The alteration and role of glycoconjugates in Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as ß-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-ß clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.

QALY-type preference and willingness-to-pay among end-of-life patients with cancer treatments: a pilot study using discrete choice experiment.

PURPOSE: Quality-adjusted life-year (QALY) is a dominant measurement of health gain in economic evaluations for pricing drugs. However, end-of-life (EoL) patients' preference for QALY gains in life expectancy (LE) and quality of life (QoL) during different disease stages remains unknown and is seldom involved in decision-making. This study aims to measure preferences and willingness-to-pay (WTP) towards different types of QALY gain among EoL cancer patients. METHODS: We attributed QALY gain to four types, gain in LE and QoL, respectively, and during both progression-free survival (PFS) and post-progression survival (PPS). A discrete choice experiment including five attributes (the four QALY attributes and one cost attribute) with three levels each was developed and conducted with 85 Chinese advanced non-small cell lung cancer patients in 2022. All levels were set with QALY gain/cost synthesised from research on anti-lung cancer drugs recently listed by Chinese National Healthcare Security Administration. Each respondent answered six choice tasks in a face-to-face interview. The data were analysed using mixed logit models. RESULTS: Patients valued LE-related QALY gain in PFS most, with a relative importance of 81.8% and a WTP of $43,160 [95% CI 26,751 ~ 59,569] per QALY gain. Respondents consistently preferred LE-related to QoL-related QALY gain regardless of disease stage. Patients with higher income or lower education levels tended to pay more for QoL-related QALY gain. CONCLUSION: Our findings suggest a prioritised resource allocation to EoL-prolonging health technologies. Given the small sample size and large individual heterogeneity, a full-scale study is needed to provide more robust results.

Arbidol: The current demand, strategies, and antiviral mechanisms.

BACKGROUND: High morbidity and mortality of influenza virus infection have made it become one of the most lethal diseases threatening public health; the lack of drugs with strong antiviral activity against virus strains exacerbates the problem. METHODS: Two independent researchers searched relevant studies using Embase, PubMed, Web of Science, Google Scholar, and MEDLINE databases from its inception to December 2022. RESULTS: Based on the different antiviral mechanisms, current antiviral strategies can be mainly classified into virus-targeting approaches such as neuraminidase inhibitors, matrix protein 2 ion channel inhibitors, polymerase acidic protein inhibitors and other host-targeting antivirals. However, highly viral gene mutation has underscored the necessity of novel antiviral drug development. Arbidol (ARB) is a Russian-made indole-derivative small molecule licensed in Russia and China for the prevention and treatment of influenza and other respiratory viral infections. ARB also has inhibitory effects on many other viruses such as severe acute respiratory syndrome coronavirus 2, Coxsackie virus, respiratory syncytial virus, Hantaan virus, herpes simplex virus, and hepatitis B and C viruses. ARB is a promising drug which can not only exert activity against virus at different steps of virus replication cycle, but also directly target on hosts before infection to prevent virus invasion. CONCLUSION: ARB is a broad-spectrum antiviral drug that inhibits several viruses in vivo and in vitro, with high safety profile and low resistance; the antiviral mechanisms of ARB deserve to be further explored and more high-quality clinical studies are required to establish the efficacy and safety of ARB.

Human monkeypox infection threat: A comprehensive overview.

BACKGROUND: In addition to the COVID-19 waves, the globe is recently facing global monkeypox (MPX) outbreak. As the daily confirmed cases of MPX infection across epidemic and nonepidemic countries are increasing, taking measures to control global pandemic remains crucial. Therefore, this review aimed to provide fundamental knowledge for the prevention and control of future outbreaks of this emerging epidemic. METHODS: The review was conducted using PubMed and Google Scholar databases; the search terms used were "monkeypox," "MPX tropism," "replication signaling of MPX," "biology and pathogenicity of MPX," "diagnosis of MPX," "treatment of MPX," "prevention of MPX," etc. The update epidemic data were collected from the websites of the World Health Organization (WHO), United States Centers for Disease Control and Prevention (CDC), and Africa Center for Disease Control and Prevention (ADCC). High-quality research results published in authoritative journals were summarized and preferred cited. Excluding all duplicates, non-English published references, and irrelevant literature, totally 1,436 articles were assessed for eligibility. RESULTS: It is still difficult to diagnose the patient as MPX simply based on clinical manifestations; therefore, under this situation, employing polymerase chain reaction (PCR) technology to provide confirmed evidence for the diagnosis of MPX seems to be the preferred and indispensable strategy. The treatment approach for MPX infection is mainly symptomatic and supportive; anti-smallpox virus drugs including tecovirimat, cidofovir, and brincidofovir can be employed in severe cases. Timely identification and isolation of confirmed cases, cutting off dissemination routes, and vaccination of close contacts are effective measures to control MPX. Also, smallpox vaccines (JYNNEOS, LC16m8, and ACAM2000) can be under consideration due to their immunological cross-protection among Orthopoxvirus. Nevertheless, given the low quality and scarcity of relevant evidence of current antiviral drugs and vaccines, deeply seeking for the MAPK/ERK, PAK-1, PI3K/Akt signaling, and other pathways involved in MPX invasion may provide potential targets for the treatment, prevention, and control of the epidemic. CONCLUSIONS: In response to the current MPX epidemic, the development of vaccines and antiviral drugs against MPX, as well as the rapid and precise diagnostic methods are still urgently needed. Sound monitoring and detection systems should be established to limit the rapid spread of MPX worldwide.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.

Systematic identification of the cancer pathways and molecules related with breast cancer immunogenicity.

To identify molecular features related to immunogenic activity in breast cancer (BC) and provide new targets and directions for BC immunotherapy, we firstly used ESTIMATE to evaluate the degree of immune cell infiltration of the BC patients in TCGA and METABRIC, and explore the relationship between the degree of immune cell infiltration and prognosis of BC patients. Then, we identified the cancer pathways, proteins and miRNAs related to BC immunogenicity, predicted the target genes of these miRNAs, and identified the pathways related to these target genes with KEGG pathway enrichment analysis. We also explored the correlation between PD-L1 expression level and cancer pathways and found that PD-L1 expression showed a positive association with cancer-related pathways. In this article we have successfully identified several cancer-related pathways, proteins, miRNAs, and their target genes, which provided promising new targets for BC immunotherapy. And PD-L1 blockade therapy may be more effective in BC patients with the activation of some cancer-related pathways.

Efficacy and safety of domestic and imported gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It was approved by the U.S. Food and Drug Administration (FDA) for clinical use in 2003. However, gefitinib has only come to China in recent years. Previous studies have not compared the efficacy and safety of domestic and imported gefitinib. Therefore, we conducted this study. METHODS: This study included 227 patients with advanced non-small cell lung cancer (NSCLC) who received gefitinib treatment in four medical institutions: The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Fudan University Shanghai Cancer Center, Shandong Provincial Institute of Cancer Prevention and Jiangsu Cancer Hospital, from January 2017 to July 2018. The patients were divided into a Yiruike group (55 patients treated with domestic gefitinib, Yiruike) and an Iressa group (172 patients treated with imported gefitinib, Iressa). Because gefitinib resistance usually occurs within 8-10 months of gefitinib administration, the patients were followed up for one year to observe their conditions and compare the occurrence of adverse reactions between the two groups. RESULTS: The two groups had no significant difference in baseline data. The median progression-free survival (PFS) of Yiruike group and that of Iressa group were 10.270±2.036 and 12.970±1.634 months, respectively. The mean PFS of Yiruike group and that of Iressa group were 12.598±1.083 and 15.958±0.987 months, respectively. The one-year disease control rate (DCR) of Yiruike group and that of Iressa group were 61.8% and 59.3%, respectively. The differences were all insignificant (P>0.05). The incidence of adverse reactions in these two groups were not significantly different. CONCLUSIONS: Yiruike was slightly superior to Iressa in terms of DCR. However, comparisons of bioequivalence and DCR were not sufficient for evaluating a drug. Other comparisons require long-term follow-up studies with a large sample size.

Esomeprazole overcomes paclitaxel-resistance and enhances anticancer effects of paclitaxel by inducing autophagy in A549/Taxol cells.

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies, and the occurrence of drug-resistance severely limits the efficacy of anticancer drugs in the treatment of NSCLC. Identification of new agents to reverse drug-resistance in NSCLC treatment is of great importance and urgency both clinically and scientifically. In the present study, we found that A549/Taxol cells displayed a high level of resistance to paclitaxel with the resistance index up to 231. Importantly, esomeprazole could potentiate the antiproliferative effect of paclitaxel in A549/Taxol cells, but not in A549 cells. Further exploration on the underlying mechanisms revealed that esomeprazole decreased the intracellular pH via inhibiting V-ATPase expression in A549/Taxol cells. Meanwhile, esomeprazole pretreatment significantly promoted paclitaxel-induced polymerization of tubulin and enhanced the proportion of G2/M-arrested cells in A549/Taxol cells. Unfortunately, esomeprazole could only result in a slight decrease in the expression of P-gp in A549/Taxol cells. Interestingly, esomeprazole significantly increased paclitaxel-induced apoptosis, which was impeded by the autophagy inhibitor 3-MA in A549/Taxol cells. Taken together, our data suggest that esomeprazole is a promising chemosensitizer against paclitaxel-resistant NSCLC by inducing autophagy. Our study also offers a new strategy to solve the paclitaxel-resistance problem during NSCLC treatment.

Comprehensive overview of COVID-19 based on current evidence.

In December 2019, twenty-seven pneumonia patients with unknown causes originated in South China seafood market in Wuhan. The virus infection spread rapidly and swept through China in less than a month. Subsequently, the virus was proven a novel coronavirus and named SARS-CoV-2. The outbreak of novel coronavirus has been determined as a Public Health Emergency of International Concern (PHEIC) by WHO on January 31, 2020. Similar to other coronaviruses like the Middle East Respiratory Syndrome (MERS) CoV and Severe Acute Respiratory Syndrome (SARS) CoV, the novel coronavirus was reported to spread via respiratory droplets and close contact from human to human, which means the virus is highly infectious and dangerous. Unfortunately, till now the virus has spread to over 200 countries/territories/areas around the world and the Coronavirus Disease 2019 (COVID-19) outbreak is continuing to grow. Currently, information sharing and transparency are essential for risk assessment and epidemic control in all endemic areas. In this article, we compared SARS-CoV-2 with SARS-CoV and influenza virus, discussed current researching progress of COVID-19, including clinical characteristics, pathological changes, treatment measures, and so on.