Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignancies. For instance, in lung cancer, however, only 20~30% of patients can achieve durable clinical benefits from ICI monotherapy. Histopathologic and molecular features such as histological type, PD-L1 expression, and tumor mutation burden (TMB), play a paramount role in selecting appropriate regimens for cancer treatment in the era of immunotherapy. Unfortunately, none of the existing features are exclusive predictive biomarkers. Thus, there is an imperative need to pinpoint more effective biomarkers to identify patients who may achieve the most benefit from ICIs. The adoption of digital pathology in clinical flow, as being powered by artificial intelligence (AI) especially deep learning, has catalyzed the automated analysis of tissue slides. With the breakthrough of multiplex bioimaging technology, researchers can comprehensively characterize the tumor microenvironment, including the different immune cells' distribution, function, and interaction. Here, we briefly summarize recent AI studies in digital pathology and share our perspective on emerging paradigms and directions to advance the development of immunotherapy biomarkers.
{"title":"Artificial Intelligence in Digital Pathology to Advance Cancer Immunotherapy.","authors":"Pingjun Chen, Jianjun Zhang, Jia Wu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignancies. For instance, in lung cancer, however, only 20<sup>~</sup>30% of patients can achieve durable clinical benefits from ICI monotherapy. Histopathologic and molecular features such as histological type, PD-L1 expression, and tumor mutation burden (TMB), play a paramount role in selecting appropriate regimens for cancer treatment in the era of immunotherapy. Unfortunately, none of the existing features are exclusive predictive biomarkers. Thus, there is an imperative need to pinpoint more effective biomarkers to identify patients who may achieve the most benefit from ICIs. The adoption of digital pathology in clinical flow, as being powered by artificial intelligence (AI) especially deep learning, has catalyzed the automated analysis of tissue slides. With the breakthrough of multiplex bioimaging technology, researchers can comprehensively characterize the tumor microenvironment, including the different immune cells' distribution, function, and interaction. Here, we briefly summarize recent AI studies in digital pathology and share our perspective on emerging paradigms and directions to advance the development of immunotherapy biomarkers.</p>","PeriodicalId":72035,"journal":{"name":"21st century pathology","volume":"2 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10277526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arijita Chakraborty, Andre Grageda, Vladimir A Kuznetsov, Wenyi Feng
Our understanding of the molecular functions of the nucleocytoplasmic FMRP protein, which, if absent or dysfunctional, causes the fragile X syndrome (FXS), largely revolves around its involvement in protein translation regulation in the cytoplasm. Recent studies have begun honing in on the nuclear and genomic functions of FMRP. We have shown that during DNA replication stress, cells derived from FXS patients sustain increased level of R-loop formation and DNA double strand breaks. Here, we describe a transcriptomic analysis of these cells in order to identify those genes most impacted by the loss of FMRP with and without replication stress. We show that FMRP loss causes transcriptomic changes previously reported in untreated conditions. Importantly, we also show that replication stress, in addition to causing excess of DSB, results in down-regulation of transcription in virtually all DNA repair pathways. This finding suggests that despite normal DNA damage response, FXS patient-derived cells experience R-loop-induced DNA breakage as well as impaired DNA repair functions, effectively a double jeopardy. We suggest that it is imperative to deepen the understanding of the nuclear functions, particularly a genome protective function, of FMRP, which will lead to discoveries of novel therapeutic interventions for the FXS.
我们对核细胞质 FMRP 蛋白分子功能的了解主要围绕其在细胞质中参与蛋白质翻译调控的过程。FMRP 蛋白一旦缺失或功能障碍，就会导致脆性 X 综合征（FXS）。最近的研究开始深入探讨 FMRP 的核功能和基因组功能。我们发现，在 DNA 复制应激过程中，FXS 患者的细胞中 R 环的形成和 DNA 双股断裂的程度会增加。在此，我们描述了对这些细胞进行的转录组分析，以确定在复制应激和非复制应激情况下，哪些基因受 FMRP 缺失的影响最大。我们发现，FMRP 的缺失会导致转录组发生变化，这些变化以前在未处理的情况下已有报道。重要的是，我们还发现复制应激除了会导致过量的 DSB 外，还会导致几乎所有 DNA 修复途径的转录下调。这一发现表明，尽管DNA损伤反应正常，但FXS患者衍生细胞在经历R环诱导的DNA断裂的同时，DNA修复功能也会受损，这实际上是一种双重危害。我们认为，当务之急是加深对 FMRP 的核功能，尤其是基因组保护功能的认识，这将有助于发现 FXS 的新型治疗干预措施。
{"title":"A Double Jeopardy: Loss of FMRP Results in DSB and Down-regulated DNA Repair.","authors":"Arijita Chakraborty, Andre Grageda, Vladimir A Kuznetsov, Wenyi Feng","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Our understanding of the molecular functions of the nucleocytoplasmic FMRP protein, which, if absent or dysfunctional, causes the fragile X syndrome (FXS), largely revolves around its involvement in protein translation regulation in the cytoplasm. Recent studies have begun honing in on the nuclear and genomic functions of FMRP. We have shown that during DNA replication stress, cells derived from FXS patients sustain increased level of R-loop formation and DNA double strand breaks. Here, we describe a transcriptomic analysis of these cells in order to identify those genes most impacted by the loss of FMRP with and without replication stress. We show that FMRP loss causes transcriptomic changes previously reported in untreated conditions. Importantly, we also show that replication stress, in addition to causing excess of DSB, results in down-regulation of transcription in virtually all DNA repair pathways. This finding suggests that despite normal DNA damage response, FXS patient-derived cells experience R-loop-induced DNA breakage as well as impaired DNA repair functions, effectively a double jeopardy. We suggest that it is imperative to deepen the understanding of the nuclear functions, particularly a genome protective function, of FMRP, which will lead to discoveries of novel therapeutic interventions for the FXS.</p>","PeriodicalId":72035,"journal":{"name":"21st century pathology","volume":"2 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/91/cf/nihms-1863323.PMC9850805.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10604397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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