Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC

Perception of the 2020 SARS-CoV-2 pandemic among medical professionals in Germany: results from a nationwide online survey

Background:The COVID-19 pandemic represents an unprecedented global challenge and implicates a wide range of burden on medical professionals. Here, we evaluated the perception of the COVID-19 pandemic among medical professionals in Germany. Methods:A total ofn = 2827 medical professionals participated in an online survey between 27 March and 11 April. Results:While most participants stated that Germany was well prepared and rated the measures taken by their employer as positive, subgroup analyses revealed decisive differences. The preventive measures were rated significantly worse by nurses compared to doctors (p < 0.001) and by participants from ambulatory healthcare centres compared to participants from maximum-care hospitals (p < 0.001). Importantly, shortage of protective medical equipment was reported more commonly in the ambulatory sector (p < 0.001) and in East German federal states (p = 0.004). Moreover, the majority of health care professionals (72.4%) reported significant restrictions of daily work routine. Finally, over 60% of medical professionals had concerns regarding their own health, which were more pronounced among female participants (p = 0.024). Conclusion:This survey may indicate starting points on how medical professionals could be supported in carrying out their important activities during the ongoing and future healthcare challenges

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

This paper deals with the use of reported speech (RS) in Spanish criminal lawsuits (querellas) and police reports (denuncias) and argues about the most suitable strategies to translate such RS into Italian. In line of principle, the written record of the statements made by the individual(s) who filed the complaint is often the result of an oral cooperation between the plaintiff and the police officer and/or their attorney, whose subjectivity is reflected on the texts in a quite different fashion in the two legal cultures. The so-called ‘verbatim assumption’ of quotations in direct speech (DS) turns out to be a fallacy in the discussed genres, insofar as the locutor (i.e. the police officer or the attorney responsible for the drafting of the document) often normalizes the original utterances of the enunciator (i.e. the plaintiff whose point of view is represented in the report) in terms of cohesion, register and sentence length. Usually, these texts are translated following a strictly ‘interlinear approach’, so much so as to result almost illegible. An adequate command  of genre conventions – both in the source and in the target language – and the abidance by the translation universals of simplification and explicitation may help the translator produce a more efficient and readable target text, consistent with the expectations of a jurist in the target culture

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models