss of efficacy is a concern. We compare up-front low-dose versus standard-dose enzalutamide.

Patients And Methods: Records of prostate cancer patients receiving enzalutamide were retrospectively retrieved. Selection criteria were: age ≥ 75, metastatic disease, surgical or medical castration, and rising prostate-specific antigen (PSA). Data were excluded of those missing follow-up PSA values. Low-dose enzalutamide (≤ 80 mg per day) was compared to standard dose (160 mg per day). Progression-free survival analyzed the time from start of enzalutamide to event, defined as ≥ 25% and ≥ 2 ng/mL PSA increase above nadir, or death from any cause.

Results: Fifty-nine patients were identified, of whom 16 received low-dose and 43 standard-dose therapy. Patients in the low-dose group were significantly old, with a median (range) age of 84.6 (74.9-93.8) years; median (range) PSA at start of enzalutamide was 59.2 (11.0-1058.3) ng/mL; 11 had bone metastases only, 2 metastatic lymph nodes only, and 3 bone and lymph node localizations. Pain score was > 3/10 in 4 patients (27%), Eastern Cooperative Oncology Group performance status was ≥ 2 in 9 (56%); 3 patients had received prior abiraterone and 3 bicalutamide. None received chemotherapy. PSA decrease of ≥ 50% at 12 weeks was observed in 67% patients (10/15), versus 45.0% with standard dose. Median (range) PSA at last follow-up was 1.6 (0-599.3) ng/mL. Median progression-free survival was 11.2 months, versus 11.9 months for patients receiving the standard dose (P = .612).

Conclusion: Low-dose enzalutamide in very old, symptomatic, poor-performance patients with metastatic disease was associated with high response rate and survival comparable to standard dose.
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http://dx.doi.org/10.1016/j.clgc.2020.03.019DOI Listing
December 2020

Effects of Gentiana delavayi Flower Extract on APP Processing in APP/PS1 CHO Cells.

Biol Pharm Bull 2020 ;43(5):767-773

College of Pharmacy and Chemistry, Dali University.

Ethnopharmacological Relevance: Gentiana delavayi Franch. (Gentianaceae) as an ethnomedicinal plant contains a variety of effective active ingredients and exhibits diverse pharmacological actions, such as hepatoprotective, anti-inflammatory and central nervous system effects. In this study we investigated the influence of G. delavayi flower extract on amyloid precursor protein (APP) processing at molecular and cellular levels. APP/PS1 Chinese hamster ovary (CHO) cells were treated with chloroform extract of G. delavayi flower in different concentrations for 24 h. Concentrations of amyloid β (Aβ) 40 and Aβ42 in the cell supernatant and activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), BACE2, and cathepsin D were determined. The expression of APP and neprilysin (NEP) within the cell were further determined. Compared with the control group, the levels of Aβ40 and Aβ42 declined notably and the activity of BACE1 was inhibited significantly in the APP/PS1 CHO cells after treatment with the chloroform extract of G. delavayi flower. Although the activities of BACE2 and cathepsin D were not changed, the expression of Aβ degrading enzyme NEP increased remarkably. Our experiments have clearly showed that the chloroform extract of G. delavayi flower inhibits the generation of β-amyloid by specifically inhibiting β-secretase and increases the expression of NEP which fastens the degradation of Aβ, exhibiting the effect of decreasing Aβ accumulation in APP/PS1 CHO cells. These results suggest that the active components from the chloroform extract of G. delavayi flower have a further prospect to be developed as potential anti-Aβ drug.
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http://dx.doi.org/10.1248/bpb.b19-00720DOI Listing
January 2021

Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus.

Transl Psychiatry 2020 05 4;10(1):130. Epub 2020 May 4.

CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

Depression may be associated with reduced monoamine neurotransmission, particularly serotonin and norepinephrine (NE). Reuptake of NE by the norepinephrine transporter (NET) is the primary mechanism by which many of the antidepressants are high-affinity substrates for NET. This study aimed to examine the effect of lentivirus-mediated shRNA targeting NET in locus coeruleus (LC) on depression-like behaviors of rats. We randomly assigned 60 male Wistar rats to 6 experimental groups: (1) Control group: without chronic unpredictable mild stress (CUMS) and without NET-shRNA treatment; (2) shRNA group: without CUMS + NET-shRNA; (3) CUMS group: 3-week CUMS without NET-shRNA; (4) CUMS + nonsense shRNA group; (5) CUMS + amygdala (Amy)-shRNA group; (6) CUMS+ locus coeruleus (LC)-shRNA group. First, recombinant lentiviral vector expressing shRNA (ShRNA-629, ShRNA-330, ShRNA-1222, ShRNA-1146 or ShRNA- negative control) against NET were produced, and their efficiency in knocking down of NET in PC12 cells were assessed by Q-PCR and western blot analysis. Second, shRNA was injected into the rat LC bilaterally to investigate whether it could prevent the depressive-like behavior induced by 3-week CUMS. Third, we tested the depressive-like behavior of the rats in the forced swimming test, the open field test, the sucrose preference test, as well as the body weight gain at the end of the seventh week. Finally, the protein expressions of NET was measured by western blot and the NE levels were measured by high performance liquid chromatography. Q-PCR and western blot showed that the ShRNA-1146 had the best interference efficiency targeting on NET in PC12 cells (p < 0.01). Compared to the depression model group, the immobility time in the forced swimming test was significantly reduced (p < 0.01), but the sucrose preference and the total scores in the open field test were significantly increased (all p < 0.01) in the group treated with shRNA in LC. Furthermore, compared with the depression model group, NET levels were significantly decreased (p < 0.01), but NE levels were significantly increased in the group treated with shRNA in LC (p < 0.05). Our findings suggest that Lentivirus-mediated shRNA targeting NET in LC downregulated NET both in vitro and in vivo, resulting in a significant decrease in depressive-like behavior of rats.
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http://dx.doi.org/10.1038/s41398-020-0808-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198598PMC
May 2020

Clinical Pathway for Early Diagnosis of COVID-19: Updates from Experience to Evidence-Based Practice.

Clin Rev Allergy Immunol 2020 Aug;59(1):89-100

Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, 1131 N 35th Avenue, Suite 220, Hollywood, FL, 33021, USA.

The COVID-19 pandemic is a significant global event in the history of infectious diseases. The SARS-CoV-2 appears to have originated from bats but is now easily transmissible among humans, primarily through droplet or direct contact. Clinical features of COVID-19 include high fever, cough, and fatigue which may progress to ARDS. Respiratory failure can occur rapidly after this. The primary laboratory findings include lymphopenia and eosinopenia. Elevated D-dimer, procalcitonin, and CRP levels may correlate with disease severity. Imaging findings include ground-glass opacities and patchy consolidation on CT scan. Mortality is higher in patients with hypertension, cardiac disease, diabetes mellitus, cancer, and COPD. Elderly patients are more susceptible to severe disease and death, while children seem to have lower rates of infection and lower mortality. Diagnostic criteria and the identification of persons under investigation have evolved as more data has emerged. However, the approach to diagnosis is still very variable from region to region, country to country, and even among different hospitals in the same city. The importance of a clinical pathway to implement the most effective and relevant diagnostic strategy is of critical importance to establish the control of this virus that is responsible for more and more deaths each day.
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http://dx.doi.org/10.1007/s12016-020-08792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180681PMC
August 2020

Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

Oncologist 2020 08 13;25(8):680-688. Epub 2020 May 13.

Penn State Cancer Institute, Hershey, Pennsylvania, USA.

Background: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear.

Materials And Methods: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI.

Results: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003).

Conclusions: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression.

Implications For Practice: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.
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http://dx.doi.org/10.1634/theoncologist.2019-0851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418353PMC
August 2020

Corrigendum: Propofol Alleviates DNA Damage Induced by Oxygen Glucose Deprivation and Reperfusion FoxO1 Nuclear Translocation in H9c2 Cells.

Front Physiol 2020;11:59. Epub 2020 Feb 6.

Department of Internal and Emergency Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.

[This corrects the article DOI: 10.3389/fphys.2019.00223.].
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http://dx.doi.org/10.3389/fphys.2020.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016201PMC
February 2020

Acute fatal myocarditis after a single dose of anti-PD-1 immunotherapy, autopsy findings: a case report.

Cardiovasc Pathol 2020 May - Jun;46:107202. Epub 2020 Jan 15.

Department of Pathology and The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Nivolumab (PD-1 inhibitor) and Ipilimumab (CTLA-34 inhibitor) are both commonly used immune checkpoint inhibitor therapies for various cancers. Various adverse events are associated with these therapies, including hepatitis, nephritis, dermatitis, and myocarditis. It is believed these adverse events occur in part because modified cellular receptors lead to enhanced CD4 and CD8 lymphoproliferation. These events usually occur after several months and rounds of treatment. Here we present a case of an 81-year-old male with recurrent renal cell carcinoma (RCC) who experienced myocarditis after only a single dose of combination therapy with Nivolumab and Ipilimumab. He presented with elevated troponins and a third-degree heart block; three days after admission he died. Histologic examination revealed a predominance of CD3 T cells (CD4 > CD8) and CD68 macrophages, with occasional CD20 B cells. C4d staining was negative in the interstitial capillaries, suggesting that antibody-mediated injury of endothelial cells did not play a significant role in the pathogenesis of this myocarditis. Additional studies ruled out an infectious etiology. Immune checkpoint inhibitors are increasingly more common, and it is important clinicians are aware patients can present with myocarditis early in the course of treatment.
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http://dx.doi.org/10.1016/j.carpath.2020.107202DOI Listing
June 2020

Impact of lack of surgery on outcomes in elderly women with nonmetastatic breast cancer-A surveillance, epidemiology, and end results 18 population based study.

Medicine (Baltimore) 2020 Jan;99(3):e18745

Penn State Cancer Institute, Hershey, PA, USA.

Elderly women with early-stage, nonmetastatic breast cancer do not always receive recommendations for definitive surgical treatment. The reasons vary and include patient and provider-related reasons.We queried the surveillance, epidemiology, and end results database from 2010 to 2013 for women age 60 and older with stage I/II/III invasive breast cancer for whom local treatment was known. We divided the patients into 3 groups: patients for whom surgery was performed; patients for whom surgery was recommended but not performed; patients for whom surgery was not recommended and not performed. We used Kaplan-Meier method to generate OS curves and the Cox proportional hazard test to compare survival outcomes.A total of 119,404 patients were eligible for study with a median age between 70 and 74 years old. Compared with patients who received breast surgery, patients who did not receive surgery had a worse overall survival (OS) (hazard ratio [HR], 7.39; 95% confidence interval [CI], 6.98-7.83, P < .001). Patients who were recommended but ultimately did not undergo surgery had better OS than those who were recommended against surgery (adjusted HR, 0.60; 95% CI, 0.53-0.69). However, their survival was significantly inferior to patients who underwent surgery (adjusted HR, 2.81; 95% CI 2.48-3.19). Similar results were found regardless of age, tumor stage, estrogen receptor, or human epidermal growth factor receptor 2 status and were recapitulated in analyses of cancer-specific survival.Upfront definitive breast surgery should be performed in medically-fit elderly patients with early-stage, nonmetastatic breast cancer given significant survival benefit.
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http://dx.doi.org/10.1097/MD.0000000000018745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220091PMC
January 2020

Curculigoside Protects against Excess-Iron-Induced Bone Loss by Attenuating Akt-FoxO1-Dependent Oxidative Damage to Mice and Osteoblastic MC3T3-E1 Cells.

Oxid Med Cell Longev 2019 17;2019:9281481. Epub 2019 Dec 17.

College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310050, China.

Summary: The present investigation found that curculigoside (CUR) can prevent excess-iron-induced bone loss in mice and cells through antioxidation and inhibiting excess-iron-induced phosphorylation of the Akt-FoxO1 pathway. CUR can attenuate the decreasing of cell viability, enhance autophagy, potentiate the antioxidant effect, and reduce apoptosis in MC3T3-E1 cells treated with excess iron through regulating the expression of FoxO1 target gene.

Introduction: Oxidative stress induced by iron overload is an important factor involved in primary osteoporosis disease and iron overload-related diseases. Curculigoside (CUR), a phenolic glycoside found abundantly in Gaertn., has been demonstrated to possess antioxidant and antiosteoporotic properties. The aim of the present study is to explore the underlying molecular mechanism of CUR on excess-iron-induced bone loss in mice and osteoblastic MC3T3-E1 cells.

Methods: An iron-overload mice model was used to study the protective effects of CUR on bone loss induced by oxidative stress. Serum bone metabolism markers and antioxidant enzymes were also measured. To explore the antioxidant mechanism of CUR, the MC3T3-E1 osteoblastic cell line was used.

Results: In vivo studies showed that BMD and microarchitectural parameters were improved after a 3-month administration of CUR. CUR improved the biochemical parameters related to bone metabolism and the expressions of Runx2, OCN, and type 1 collagen and increased the formation of bone-mineralized nodules . CUR also inhibited ROS generation and increased the activities of antioxidant enzymes both and treated with excess iron. CUR can upregulate the level of FoxO1 and Nrf2, downregulate the level of p53 and the phosphorylation level of FoxO1, improve nuclear translocation of FoxO1, probably by inhibiting the IGFR/AKT signaling pathway, then increased cell viability and autophagy, and reduced apoptosis of MC3T3-E1 cells treated with excess iron by regulating the expression of FoxO1 target genes MnSOD, Gadd45a, Bim, FasL, and Rab7.

Conclusions: These results demonstrated that CUR was able to alleviate bone loss induced by oxidative stress resulting from iron overload, suggesting its potential use for the treatment of primary osteoporosis and bone loss in iron-overload-related diseases.
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http://dx.doi.org/10.1155/2019/9281481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948300PMC
June 2020

Decreased inward rectifier and voltage-gated K currents of the right septal coronary artery smooth muscle cells in pulmonary arterial hypertensive rats.

Korean J Physiol Pharmacol 2020 Jan 20;24(1):111-119. Epub 2020 Dec 20.

Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.

In vascular smooth muscle, K channels, such as voltage-gated K channels (Kv), inward-rectifier K channels (Kir), and big-conductance Ca-activated K channels (BK), establish a hyperpolarized membrane potential and counterbalance the depolarizing vasoactive stimuli. Additionally, Kir mediates endothelium-dependent hyperpolarization and the active hyperemia response in various vessels, including the coronary artery. Pulmonary arterial hypertension (PAH) induces right ventricular hypertrophy (RVH), thereby elevating the risk of ischemia and right heart failure. Here, using the whole-cell patch-clamp technique, we compared Kv and Kir current densities (I and I) in the left (LCSMCs), right (RCSMCs), and septal branches of coronary smooth muscle cells (SCSMCs) from control and monocrotaline (MCT)-induced PAH rats exhibiting RVH. In control rats, (1) I was larger in RCSMCs than that in SCSMCs and LCSMCs, (2) I inactivation occurred at more negative voltages in SCSMCs than those in RCSMCs and LCSMCs, (3) I was smaller in SCSMCs than that in RCSMCs and LCSMCs, and (4) I did not differ between branches. Moreover, in PAH rats, I and I decreased in SCSMCs, but not in RCSMCs or LCSMCs, and I did not change in any of the branches. These results demonstrated that SCSMC-specific decreases in I and I occur in an MCT-induced PAH model, thereby offering insights into the potential pathophysiological implications of coronary blood flow regulation in right heart disease. Furthermore, the relatively smaller I in SCSMCs suggested a less effective vasodilatory response in the septal region to the moderate increase in extracellular K concentration under increased activity of the myocardium.
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http://dx.doi.org/10.4196/kjpp.2020.24.1.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940494PMC
January 2020

Advances in Penetrating Multichannel Microelectrodes Based on the Utah Array Platform.

Adv Exp Med Biol 2019 ;1101:1-40

University of Utah, Salt Lake City, UT, USA.

The Utah electrode array (UEA) and its many derivatives have become a gold standard for high-channel count bi-directional neural interfaces, in particular in human subject applications. The chapter provides a brief overview of leading electrode concepts and the context in which the UEA has to be understood. It goes on to discuss the key advances and developments of the UEA platform in the past 15 years, as well as novel wireless and system integration technologies that will merge into future generations of fully integrated devices. Aspects covered include novel device architectures that allow scaling of channel count and density of electrode contacts, material improvements to substrate, electrode contacts, and encapsulation. Further subjects are adaptations of the UEA platform to support IR and optogenetic simulation as well as an improved understanding of failure modes and methods to test and accelerate degradation in vitro such as to better predict device failure and lifetime in vivo.
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http://dx.doi.org/10.1007/978-981-13-2050-7_1DOI Listing
November 2019