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Atypical hemolytic uremic syndrome (aHUS) is a rare disease triggered by dysregulation of the alternative complement pathway, consisting of a characteristic triad of nonimmune hemolytic anemia, thrombocytopenia, and renal failure. The risk of aHUS onset, recurrence, and allograft loss depends on the genetic background of a patient. We show a series of cases from a single family whose five members were affected by aHUS and presented distinct clinical outcomes. Next-generation sequencing revealed combined mutations in both complement factor H and membrane cofactor protein CD46. Out of eight siblings, aHUS affected three adult brothers, and, subsequently, affected two children of an unaffected sister. The first patient died due to aHUS, and two other brothers underwent successful kidney transplantation with no aHUS recurrence. The younger, 10-month-old child presented with a severe course of the disease with cardiac involvement and persistent hemolytic anemia limited by eculizumab, while the 2-year-old recovered completely on eculizumab. The study shows a highly variable disease penetrance.

Background Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients’ phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. Methods We employed next‐generation sequencing to identify mutations in culpable genes. Results and Conclusion In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients’ family revealed that the mutation occurred de novo in the proband and was transmitted to his 26‐month‐old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult., In this study, we have identified a family with two members affected by brachydactyly type A2 caused by BMPR1B mutation.

Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative&mdash, OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.

// Halina Was 1, 2 , Kamila Barszcz 1, 2 , Joanna Czarnecka 1, 2 , Agata Kowalczyk 3 , Tytus Bernas 4 , Ewelina Uzarowska 5 , Paulina Koza 5, 6 , Agata Klejman 5 , Katarzyna Piwocka 3 , Bozena Kaminska 2 , Eva Sikora 1 1 Laboratory of Molecular Basis of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 2 Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 3 Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 4 Laboratory of Imaging Tissue Structure and Function, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 5 Laboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 6 Laboratory of Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland Correspondence to: Halina Was, email: h.was@nencki.gov.pl Keywords: colon cancer, chemotherapy, senescence, autophagy, angiogenesis Received: June 07, 2016 Accepted: December 12, 2016 Published: December 21, 2016 ABSTRACT Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent – doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls. Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment.

Atypical hemolytic-uremic syndrome (aHUS) results from excessive, uncontrolled activation of the alternative pathway of the complement system. It is important to distinguish aHUS from other thrombotic microangiopathies. The aim of this paper is to discuss the complexity and relevance of the genetic background of aHUS patients. The review discusses the genetic variants that are important for diagnosis, treatment and prognosis of patients, which is inevitably important for the qualification of patients for treatment with eculizumab. These variants are not only found in the genes involved in the control of complement system but are also related to the coagulation system. The paper emphasizes the diagnostic difficulties resulting from the extremely diverse genetic background of the patients. It is important to conduct further genetic studies of aHUS patients, also paying attention to genes unrelated to the complement system. The paper contains information on the role of genetic predisposition in tailoring the risk for aHUS and determining its clinical outcome, including qualification for eculizumab therapy.