m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma. © 2019, The Author(s)

Cost-effectiveness analysis of toripalimab for metastatic or recurrent triple-negative breast cancer

BackgroundToliparibizumab in combination with nab-paclitaxel (T+N) has excellent efficacy inmetastatic or recurrent triple-negative breast cancer (TNBC), but the optimal choice of sequence of therapy is unclear given the trade-offs between quality of life and cost. Cost-effectiveness analyses can quantify these tradeoffs, leading to more informed decisions. Our objective was to assess the societal cost-effectiveness of the T+N regimen for metastatic or recurrent TNBC.MethodsClinical data were extracted from a multicenter, randomized, double-blind trial, TORCHLIGHT (NCT04085276). Patients were randomized into the T+N group or placebo plus nab-paclitaxel (P+N) group. 531 patients from 53 study locations were randomly assigned (T+N, n=353; P+N, n=178) into intend to treat (ITT) population; 200 and 100 patients, respectively had programmed death protein 1 (PD-L1) positive TNBC. A Markov model was established with a 21-day cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER).ResultsThe cost differences were 47,538.3 CNY in ITT population (T+N, 143,725.67 CNY; P+N group, 96,187.37 CNY) and 29,258.84 CNY in PD-L1+ subgroup (T+N, 100,128.28 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs were 0.03409 in the ITT population (T+N, 0.55323 QALY; P+N, 0.51914 QALY) and 0.03409 in the PD-L1+ subgroup (T+N, 0.42327 QALY; P+N, 0.37628 QALY). The ICERs between T+N and P+N groups were 1,394,548.41 CNY/QALY in the ITT population and 622,663.98 CNY/QALY in the PD-L1+ subgroup. We also analyzed the cost-effectiveness of toripalimab could be received in the Chinese medical insurance catalog. If toripalimab could be reimbursed at an 80% rate, the cost differences were changed to 16,598.99 CNY in ITT population (T+N, 112,786.36 CNY; P+N group, 96,187.37 CNY) and 7,704.58 CNY in PD-L1+ subgroup (T+N, 78,574.03 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs remained unchanged. The ICERs between T+N and P+N groups were changed to 486,935.82 CNY/QALY in the ITT population and 163,962.96 CNY/QALY in the PD-L1+ subgroup. Sensitivity analyses indicated the stability of the model and the impact of utility.ConclusionAt current drug prices, the T+N group is not more cost-effective than the P+N group, but after incorporating toripalimab into medical insurance, the T+N group will be more cost-effective for patients with PD-L1+ metastatic or recurrent triple-negative breast cancer

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance

Incorporating Participatory Action Research in Attention Bias Modification Interventions for Addictive Disorders: Perspectives

Participatory action research was introduced in the 1960s and early 1970s, but it has only been more widely adopted in the recent years. Such methodologies have since been applied to several web & mobile-based interventions in psychiatry. To date no prior review has scoped the extent of the application of such methodologies for web & mobile-based interventions in psychiatry. In this article, a scoping literature review was performed, and seven articles have been identified. The most common methodologies are that of co-design workshops; and increasingly service users and participants are included in these workshops. There remains a lack of application of such methodologies for addiction research. Increasingly, attention and cognitive bias modification interventions are more commonplace, given that they have been found to be effective in modifying underlying biases amongst individuals with addictive disorders. Unfortunately, there remains to be inherent limitations with web and mobile versions of attention and cognitive bias modification interventions. Participatory design research methods could help address these limitations and future research involving the conceptualization of new attention or cognitive bias modification applications ought to consider the incorporation of these research methods

Can Digital Finance Narrow the Household Consumption Gap of Residents on Either Side of the Hu Line?

The Hu line is a geo-demographic demarcation line in China. The eastern side of the line supports more than 96% of the population, despite constituting less than 44% of the national territory. The domestic household consumption level gradually exhibited an asymmetrical spatial pattern, with the Hu line serving as a demarcation line spanning from the north to the south. Continuous advancements in network and digital development domestically have allowed for an integration of digital technology with traditional financial services, thereby creating digital finance. Based on this, can digital finance narrow the household consumption gap among residents on both sides of the Hu line? By applying a geographical detector that could empirically detect the spatial causality, this paper aimed to explore whether digital finance can narrow the gap between the consumption levels of residents on both sides of the Hu line. The study results indicated that digital finance was a key factor influencing domestic household consumption. Combining digital finance with other factors such as marketization degree, the urban–rural income gap, and the urbanization level, our understanding of how it affects household consumption was further enhanced. Digital finance and household consumption levels had the same spatial structure, with the Hu line serving as their spatial axis. Additionally, the southeast side of the Hu line had significantly higher consumption levels than the northwest side. Digital finance in provinces on the southeast side of the line improved household consumption and simultaneously shared the positive benefits with neighboring provinces. In contrast, digital finance in provinces on the northwest side of the line decreased household consumption and shared this negative impact with neighboring provinces. We believe this study has provided a new perspective for academia to explore the relationship between the development of digital finance and residents’ consumption levels

Joint Strategy of Dynamic Ordering and Pricing for Competing Perishables with Q-Learning Algorithm

We use Machine Learning (ML) to study firms’ joint pricing and ordering decisions for perishables in a dynamic loop. The research assumption is as follows: at the beginning of each period, the retailer prices both the new and old products and determines how many new products to order, while at the end of each period, the retailer decides how much remaining inventory should be carried over to the next period. The objective is to determine a joint pricing, ordering, and disposal strategy to maximize the total expected discounted profit. We establish a decision model based on Markov processes and use the Q-learning algorithm to obtain a near-optimal policy. From numerical analysis, we find that (i) the optimal number of old products carried over to the next period depends on the upper quantitative bound for old inventory; (ii) the optimal prices for new products are positively related to potential demand but negatively related to the decay rate, while the optimal prices for old products have a positive relationship with both; and (iii) ordering decisions are unrelated to the quantity of old products. When the decay rate is low or the variable ordering cost is high, the optimal orders exhibit a trapezoidal decline as the quantity of new products increases

Web-based cognitive bias modification interventions for psychiatric disorders : scoping review

Background: Cognitive biases refer to automatic attentional or interpretational tendencies, which result in individuals with addictive disorders to automatically attend to substance-related stimuli and those with anxiety disorders to attend to threatening stimuli. To date, several studies have examined the efficacy of cognitive bias modification, and meta-analytical studies have synthesized the evidence for overall efficacy. The clinical utility of cognitive bias modification interventions has previously been limited to the confines of a laboratory, but recent advances in Web technologies can change this. Objective: This scoping review aimed to determine the scope of Web-based cognitive bias interventions and highlight their effectiveness. Methods: Databases (PubMed and MEDLINE, EMBASE, PsycINFO, ScienceDirect, and Cochrane Central) were searched from inception to December 5, 2017. The following search terminologies were used: (“attention bias” OR “cognitive bias” OR “approach bias” OR “avoidance bias” OR “interpretative bias”) AND (“Internet” OR “Web” OR “Online”). The methods for this scoping review are based on the previously published protocol. For the synthesis of the evidence, a narrative synthesis was undertaken, as a meta-analysis was not appropriate, given the lack of reported effect sizes and the heterogeneity in the outcomes reported. Results: Of the 2674 unique articles identified, we identified 22 randomized controlled studies that met our inclusion criteria: alcohol use disorder (n=2), tobacco use disorder (n=2), depressive disorder (n=3), anxiety and depressive symptoms in adolescents (n=3), obsessive-compulsive disorder (OCD; n=2), social anxiety disorder (n=9), and anxiety disorder (n=1). The sample sizes of these studies ranged from 16 to 434 participants. There is preliminary evidence to suggest that Web-based interventions could reduce biases among adolescents with heightened symptoms of anxiety and depression and among individuals with OCD. Conclusions: This is the first scoping review that mapped out the scope of cognitive bias modification interventions for psychiatric disorders. Web-based interventions have been applied predominantly for social anxiety and addictive disorders. Larger cohorts must be used in future studies to better determine the effectiveness of Web-based cognitive bias interventions.Published versio