Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

Aging: immune protein's role in delayed bone fracture healing Neutralizing a key cytokine, a signaling protein affecting the immune system could rejuvenate the healing process following prolonged inflammatory responses to bone fractures in elderly patients. Healing patterns vary widely in the elderly following injuries such as bone fractures, and scientists now believe that a patient's individual innate and adaptive immune profile directly affects the healing process. A short-lived pro-inflammatory response is needed to kickstart healthy healing, but a longer-lasting response can be damaging. In experiments on aged mouse models, the team led by Katharina Schmidt-Bleek at the Julius Wolff Institute in Berlin, Germany, demonstrated that high levels of the cytokine interleukin-22 impaired bone regeneration. Elevated interleukin-22 levels resulted from chronically elevated inflammation and inflammaging, prevalent in elderly patients. The team treated the mice to neutralize interleukin-22, which accelerated the healing process. With increasing age, the risk of bone fractures increases while regenerative capacity decreases. This variation in healing potential appears to be linked to adaptive immunity, but the underlying mechanism is still unknown. This study sheds light on immunoaging/inflammaging, which impacts regenerative processes in aging individuals. In an aged preclinical model system, different levels of immunoaging were analyzed to identify key factors that connect immunoaged/inflammaged conditions with bone formation after long bone fracture. Immunological facets, progenitor cells, the microbiome, and confounders were monitored locally at the injury site and systemically in relation to healing outcomes in 12-month-old mice with distinct individual levels of immunoaging. Bone tissue formation during healing was delayed in the immunoaged group and could be associated with significant changes in cytokine levels. A prolonged and amplified pro-inflammatory reaction was caused by upregulated immune cell activation markers, increased chemokine receptor availability and a lack of inhibitory signaling. In immunoaged mice, interleukin-22 was identified as a core cell signaling protein that played a central role in delayed healing. Therapeutic neutralization of IL-22 reversed this specific immunoaging-related disturbed healing. Immunoaging was found to be an influencing factor of decreased regenerative capacity in aged individuals. Furthermore, a novel therapeutic strategy of neutralizing IL-22 may successfully rejuvenate healing in individuals with advanced immune experiences

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

Sarcoma of the sella after radiotherapy for pituitary adenoma

Secondary malignancies are infrequent sequelae of pituitary radiotherapy. The goal of the present case study is to analyze clinical features of a selected group of cases to define the special characteristics of these tumors. We report the illustrative case of a 38-year-old man with acromegaly who had transsphenoidal surgery and radiotherapy 7 years before presenting with a sellar high-grade sarcoma. Transsphenoidal and transcranial resection, as well as repeated gamma knife radiosurgery, could not prevent tumor progression and development of meningiosis sarcomatosa. We performed a thorough search of the literature and reviewed numerous publications and reports on primary and secondary sarcomas of the sella. Our search revealed 51 cases of mesenchymal malignancies after sellar radiotherapy. For further analysis, we identified and selected a group of patients based on the criteria for studying radiation-induced tumors as described by Cahan.Compared to the surgically treated group, secondary sarcomas of the sella are more frequent in patients who have had radiotherapy. These tumors occur at normal dose schedules with long latencies. Their growth is very aggressive and they may develop meningiosis sarcomatosa. Until now, no treatment modalities have been able to stop the progression of these neoplasms. Radiation-induced sarcoma is a rare sequela of pituitary radiotherapy. It is important for the treating physician to keep in mind the possibility of post-radiation sarcoma development. Additionally, one must include these tumors into the differential diagnosis in pituitary patients presenting with tumor recurrence more than 5 years after radiotherapy in combination with a secondary lack of hormonal activity