Cyclin B1 expression as an independent prognostic factor for lung adenocarcinoma and its potential pathways.

Although great progress has been made in the early diagnosis and targeted therapy of lung adenocarcinoma (LUAD), the survival of patients with LUAD remains unsatisfactory. There is an urgent requirement for new biomarkers to guide the diagnosis, prognosis and treatment of LUAD. Following an initial bioinformatics screen, the present study focused on cyclin B1 (CCNB1) in LUAD. A total of 94 patients with LUAD from a single hospital were included in the study. CCNB1 protein expression was detected and scored in 94 LUAD samples and 30 normal tissue samples by immunohistochemistry. The associations between CCNB1 expression and the clinicopathological features of the patients with LUAD were analyzed. Furthermore, the relationship between prognosis and the CCNB1 expression level was analyzed using Cox regression and survival analyses. Weighted gene co-expression network analysis and RNA-sequencing were also applied to identify the potential molecular mechanisms of CCNB1 in LUAD. CCNB1 was highly expressed in patients with LUAD and was associated with poor prognosis. It may affect the expression of CPLX1, PPIF, SRPK2, KRT8, SLC20A1 and CBX2 genes and function via different pathways. CCNB1 has the potential to become a novel prognostic target for LUAD.

Distribution of CD8 T Cells and NK Cells in the Stroma in Relation to Recurrence or Metastasis of Nasopharyngeal Carcinoma.

Objective: The purpose of this study was to explore the expression and distribution of tumor-infiltrating immune cells (TIICs) and their relationship with recurrence and metastasis of nasopharyngeal carcinoma (NPC). Methods: The gene expression profiles of NPC were downloaded from GEO database (GSE53819 and GSE64634). The abundance of TIICs in NPC samples was calculated by the CIBERSORT algorithm, and TIICs with higher expression were screened in NPC. Then, we performed immunohistochemistry experiments to evaluate the expression of selected TIICs in 94 NPC samples from the Affiliated Hospital of Zunyi Medical University. We further explored the relationship between TIICs and recurrence and metastasis of NPC. Results: The results based on the GEO database showed that the expression of CD8 T cells, NK cells, macrophages and plasma cells was higher than that in normal tissues. Immunohistochemistry results showed that CD8 T cells, NK cells, macrophages and plasma cells were mainly expressed in the stroma, and the expression of CD8 T cells and NK cells in the stroma of patients without recurrence or metastasis was significantly higher than that in patients with recurrence or metastasis of NPC. Kaplan-Meier analysis showed that patients with high CD8 T cells and high NK cells expression in the stroma had favorable recurrence or metastasis-free survival and overall survival (P<0.05). Univariate and multivariate Cox analyses indicated that CD8 T cells and NK cells in the stroma were independent factors for the recurrence or metastasis of NPC. Conclusion: The expression of CD8 T cells, NK cells, macrophages and plasma cells is significantly higher than that in normal tissues. Among them, the expression of CD8 T cells and NK cells is closely related to the recurrence and metastasis of NPC. They are independent factors affecting the recurrence and metastasis of NPC.

Efficacy of endoscopic resection and intensity-modulated radiotherapy for thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: a case report.

Background: Among the malignant tumors that occur in the nasopharynx, nasopharyngeal carcinoma is the most common. Nasopharyngeal carcinoma (NPC) is commonly diagnosed in Southeastern Asia, particularly in southern China. It originates from the epithelial lining of the nasopharynx and has a variety of pathological subtypes. The vast majority of NPC cases are keratinizing or nonkeratinizing squamous cell carcinoma. Low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is an extremely rare malignant tumor. Most reports regarding this disease mainly focus on clinical diagnosis and pathology; however, reports regarding therapy and follow-up are relatively limited. The case in the study presents a female patient with LGNPPA. The patient underwent endoscopic resection and adjuvant radiotherapy. Following-up 6 years, the patient was free of local recurrence and distant metastasis. Because of the very low incidence, there are no guidelines or protocols developed for proper, standardized therapy, we aim to provide useful recommendations regarding optimal treatment strategies by exploring the therapeutic expectancies of the rare disease. Case Description: A 45-year-old female of Han ethnicity visited a local hospital for over 2 years of recurrent nasal congestion. The patient had no previous medical history, had a history of smoking (6 years, 20 cigarettes per day) and drank occasionally. but had no family history of cancer. Epstein-Barr virus (EBV) DNA was <500×102 IU/mL. Based on findings from computed tomography (CT) scans of the nasal cavity and paranasal sinuses, nasal endoscopy, and postoperative pathology, the diagnosis was low-grade papillary adenocarcinoma located at the upper nasopharynx (T1N0M0, stage I). This patient underwent endoscopic resection. After the endoscopic resection, she received intensity-modulated radiotherapy. After radiotherapy, there was no residual by nasopharyngo-fiberoscope. And she was free of local recurrence and distant metastasis at 6 years of follow-up. Conclusions: Although primary nasopharyngeal adenocarcinomas (NPACs) are very rare, they also should be pay attention to. As far as treatment policy, no standard treatment exists for the tumors. So through this case report, we want to provide a possible useful recommendations regarding optimal treatment strategies by exploring the therapeutic expectations of this rare disease.

Successful treatment of two patients with unresectable lung squamous cell carcinoma with tislelizumab regardless of programmed death-ligand 1 expression: a report of two cases.

Since the treatment of lung squamous cell carcinoma (SCC) was limited due to a lack of appropriate biomarkers and novel target agents. Immune checkpoint inhibitors can offer an effective treatment for patients with advanced non-small cell lung cancer. Here, we described the cases of two patients with SCC who showed a good response following treatment with tislelizumab. We encountered two patients with unresectable lung SCC who were treated with immunotherapy and chemotherapy. One patient had negatively programmed death-ligand 1 expression, and the primary lesion becomes a thick wall cavity after the tislelizumab combined with chemotherapy. Another patient was diagnosed with advanced lung SCC with negative programmed death-ligand 1 expression. After the treatment, the fluorine-18-fluorodeoxyglucose PET/computed tomography indicated that no abnormal increase in radioactivity uptake and tend to complete remission. We found a significant response or even complete response in unresectable SCC treated with tislelizumab combined with chemotherapy. Our cases added evidence of the feasibility and efficacy of tislelizumab combined with chemotherapy in unresectable lung SCC.

IoT Platform for COVID-19 Prevention and Control: A Survey.

As a result of the worldwide transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has evolved into an unprecedented pandemic. Currently, with unavailable pharmaceutical treatments and low vaccination rates, this novel coronavirus results in a great impact on public health, human society, and global economy, which is likely to last for many years. One of the lessons learned from the COVID-19 pandemic is that a long-term system with non-pharmaceutical interventions for preventing and controlling new infectious diseases is desirable to be implemented. Internet of things (IoT) platform is preferred to be utilized to achieve this goal, due to its ubiquitous sensing ability and seamless connectivity. IoT technology is changing our lives through smart healthcare, smart home, and smart city, which aims to build a more convenient and intelligent community. This paper presents how the IoT could be incorporated into the epidemic prevention and control system. Specifically, we demonstrate a potential fog-cloud combined IoT platform that can be used in the systematic and intelligent COVID-19 prevention and control, which involves five interventions including COVID-19 Symptom Diagnosis, Quarantine Monitoring, Contact Tracing & Social Distancing, COVID-19 Outbreak Forecasting, and SARS-CoV-2 Mutation Tracking. We investigate and review the state-of-the-art literatures of these five interventions to present the capabilities of IoT in countering against the current COVID-19 pandemic or future infectious disease epidemics.

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines.

Neuroblastoma (NB) is the most common pediatric malignant extracranial solid tumor. Despite multi-modality therapies, the emergence of drug resistance is an obstacle in the treatment of high-risk NB patients (with MYCN amplification). In our previous study, we found that rapamycin and MK-2206 synergistically induced cell death in MYCN-amplified cell lines but the mechanisms remained unclear. In our present study, either 3-MA or necroatatin-1 blocked the cell death induced by rapamycin and MK-2206, but z-VAD-fmk did not block this cell death. The expressions of autophagy markers (ATG5, ATG7, Beclin-1, LC3 B) and the necroptosis marker RIPK3 increased and another necroptosis marker RIPK1 decreased after the combination treatment of rapamycin and MK-2206, and were accompanied by the morphological characteristics of autophagy and necroptosis. In NB xenograft tumor tissues, the expressions of autophagy and necroptosis markers were consistent with observations in vitro. These data suggested that autophagy and necroptosis contributed to the cell death induced by rapamycin and MK-2206 in NB cells. To understand the role of MYCN in this process, MYCN expression was downregulated in MYCN-amplified cell lines (NGP, BE2) using siRNAs and was upregulated in MYCN non-amplified cell lines (AS, SY5Y) using plasmid. We found the cell death induced by rapamycin and MK-2206 was MYCN-dependent. We also found that the metabolic activity in NB cells was correlated with the expression level of MYCN. This study delineates the role of MYCN in the cell death induced by combination treatment of rapamycin and MK-2206 in MYCN-amplified NB cells.

A Smartphone-Only Pulse Transit Time Monitor Based on Cardio-Mechanical and Photoplethysmography Modalities.

This paper reports a system for monitoring pulse transit time (PTT). Using an Android smartphone and a customized sensing circuit, the system collects seismo-cardiogram (SCG), gyro-cardiogram (GCG), and photoplethysmogram (PPG) recordings. There is no need for any other external stand-alone systems. The SCG and GCG signals are recorded with the inertial sensors of the smartphone, while the PPG signal is recorded using a sensing circuit connected to the audio jack of the phone. The sensing circuit is battery-less, powered by the audio output of the smartphone using an energy harvester that converts audio tones into DC power. PPG waveforms are sampled via the microphone channel. A signal processing framework is developed and the system is experimentally verified on twenty healthy subjects at rest. The PTT is measured as the time difference between the aortic valve (AO) opening points in SCG or GCG and the fiducial points in PPG. The root-mean-square errors between the results from a stand-alone sensor system and the proposed system report 3.9 ms from SCG-based results and 3.4 ms from GCG-based results. The detection rates report more than 97.92% from both SCG and GCG results. This performance is comparable with stand-alone sensor nodes at a much lower cost.

PF4V1, an miRNA-875-3p target, suppresses cell proliferation, migration, and invasion in prostate cancer and serves as a potential prognostic biomarker.

BACKGROUND: PF4V1 is a novel protein in inflammation, angiogenesis, and cancer. However, the pathogenesis, underlying mechanisms, and the prognostic value of PF4V1 in prostate cancer (PCa) are still unclear. MATERIALS AND METHODS: The PF4V1 expression and relation with survival were analyzed based on a large sample size in the Cancer Genome Atlas. In vitro, the overexpression of PF4V1 was conducted in DU145 and LNCaP cells. Cell Counting Kit-8, colony formation, wound healing, and Transwell® assays were preformed to test biological functions of PF4V1 and miR-875-3p in PCa. Western blotting was used to measure downstream markers in AKT pathways and epithelial-mesenchymal transition (EMT). In vivo experiments were performed to test the therapeutic effect of PF4V1 protein to PCa via a mouse model. RESULTS: The expression of PF4V1 was significantly lower in 497 PCa samples than in 52 normal controls (P=0.0012). High PF4V1 expression (normalized by TP53) was associated with poor disease-free survival (DFS) and good overall survival (OS) in PCa (P<0.05). PF4V1 was underexpressed in four PCa cell lines than in normal prostate cells. Overexpression of PF4V1 could significantly suppress the proliferation, migration, and invasion of DU145 and LNCaP cells (P<0.05). Moreover, miR-875-3p targeted the 3'-untranslated region of PF4V1 and derepressed the inhibitory function of PF4V1 in PCa (P<0.05). Key proteins such as p-AKT/p-ERK/Snail/Slug/N-cadherin were downregulated, while E-cadherin was upregulated when PF4V1 was overexpressed in PCa cells. Finally, intratumoral injection of PF4V1 protein could significantly inhibit PCa growth in vivo. CONCLUSION: PF4V1 can suppress the proliferation, migration, and invasion of PCa cells by regulating AKT/ERK pathways and EMT. Elevated PF4V1/TP53 expression is correlated with poorer DFS and better OS in the patients with PCa. The miR-875-3p-PF4V1 axis may be a new therapeutic target site in PCa.

A Low-cost, Smartphone-only Pulse Transit Time Measurement System Using Cardio-mechanical Signals and Optical Sensors.

This paper presents a smartphone-only solution for measuring pulse transit time (PTT). An application based on an Android smartphone is developed to collect seismocardiogram (SCG), gyrocardiogram (GCG), and photoplethysmography (PPG) recordings. The system does not need any other external system for measurements, so the total cost and system complexity are minimized. PTT metrics are calculated as the time difference between the aortic valve opening points in the SCG or GCG signals recorded by the accelerometer or gyroscope of a smartphone respectively, and the fiducial points in the PPG signal recorded by a modified optical sensor connected to the audio input. A digital signal processing (DSP) system is developed in a post-processing environment and experimentally validated on ten healthy subjects at rest. Our results indicate that a smartphone-only PTT measurement system is feasible and comparable with stand-alone sensor node systems.

P53/PUMA are potential targets that mediate the protection of brain-derived neurotrophic factor (BDNF)/TrkB from etoposide-induced cell death in neuroblastoma (NB).

The over-expressions of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to induce chemo-resistance in neuroblastoma (NB) cells. In this study, we investigated the roles of P53 and BCL2 family members in the protection of BDNF/TrkB from etoposide-induced NB cell death. TB3 and TB8, two tetracycline (TET)-regulated TrkB-expressing NB cell lines, were utilized. The expressions of P53 and BCL2 family members were detected by Western blot or RT-PCR. Transfection of siRNAs was used to knockdown P53 or PUMA. Activated lentiviral was used to over-express PUMA. Cell survival was performed by MTS assay, and the percentage of cell confluence was measured by IncuCyte ZOOM. Our results showed that etoposide treatment induced significant and time-dependent increase of P53, which could be blocked by pre-treatment with BDNF, and knockdown P53 by transfecting siRNA attenuated etoposide-induced TrkB-expressing NB cell death. PUMA was the most significantly changed BCL2 family member after treatment with etoposide, and pre-treatment with BDNF blocked the increased expression of PUMA. Transfection with siRNA inhibited etoposide-induced increased expression of PUMA, and attenuated etoposide-induced NB cell death. We also found that over-expression of PUMA by infection of activated lentiviral induced TrkB-expressing NB cell death in the absence of etoposide, and treatment of BDNF protected NB cells from PUMA-induced cell death. Our results suggested that P53 and PUMA may be potential targets that mediated the protection of BDNF/TrkB from etoposide-induced NB cell death.

Dose-response relation between dietary inflammatory index and human cancer risk: evidence from 44 epidemiologic studies involving 1,082,092 participants.

Background: A newly developed dietary inflammatory index (DII) to evaluate the inflammatory potential of diets was published recently. Many studies have investigated the link between diet-related inflammation and human cancer risk, but the results remain controversial. Objective: We sought to determine the dose-response relation between DII and human cancer risk based on published epidemiologic literature. Design: To summarize evidence, we performed a dose-response meta-analysis to investigate the association between DII and cancer incidence. We systematically searched PubMed, Embase, Web of Science, and the Cochrane library up to 5 November 2017. After data extraction, pooled RRs were calculated and dose-response analyses were performed using a restricted cubic spline model with 4 knots. Subgroup analyses, sensitivity analyses, and tests for publication bias were also performed. Results: In all, 44 high-quality studies with 1,082,092 participants were included. The results showed that an elevated DII (continuous-RR: 1.13; 95% CI: 1.09, 1.16; category DIIhighest vs lowest-RR: 1.58; 95% CI: 1.45, 1.72) independently indicated higher cancer risk except for lung cancer and Australian studies. A linear dose-response relation between DII and overall cancer risk was found, with an 8.3% increase in the risk of cancer per DII score. The pooled RR of DII and cancer risk was 1.86 (95% CI: 1.63, 2.13) from 30 case-control studies but was lower in 14 prospective cohorts (RR: 1.29; 95% CI: 1.19, 1.40). The sensitivity analysis and Egger's test supported the main results. Conclusions: Our analysis indicated that higher DII is significantly correlated with cancer risk. More prospective studies with large sample sizes, involving more ethnic groups and different cancer types, are required in the future. This review was registered with PROSPERO as CRD42017077075.

Quantitative ubiquitylome analysis and crosstalk with proteome/acetylome analysis identified novel pathways and targets of perifosine treatment in neuroblastoma.

BACKGROUND: Perifosine, is a third generation alkylphospholipid analog which has promising anti-tumor efficacy in clinical trials of refractory/recurrent neuroblastoma (NB). However, perifosine's mechanism of action remains unclear. Previously, we have shown that perifosine changes global proteome and acetylome profiles in NB. METHODS: To obtain a more comprehensive understanding of the perifosine mechanism, we performed a quantitative assessment of the lysine ubiquitylome in SK-N-AS NB cells using SILAC labeling, affinity enrichment and high-resolution liquid chromatography combined with mass spectrometry analysis. To analyse the data of ubiquitylome, we performed enrichment analysis with gene ontology (GO), the Encyclopedia of Genes and Genomes (KEGG) pathway, ubiquitylated lysine motif, protein complex and protein domain. Protein-protein interaction was conducted to explore the crosstalk between ubiquitylome and previous global proteome/acetylome. Co-immunoprecipitation and western blotting were used to validate the results of the ubiquitylome analysis. RESULTS: Altogether, 3,935 sites and 1,658 proteins were quantified. These quantified ubiquitylated proteins participated in various cellular processes such as binding, catalytic activity, biological regulation, metabolic process and signaling pathways involving non-homologous end-joining, steroid biosynthesis and Ras signaling pathway. Ubiquitylome and proteome presented negative connection. We identified 607 sites which were modified with both ubiquitination and acetylation. We selected 14 proteins carrying differentially quantified lysine ubiquitination and acetylation sites at the threshold of 1.5 folds as potential targets. These proteins were enriched in activities associated with ribosome, cell cycle and metabolism. CONCLUSIONS: Our study extends our understanding of the spectrum of novel targets that are differentially ubiquitinated after perifosine treatment of NB tumor cells.

Prognostic value of bone scan index as an imaging biomarker in metastatic prostate cancer: a meta-analysis.

BACKGROUND: The prognostic value of the bone scan index (BSI) in metastatic prostate cancer (mPCa) remained controversial. Therefore, we performed a meta-analysis to determine the predictive value of BSI and survival in patients with mPCa. MATERIALS AND METHODS: A literature search was performed in PubMed, Embase, Web of Science and Cochrane library databases. Hazard ratios (HRs), concordance indices (C-indices) were extracted to estimate the relationship between BSI and survival in patients with mPCa. Subgroup analyses were conducted on different types of mPCa, ethnics, cut-off values and sample sizes. RESULTS: 14 high quality studies involving 1295 patients with mPCa were included in this meta-analysis. The pooled results indicated that high basline BSI and elevated BSI change on treatment (ΔBSI) were significantly predictive of poor overall survial (HR = 1.29, P < 0.001; HR = 1.27, P < 0.001, respectively). Baseline BSI was also significantly related to cancer specific survival (HR = 1.65, P = 0.019) and prostate specific antigen recurrence survival (HR = 2.26, P < 0.001). Subgroup analysis supported main results. Moreover, BSI could increase the C-indices of predictive models. CONCLUSIONS: Baseline BSI and ΔBSI may be beneficial to mPCa prognosis in clinical monitor and treatment. Further high quality studies with larger sample size are required in the future.

Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma.

Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to perifosine's anti-tumor activity. To gain insight into perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS analysis. Bioinformatic analysis indicates that, a total of 5,880 proteins and 3,415 lysine acetylation sites were quantified in SK-N-AS cells and 216 differentially expressed proteins and 115 differentially expressed lysine acetylation sites were obtained. These differentially expressed proteins and lysine acetylated proteins were involved in a number of different biological functions, metabolic pathways and pathophysiological processes. This study details the impact of perifosine on proteome and lysine acetylome in SK-N-AS cells and expands our understanding of the mechanisms of perifosine action in neuroblastoma.

PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma.

Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells. A tumor xenograft model using SCID-Beige mice was utilized to detect the metastasis of NB tumors in vivo. Inhibitors of PI3K, MAPK, Akt, and mTOR were used. Western blotting was performed to study the expressions of P-Akt, P-Erk, and P-mTOR. Our results showed that in TrkB-expressing NB cells, BDNF treatment significantly increased gap closing (P < 0.01) in scratch wound healing assay, also significantly enhanced the numbers of migrating cells (P < 0.01) and invading cells (P < 0.01) in the Boyden chamber migration and invasion assays. In vivo, NB distant metastases were significantly increased in mice with TrkB-expressing xenograft tumors compared to those with non-TrkB-expressing tumors (P < 0.05). Pre-treatment with any of the inhibitors for PI3K (LY294002), MAPK (PD98059), Akt (perifosine), or mTOR (rapamycin) blocked the BDNF/TrkB-induced increases of cell migration and invasion in TB3 cells, and also blocked the BDNF/TrkB-induced expressions of P-Akt, P-Erk, and P-mTOR. These data indicated that BDNF/TrkB increased metastasis in NB via PI3K/Akt/mTOR and MAPK pathways, and BDNF/TrkB and the downstream targets may be potential targets for the treatment of NB metastasis.