The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

Cellular senescence is a stress response program characterized by a robust cell cycle arrest and the induction of a proinflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that, during oncogene-induced senescence (OIS), the Toll-like receptor 2 (TLR2) and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumor suppressors p53-p21 , p16 , and p15 and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAAs) that, in turn, function as the damage-associated molecular patterns (DAMPs) signaling through TLR2 in OIS. Last, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAAs expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS

Towards a roadmap for COSEB: the next steps in harmonization of outcomes for epidermolysis bullosa

The COSEB initiative aims for standardized and uniform measurement by developing core outcome sets for epidermolysis bullosa. This report describes the COSEB workshop organized in December 2023, which led to a broad stakeholder consensus-based roadmap. Moreover, it highlights novel features of COSEB, including the pro-active engagement of stakeholders from the very beginning and the appointment of a multi-stakeholder advisory panel

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Background Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Methods Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. Results The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). Conclusions G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

Holocene climate variability, vegetation dynamics and fire regime in the central Pyrenees: the Basa de la Mora sequence (NE Spain)

High resolution multiproxy data (pollen, sedimentology, geochemistry, chironomids and charcoal) from the Basa de la Mora (BSM) lake sequence (42° 32′ N, 0° 19′ E, 1914 m a.s.l.) show marked climate variability in the central southern Pyrenees throughout the Holocene. A robust age model based on 15 AMS radiocarbon dates underpins the first precise reconstruction of rapid climate changes during the Holocene from this area. During the Early Holocene, increased winter snowpack and high snowmelt during summer, as a consequence of high seasonality, led to higher lake levels, a chironomid community dominated by non-lacustrine taxa (Orthocladiinae) related to higher inlet streams, and a forested landscape with intense run-off processes in the watershed. From 9.8 to 8.1 cal ka BP, climate instability is inferred from rapid and intense forest shifts and high fluctuation in surface run-off. Shifts among conifers and mesophytes reveal at least four short-lived dry events at 9.7, 9.3, 8.8 and 8.3 cal ka BP. Between 8.1 and 5.7 cal ka BP a stable climate with higher precipitation favoured highest lake levels and forest expansion, with spread of mesophytes, withdrawal of conifers and intensification of fires, coinciding with the Holocene Climate Optimum. At 5.7 cal ka BP a major change leading to drier conditions contributed to a regional decline in mesophytes, expansion of pines and junipers, and a significant lake level drop. Despite drier conditions, fire activity dropped as consequence of biomass reduction. Two arid intervals occurred between 2.9 and 2.4 cal ka BP and at 1.2–0.7 cal ka BP (800–1300 AD). The latter coincides with the Medieval Climate Anomaly and is one of the most arid phases of the Holocene in BSM sequence. Anthropogenic disturbances were small until 700 AD, when human pressure over landscape intensified, with Olea cultivation in the lowlands and significant deforestation in highlands. Colder and unfavourable weather conditions during the second part of the Little Ice Age caused a temporary cease of high-land management. The most intense anthropogenic disturbances occurred during the second half of 19th century. Last decades are characterized by recovery of the vegetation cover as a result of land abandonment, and lowered lake levels, probably due to higher temperatures

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT autoimmune diseases working party (ADWP) and the joint accreditation committee of EBMT and ISCT (JACIE)

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials

Condensin II mutation causes T cell lymphoma through tissue-specific genome instability

Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2nes) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4+CD8+ T-cell stage from which tumors initiate. Premalignant CD4+CD8+ T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 single-mutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis