Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications

Autosomal dominant osteopetrosis type 2 (ADO2) is a high-density brittle bone disease characterized by bone pain,multiple fractures and skeletal-related events,including nerve compression syndrome and hematological failure.We demonstrated that in mice carrying the heterozygous Clcn7^G213R mutation,whose human mutant homolog CLCN7^G215R affects patients,the clinical impacts of ADO2 extend beyond the skeleton,affecting several other organs.The hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis,associated with high numbers of macrophages and lymphoid infiltrates.Fragmented clinical information in a small cohort of patients confirms extra-skeletal alterations consistent with a systemic disease,in line with the observation that the CLCN7 gene is expressed in many organs.ADO2 mice also show anxiety and depression and their brains exhibit not only perivascular fibrosis but also β-amyloid accumulation and astrogliosis,suggesting the involvement of the nervous system in the pathogenesis of the ADO2 extra-skeletal alterations.Extra-skeletal organs share a similar cellular pathology,confirmed also in vitro in bone marrow mononuclear cells and osteoclasts,characterized by an impairment of the exit pathway of the Clcn7 protein product,ClC7,through the Golgi,with consequent reduced ClC7 expression in late endosomes and lysosomes,associated with high vesicular pH and accumulation of autophagosome markers.Finally,an experimental siRNA therapy,previously proven to counteract the bone phenotype,also improves the extra-skeletal alterations.These results could have important clinical implications,supporting the notion that a systematic evaluation of ADO2 patients for extra-skeletal symptoms could help improve their diagnosis,clinical management,and therapeutic options.

Recent advances in immunotherapy for pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan and oxaliplatin),and gemcitabine plus nab-paclitaxel.Despite the improvement noted in these trials,PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance.The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments.Therapeutic vaccines,combination treatments,adoptive T cell transfer,as well as immunomodulators are being explored.With the emerging use of immunotherapy and immunomodulators,the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC.Overall,results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.