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Background: Neuroendocrine neoplasm is a rare cancer of head and neck. This study aimed to evaluate clinical features, treatment outcomes, and prognostic factors of neuroendocrine neoplasm of head and neck treated at a single institution. Methods: Between Nov 2000 and Nov 2021, ninety-three patients diagnosed with neuroendocrine neoplasms of head and neck treated at our institution were reviewed retrospectively. The initial treatments included chemotherapy (induction, adjuvant, or concurrent) combined with radiotherapy in 40 patients (C + RT group), surgery followed by post-operative RT in 34 (S + RT group), and surgery plus salvage therapy in 19 patients (S + Sa group). Results: The median follow-up time was 64.5 months. 5-year overall survival rate (OS), progression-free survival rate (PFS), loco-regional relapse-free survival free rate (LRRFS) and distant metastasis-free survival rate (DMFS) were 64.5%, 51.6%, 66.6%, and 62.1%, respectively. For stage I–II, the 5-year LRRFS for patients' treatment regimen with or without radiotherapy (C + RT and S + RT groups versus S + Sa group) was 75.0% versus 12.7% (p = 0.015) while for stage III–IV, the 5-year LRRFS was 77.8% versus 50.0% (p = 0.006). The 5-year DMFS values for patients with or without systemic therapy (C + RT group versus S + RT or S + Sa) were 71.2% and 51.5% (p = 0.075). 44 patients (47.3%) experienced treatment failure and distant metastasis was the main failure pattern. Conclusions: Radiotherapy improved local–regional control and played an important role in the management of HNNENs. The optimal treatment regimen for HNNENs remains the combination of local and systemic treatments. [ABSTRACT FROM AUTHOR]

Objective: Afatinib is an oral, irreversible ErbB family blocker. It binds covalently to the kinase domains of epidermal growth factor (EGFR), HER2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Our trial compared the bioequivalence and safety between afatinib produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and Giotrif® produced by Boehringer Ingelheim. Methods: Healthy Chinese subjects (N = 36) were randomly divided into two groups at a ratio of 1:1. There was a single dose per period of afatinib and Giotrif®. The washout was set as 14 days. Plasma drug concentrations of afatinib and Giotrif® were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. Results: The geometric mean ratios (GMRs) of Cmax, AUC0−t, and AUC0−∞ for afatinib and Giotrif® were 102.80%, 101.83%, and 101.58%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both drugs showed a good safety profile during the trial. Conclusion: This study showed that afatinib was bioequivalent to Giotrif® in healthy Chinese subjects with well safety. Chinese Clinical trial registry: This trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20171160). [ABSTRACT FROM AUTHOR]

Background: There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Methods: Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m2 (33 mg/m2/days [d]1–3) every 3 weeks for two cycles. All patients were given oral aprepitant 125 mg once on d1, then 80 mg once on d2–5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8 mg on d2–5. The primary endpoint was complete response (CR). Pursuant to δ = 0.2 and α = 0.05, the expected CR rate was 80%. Results: A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1–94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9–96.1) and 89.2% (95% CI: 74.6–97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3–84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9–96.1) and 60.5% (95% CI: 44.4–75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1–2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage. Conclusion: The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy. [ABSTRACT FROM AUTHOR]

Sentiment analysis is an essential task in natural language processing researches. Although existing works have gained much success with both statistical and neural-based solutions, little is known about the human decision process while performing this kind of complex cognitive task. Considering recent advances in human-inspired model design for NLP tasks, it is necessary to investigate the human reading and judging behavior in sentiment classification and adopt these findings to reconsider the sentiment analysis problem. In this paper, we carefully design a lab-based user study in which users' fine-grained reading behaviors during microblog sentiment classification are recorded with an eye-track device. Through systematic analysis of the collected data, we look into the differences between human and machine attention distributions and the differences in human attention while performing different tasks. We find that (1) sentiment judgment is more like an auxiliary task of content comprehension for humans. (2) people have different reading behavior patterns while reading microblog posts with varying labels of sentiment. Based on these findings, we build a human behavior-inspired sentiment prediction model for microblog posts. Experiment results on public-available benchmarks show that the proposed classification model outperforms existing solutions over 2.13% in terms of macro F1-score by introducing behavior features. Our findings may bring insight into the research of designing more effective and explainable sentiment analysis methods. [ABSTRACT FROM AUTHOR]

The HIV-1 coat protein gp120 continues to be implicated in the pathogenesis of HIV-1 associated neurocognitive disorder (HAND); a condition known to affect ~50% of people living with HIV-1 (PLWH). Autopsy brain tissues of HAND individuals display morphological changes to mitochondria and endolysosomes, and HIV-1 gp120 causes mitochondrial dysfunction including increased levels of reactive oxygen species (ROS) and de-acidification of endolysosomes. Ferrous iron is linked directly to ROS production, ferrous iron is contained in and released from endolysosomes, and PLWH have elevated iron and ROS levels. Based on those findings, we tested the hypothesis that HIV-1 gp120-induced endolysosome de-acidification and subsequent iron efflux from endolysosomes is responsible for increased levels of ROS. In U87MG glioblastoma cells, HIV-1 gp120 de-acidified endolysosomes, reduced endolysosome iron levels, increased levels of cytosolic and mitochondrial iron, and increased levels of cytosolic and mitochondrial ROS. These effects were all attenuated significantly by the endolysosome-specific iron chelator deferoxamine, by inhibitors of endolysosome-resident two-pore channels and divalent metal transporter-1 (DMT-1), and by inhibitors of mitochondria-resident DMT-1 and mitochondrial permeability transition pores. These results suggest that oxidative stress commonly observed with HIV-1 gp120 is downstream of its ability to de-acidify endolysosomes, to increase the release of iron from endolysosomes, and to increase the uptake of iron into mitochondria. Thus, endolysosomes might represent early and upstream targets for therapeutic strategies against HAND. [ABSTRACT FROM AUTHOR]

HIV-1 transactivator of transcription (Tat) protein is required for HIV-1 replication, and it has been implicated in the pathogenesis of HIV-1-associated neurocognitive disorder (HAND). HIV-1 Tat can enter cells via receptor-mediated endocytosis where it can reside in endolysosomes; upon its escape from these acidic organelles, HIV-1 Tat can enter the cytosol and nucleus where it activates the HIV-1 LTR promoter. Although it is known that HIV-1 replication is affected by the iron status of people living with HIV-1 (PLWH), very little is known about how iron affects HIV-1 Tat activation of the HIV-1 LTR promoter. Because HIV-1 proteins de-acidify endolysosomes and endolysosome de-acidification affects subcellular levels and actions of iron, we tested the hypothesis that the endolysosome pool of iron is sufficient to affect Tat-induced HIV-1 LTR transactivation. Ferric (Fe3+) and ferrous (Fe2+) iron both restricted Tat-mediated HIV-1 LTR transactivation. Chelation of endolysosome iron with deferoxamine (DFO) and 2–2 bipyridyl, but not chelation of cytosolic iron with deferiprone and deferasirox, significantly enhanced Tat-mediated HIV-1 LTR transactivation. In the presence of iron, HIV-1 Tat increasingly oligomerized and DFO prevented the oligomerization. DFO also reduced protein expression levels of the HIV-1 restriction agent beta-catenin in the cytosol and nucleus. These findings suggest that DFO increases HIV-1 LTR transactivation by increasing levels of the more active dimeric form of Tat relative to the less active oligomerized form of Tat, increasing the escape of dimeric Tat from endolysosomes, and/or reducing beta-catenin protein expression levels. Thus, intracellular iron might play a significant role in regulating HIV-1 replication, and these findings raise cautionary notes for chelation therapies in PLWH. [ABSTRACT FROM AUTHOR]

Extensive work has characterized endoplasmic reticulum (ER) and mitochondrial stress responses. In contrast, very little has been published about stress responses in lysosomes; subcellular acidic organelles that are physiologically important and are of pathological relevance. The greater lysosomal system is dynamic and is comprised of endosomes, lysosomes, multivesicular bodies, autophagosomes, and autophagolysosomes. They are important regulators of cellular physiology, they represent about 5% of the total cellular volume, they are heterogeneous in their sizes and distribution patterns, they are electron dense, and their subcellular positioning within cells varies in response to stimuli, insults and pH. These organelles are also integral to the pathogenesis of lysosomal storage diseases and it is increasingly recognized that lysosomes play important roles in the pathogenesis of such diverse conditions as neurodegenerative disorders and cancer. The purpose of this review is to focus attention on lysosomal stress responses (LSR), compare LSR with better characterized stress responses in ER and mitochondria, and form a framework for future characterizations of LSR. We synthesized data into the concept of LSR and present it here such that the definition of LSR can be modified as new knowledge is added and specific therapeutics are developed. [ABSTRACT FROM AUTHOR]

In the absence of regulatory guidelines for the bioanalysis of new drug modalities, many of which contain multiple functional domains, bioanalytical strategies have been carefully designed to characterize the intact drug and each functional domain in terms of quantity, functionality, biotransformation, and immunogenicity. The present review focuses on the bioanalytical challenges and considerations for RNA-based drugs, bispecific antibodies and multi-domain protein therapeutics, prodrugs, gene and cell therapies, and fusion proteins. Methods ranging from the conventional ligand binding assays and liquid chromatography-mass spectrometry assays to quantitative polymerase chain reaction or flow cytometry often used for oligonucleotides and cell and gene therapies are discussed. Best practices for method selection and validation are proposed as well as a future perspective to address the bioanalytical needs of complex modalities. [ABSTRACT FROM AUTHOR]

In order to provide some insight into the complex fluid behavior involved in ultrasonic vibration-assisted abrasive waterjet machining, a three-dimensional CFD model is established to investigate the cavitating characteristics. Governing equations of the impacting jet flow field are solved accompanied with the mass transfer equation which is based on Schnerr-Sauer cavitation model. Vibrating motion of the target surface is performed through adopting a moving wall boundary with dynamic mesh method. The evolution of cavitating bubbles and fluid pressure at the impact zone is analyzed. The results imply that the variation of vapor phase fraction has a close correspondence with the pressure fluctuation. Moreover, an increase of vibration amplitude can effectively enhance on the intensity of cavitation. The maximum volume fraction is increased by 78% with a 20 μm increase of amplitude. The experimental results indicate that irregular craters induced by cavitation are formed on the eroded surface when applying ultrasonic vibration to the workpiece. [ABSTRACT FROM AUTHOR]

The impact erosion of particle in abrasive waterjet has the features of short duration of time and small scale of the deformation area, which lead to difficulty on implementing comprehensive investigation. As a meshless method, smoothed particle hydrodynamics is appropriate for dealing with high strain rate and large deformation issues such as impact dynamics. In this work, the erosive wear of aluminum nitride target material induced by incident particle in ultrasonic-assisted abrasive waterjet machining was investigated through establishing a 3D hybrid smoothed particle hydrodynamics-finite elements model. The results indicated that the parameters such as particle shape, impact angle, and impact velocity have remarkable effects on the erosion mechanism. The ultrasonic vibration influences the dynamic process of particle penetration and the deformation of eroded target material. Multi-impacts were also simulated and the results indicated that the erosion was influenced by the overlapping condition and ultrasonic vibration. The numerical results were verified by the experiments utilizing the specially developed setup. [ABSTRACT FROM AUTHOR]

The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (Aβ) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase Aβ generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal Aβ generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced Aβ generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (AβPP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of Aβ as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of Aβ, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of Aβ. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent. [ABSTRACT FROM AUTHOR]

We studied the effects of perfluorooctane sulfonate (PFOS) on the chlorophyll content, cell permeability, and antioxidant defense systems of the green alga Chlorella vulgaris. The results showed that the production of reactive oxygen species increased in a concentration-dependent manner after exposure to PFOS for 96 h. Superoxide dismutase and catalase activity was elevated after exposure to the lower concentrations and then decreased with higher concentrations. Malondialdehyde content was significantly higher than that of controls at the higher PFOS concentrations. Cell membrane permeability increased. These results indicate that PFOS exposure leads to oxidative damage in C. vulgaris. At these concentrations, chlorophyll and the structure of chloroplasts were destroyed. [ABSTRACT FROM AUTHOR]

Background: Previous reports have shown that patients with bilateral primary breast cancer (BPBC) had comparable or moderately poor survival compared with patients experiencing unilateral primary breast cancer (UPBC). However, studies are conflicting in their analyses of correlations between survival and clinicopathological and prognostic characteristics in BPBC patients. The aim of our study was to compare the clinicopathological features and prognoses of BPBC and UPBC patients in Heilongjiang Province, northeast China. Methods: We retrospectively reviewed the records of 2,695 patients who underwent modified radical mastectomy or lumpectomy from 2005 to 2008 in the Tumor Hospital of Harbin Medical University. Eighty-one patients (3.0 %) had BPBC and 2,614 patients had UPBC. Multivariate analysis was performed using Cox's proportional hazards model. Results: There were significant differences between patients with BPBC and UPBC in the age of onset (referring to the age when the first tumor in BPBC was diagnosed), T stage, menopause status (referring to the age when the second tumor in BPBC was diagnosed), and breast cancer family history. The overall 5-year survival of patients with BPBC was 70.1 % compared with 87.1 % for patients with UPBC ( p = 0.004). Furthermore, multivariate analysis showed that HER-2 status, menopause status, and mammary disease history were significant factors affecting survival among the patients with BPBC. Conclusions: Our results confirmed previous findings that BPBC patients had moderately poor survival. However, when T stages were matched, BPBC patients had a survival rate similar to UPBC patients. Premenopause status, HER-2 positivity and family history of breast cancer were major risk factors for BPBC. [ABSTRACT FROM AUTHOR]

Magnesium lithospermate B (MLB) is one of the major bioactive components of Radix Salviae miltiorrhizae (Dan Shen), which is a Chinese traditional herbal medicine with therapeutic effects on cardiovascular and cerebrovascular diseases. The aim of this study was to investigate the neuroprotective effects of MLB on N-methyl- d-aspartic acid (NMDA)-injured neurons and against kainic acid (KA)-induced neurodegeration in mice. In cultured mouse primary hippocampal neurons, MLB significantly reduced NMDA-induced cell death and promoted neurite growth in a dose-dependent manner. In FVB mice, MLB attenuated KA-induced neurodegeneration. Additionally, MLB prevented the decrease in phosphorylated Akt and glycogen synthase kinase-3β (GSK-3β) levels both in NMDA-injured neurons and KA-injured mouse brain. This effect was blocked by phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and Akt inhibitor triciribine, thus indicating the neuroprotective effects of MLB are most likely mediated by the PI3K/Akt/GSK-3β pathway. Taken together, these results show the efficacy and underlying mechanism of MLB against neuronal injury and raise its therapeutic potential in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In the field of stem cell research, SP (side population) phenotype is used to define the property that cells maintain a high efflux capability for some fluorescent dye, such as Hoechst 33342. Recently, many researches proposed that SP phenotype is a phenotype shared by some stem cells and some progenitor cells, and that SP phenotype is regarded as a candidate purification marker for stem cells. In this research, murine fertilized ova (including conjugate and single nucleus fertilized ova), 2-cell stage and 8-cell stage blastomeres, morulas and blastocysts were isolated and directly stained by Hoechst 33342 dye. The results show that fertilized ovum, blastomere and morula cells do not demonstrate any ability to efflux the dye. However, the inner cell mass (ICM) cells of blastocyst exhibit SP phenotype, which is consistent with the result of embryonic stem cells (ESCs) in vitro. These results indicate that the SP phenotype of ICM-derived ESCs is an intrinsic property and independent of the culture condition in vitro, and that SP phenotype is one of the characteristics of at least some pluripotent stem cells, but is not shared by totipotent stem cells. In addition, the result that the SP phenotype of ICM cells disappeared when the inhibitor verapamil was added into medium implies that the SP phenotype is directly associated with ABCG2. These results suggest that not all the stem cells demonstrate SP phenotype, and that SP phenotype might act as a purification marker for partial stem cells such as some pluripotent embryonic stem cells and multipotent adult stem cells, but not for all stem cells exampled by the totipotent stem cells in the very early stage of mouse embryos. [ABSTRACT FROM AUTHOR]