Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover ...novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10
) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.
This commentary is on the original articles by Palacios‐Ceña et al. and Robertson et al. on pages 195–205 and 206–215 of this issue.
Chinese translation of this Commentary is available in the online ...issue.
Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have ...rarely been performed in these populations.
We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients.
Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions.
We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.
The present research examined the effectiveness of digital storytelling (DST) on foreign language learners' English speaking and creative thinking. In this study, DST was realized in the form of an ...interdisciplinary project integrated in a partnership between an English course and a computer course, with the class time of the former devoted to the content design and that of the latter to the multimedia design of learner-generated digital stories. The participants were required to work in small groups to create their digital stories in the target language, English, under an eight-week interdisciplinary curriculum. A two-group quasi-experiment with a pretest and posttest design was then conducted to compare the participants' learning outcomes. The findings reveal the authentic and meaningful learning opportunities that DST has to offer for effectively fostering the students' development of becoming proficient English speakers and creative thinkers. Future implementations on interdisciplinary DST projects are thus recommended for educators.
Herein, we report the photocatalytic decarboxylative alkenylation reactions of N-(acyloxy)phthalimide derived from α-amino and α-hydroxy acids with 1,1-diarylethene, and with cinnamic acid ...derivatives through double decarboxylation, using sodium iodide and triphenylphosphine as redox catalysts. The reaction proceeds under mild irradiation conditions with visible blue light (440 nm or 456 nm) in an acetone solvent without recourse to transition-metal or organic dye based photoredox catalysts. The reaction proceeds via photoactivation of a transiently self-assembled chromophore from N-(acyloxy)phthalimide and NaI/PPh3. Solvation plays a crucial role in the reactivity.
The COVID-19 pandemic has disrupted healthcare, including immunization practice and well child visit attendance. Maintaining vaccination coverage is important to prevent disease outbreaks and ...morbidity. We assessed the impact of the COVID-19 pandemic on pediatric and adolescent vaccination administration and well child visit attendance in the United States.
This cross-sectional study used IBM MarketScan Commercial Database (IMC) with Early View (healthcare claims database) and TriNetX Dataworks Global Network (electronic medical records database) from January 2018–March 2021. Individuals ≤ 18 years of age who were enrolled during the analysis month of interest (IMC with Early View) or had ≥ 1 health encounter at a participating institution (TriNetX Dataworks) were included. We calculated the monthly percent difference between well child visit attendance and vaccine administration rates for 10 recommended pediatric/adolescent vaccines in 2020 and 2021 compared with 2018–2019. Data were stratified by the age groups 0–2 years, 4–6 years, and 9–16 years.
In IMC with Early View, the average monthly enrollment for children 0–18 years of age was 5.2 million. In TriNetX Dataworks, 12.2 million eligible individuals were included. Well child visits and vaccinations reached the lowest point in April 2020 compared with 2018–2019. Well child visit attendance and vaccine administration rates were inversely related to age, with initial reductions highest for adolescents and lowest for ages 0–2 years. Rates rebounded in June and September 2020 and stabilized to pre-pandemic levels in Fall 2020. Rates dropped below baseline in early 2021 for groups 0–2 years and 4–6 years.
We found substantial disruptions in well child visit attendance and vaccination administration for children and adolescents during the COVID-19 pandemic in 2020 and early 2021. Continued efforts are needed to monitor recovery and catch up to avoid outbreaks and morbidity associated with vaccine-preventable diseases.
Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical ...practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant
(CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with
activity against CRE; and eravacycline, which is a tetracycline class antibacterial with
activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.
Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis ...has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.
Aims
Although the morphological assessment of melanoma is generally straightforward, diagnosis can be especially difficult when the significant morphological and immunohistochemical results overlap ...with those of benign and malignant melanocytic tumours and histological mimics. This study assessed the potential diagnostic utility of measuring PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemically in naevi, melanomas and clear cell sarcomas (CCSs) in Chinese patients.
Methods
We examined the immunohistochemical expression of PRAME in 317 melanocytic naevi, 178 primary melanomas, 72 metastatic melanomas and 19 CCSs and compared the sensitivity and specificity of PRAME immunohistochemistry (IHC) in the differential diagnosis of melanocytic tumours and histological mimics.
Results
Of the 317 melanocytic naevi, 98.1%were completely negative for PRAME; six cases showed focal PRAME immunoreactivity in a minor population of lesional melanocytes. Diffuse nuclear immunoreactivity for PRAME was found in 89.9% of primary melanomas and 93.1% of metastatic melanomas. Regarding melanoma subtypes, PRAME was expressed in 100% of superficial spreading melanomas, 100% of melanomas arise in congenital naevus, 91.4% of nodular melanomas, 87.8% of acral lentigo melanomas, 80.0% of lentigo malignant melanomas, 60.0% of Spitz melanomas, 96.2% of mucosal melanomas and 80.0% of uveal melanomas. None of the two desmoplastic melanomas expressed PRAME. Of the 19 CCS cases, 89.5% were negative for PRAME and 10.5% showed focal weak PRAME immunoreactivity in a minor population of tumour cells.
Conclusions
Our findings indicate that PRAME may be a useful marker to support a suspected diagnosis of melanoma. In addition, lack of PRAME expression is a valuable hint to CCS in a suspected case, and then molecular confirmation of the presence of EWSR1 rearrangement is necessary.
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