ABSTRACT Antimicrobial‐resistant bacteria, a growing worldwide concern, reduce the effectiveness of antibiotics against a wide range of microbial infections. Various bacterial species have quickly developed antibiotic resistance since the first mention of penicillin resistance in 1947. A rise in mortality, more extended hospital stays, more healthcare expenditures, and morbidity are all brought about by these bacteria that are resistant to antibiotics. To develop resistance, bacteria may undergo genetic changes, engage in horizontal gene transfer, produce β‐lactamase, activate efflux pumps, form biofilms, and alter their metabolism to become less susceptible to drugs. Environmental factors and sublethal antibiotic exposure exacerbate resistance, particularly in cases of persistent infections caused by biofilms. This tendency is prompted by the overuse of antibiotics in both human and veterinary medicine, as well as inadequate infection control measures and environmental pollution. This review presents an extensive survey of antimicrobial resistance across bacterial taxa, with a focus on the physiological and genetic processes underlying this phenomenon. It delves into the current therapeutic landscape and showcases cutting‐edge methods—such as artificial intelligence‐driven antibiotic discovery and resistance prediction—to inform the development of next‐generation antibiotics and containment systems.
Global, Regional, and National Burden of Nontraumatic Subarachnoid Hemorrhage
Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.
Burden of Ischemic and Hemorrhagic Stroke Across the US From 1990 to 2019
ImportanceStroke is a leading cause of death and disability in the US. Accurate and updated measures of stroke burden are needed to guide public health policies.ObjectiveTo present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and describe trends from 1990 to 2019 by age, sex, and geographic location.Design, Setting, and ParticipantsAn in-depth cross-sectional analysis of the 2019 Global Burden of Disease study was conducted. The setting included the time period of 1990 to 2019 in the US. The study encompassed estimates for various types of strokes, including all strokes, ischemic strokes, intracerebral hemorrhages (ICHs), and subarachnoid hemorrhages (SAHs). The 2019 Global Burden of Disease results were released on October 20, 2020.ExposuresIn this study, no particular exposure was specifically targeted.Main Outcomes and MeasuresThe primary focus of this analysis centered on both overall and age-standardized estimates, stroke incidence, prevalence, mortality, and DALYs per 100 000 individuals.ResultsIn 2019, the US recorded 7.09 million prevalent strokes (4.07 million women [57.4%]; 3.02 million men [42.6%]), with 5.87 million being ischemic strokes (82.7%). Prevalence also included 0.66 million ICHs and 0.85 million SAHs. Although the absolute numbers of stroke cases, mortality, and DALYs surged from 1990 to 2019, the age-standardized rates either declined or remained steady. Notably, hemorrhagic strokes manifested a substantial increase, especially in mortality, compared with ischemic strokes (incidence of ischemic stroke increased by 13% [95% uncertainty interval (UI), 14.2%-11.9%]; incidence of ICH increased by 39.8% [95% UI, 38.9%-39.7%]; incidence of SAH increased by 50.9% [95% UI, 49.2%-52.6%]). The downturn in stroke mortality plateaued in the recent decade. There was a discernible heterogeneity in stroke burden trends, with older adults (50-74 years) experiencing a decrease in incidence in coastal areas (decreases up to 3.9% in Vermont), in contrast to an uptick observed in younger demographics (15-49 years) in the South and Midwest US (with increases up to 8.4% in Minnesota).Conclusions and RelevanceIn this cross-sectional study, the declining age-standardized stroke rates over the past 3 decades suggest progress in managing stroke-related outcomes. However, the increasing absolute burden of stroke, coupled with a notable rise in hemorrhagic stroke, suggests an evolving and substantial public health challenge in the US. Moreover, the significant disparities in stroke burden trends across different age groups and geographic locations underscore the necessity for region- and demography-specific interventions and policies to effectively mitigate the multifaceted and escalating burden of stroke in the country.
The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories
ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Abstract Lung cancer has the highest mortality across all cancers in the world. Epidermal growth factor receptor (EGFR) is commonly mutated in lung adenocarcinomas from Asian non-smoking females. These tumors usually respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but the outcomes vary in different patients. Though EGFR T790M, amplification of MET and other mechanisms have been shown to confer EGFR-TKI resistance, the molecular mechanisms in around 30% of patients are still unknown. To uncover novel candidate pathways of EGFR-TKI resistance, we analyzed the whole exome mutation profiles of pre-treatment, EGFR T790M-free lung adenocarcinomas with typical activating mutations (L858R, exon 19 deletions). Amongst 19 non-responding (NR) tumors without significant shrinkage after gefitinib or erlotinib treatment, 67 cancer-related genes showed coding region non-synonymous single nucleotide variations (SNV) or insertion-deletions (indels) but they were not detected in 22 responding tumors. Gene set enrichment analysis (GSEA) showed 14 of the 67 genes were involved in the EGFR and WNT signaling network (false discovery rate q=1.14 e-8 for EGFR and q=4.3 e-9 for WNT), including well-known TKI resistance-related genes PIK3CA, PTEN and NF1. Notably, ARID1A, which encodes a subunit of the chromatin remodeling complex, showed nonsense mutations in 2 NR but not responding tumors, which were validated by Sanger sequencing. More than 40% of ARID1A mutations in lung adenocarcinomas recorded in COSMIC were nonsense mutations or frameshift indels. Loss of function mutations of ARID1A have also been reported in various cancers, together suggesting ARID1A might be a tumor suppressor but its involvement in EGFR mutant lung cancers is unknown. To investigate the potential role of ARID1A, its expression was first studied using Kaplan-Meier plotter. Low expression of ARID1A is associated with significantly better overall survival than high expression level in lung adenocarcinoma patients (p=8.5 e-7). To test whether loss of ARID1A could cause TKI resistance, ARID1A was knocked down by shRNA in HCC827 lung cancer cell line harboring EGFR exon19 deletion. MTT cell viability assay using gefitinib showed increase of IC50. Western blot assay further showed ARID1A knockdown increased phosphorylation of AKT at Ser473. Together, the findings suggest loss of ARID1A could lead to EGFR bypass and promote activation of the downstream PI3K/AKT pathway, leading to EGFR TKI resistance. Overall, our findings suggest EGFR-TKI resistance mutations could be detected before TKI drug selection. Resistant gene mutations present in pre-treatment tumors could help to predict the treatment response. More specifically, our study identified a promising gene list involved in EGFR-TKI resistance, and suggested ARID1A loss could be a novel EGFR-TKI resistance mechanism. Citation Format: Xuyuan Gao, Hang Xu, James CM Ho, Oscar SH Chan, Feng Xu, Junwen Wang, Victor HF Lee, Vicky PC Tin, Zhijie Xiao, Siqi Wang, Judy WP Yam, Maria P Wong. EGFR-mutant lung adenocarcinomas mutation profiles reveal ARID1A might be a novel tyrosine kinase resistance pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-196.
Author response: NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma
Abstract Lung cancer is the most lethal malignancy around the world. In Hong Kong, chronic tobacco use is prevalent in male but <20% of female patients smoke. Epidermal growth factor receptor (EGFR) mutations affect 30% and 67% of male and female lung adenocarcinomas, respectively. Treatment responses to tyrosine kinase inhibitors (TKI) are not uniform and all patients eventually develop drug resistance. Mutation screening of immediate pre-treatment tumors is the most ideal for assessing drug targets but in practice, excision specimens of primary or metastatic sites are more efficient in terms of tumor quantity, timeliness and patient acceptance. However, information on the applicability of this approach and correlation with the clinical outcome is limited. For this purpose, we compared the whole exome mutation profiles of 39 excised EGFR mutant cancers treated with first line TKI with the clinical response type, including 15 stage I/II and 24 stage III/IV tumors. They included 16 non-responders (NR) defined clinically as those with stable or progressive disease, and 23 responders (R) defined by partial or complete tumor shrinkage. Considering only the non-synonymous SNV and INDEL mutations of coding regions of known actionable targets and genes listed in both the CGC and COSMIC cancer databases, the tumors harbored 54 mutated genes including 26 recurrently mutated and 28 genes involving only 1 tumor. Excluding EGFR, TP53 was the most commonly mutated gene occurring in 25/39 (64.1%) cases. Most known resistant genes involved in the EGFR and bypass signaling network showed mutations only in the NR group including recurrent mutations of PTEN (3/16), PIK3CA (2/16) and NF1 (2/16), and single case mutations of AKT1, ALK, RAF1 and KDR. Two EGFR network candidates showed mutations in both the NR and R groups, including HGF (2/16 NR, 1/23 R) and ROS1 (1 case in either group). Four post-treatment (post-TKI) tumors of acquired resistance were also analyzed, all of which showed EGFR T790M while no pre-treatment NR or R tumor harbored this mutation. Notably, mutations in the β-catenin pathway were prominent in the NR and post-TKI tumors, including APC (2/16 NR), CTNNB1 (1/16 NR, 1/4 post-TKI) and c-MYC (1/16 NR, 1/4 post-TKI) while they were not detected in the R tumors. Also, nonsense mutations of ARID1A was observed in 2/16 NR but none of the R tumors. In summary, our findings revealed candidate TKI resistant mutations involving the EGFR and bypass signaling networks in pre-treatment excision specimens particularly in non-responding patients. The EGFR T790M was not detectable in pre-treatment samples but was prevalent in post-TKI treated cancers. While this study is limited by its small cohort size, the findings indicate deep sequencing analysis of pre-treatment excision specimens of EGFR-mutant lung adenocarcinomas is warranted for detection of resistant mutations and predicting treatment response. Note: This abstract was not presented at the meeting. Citation Format: Xu-yuan Gao, Hang Xu, James CM Ho, Oscar SH Chan, Feng Xu, Junwen Wang, Victor HF Lee, Vicky PC Tin, Zhijie Xiao, Siqi Wang, Judy WP Yam, Maria P. Wong. Whole-exome sequencing reveals tyrosine kinase-resistant mutations in pretreatment EGFR-mutant lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2017-LB-274
NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma
Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.