Summary Following fertilization, totipotent cells undergo asymmetric cell divisions, resulting in three distinct cell types in the late pre-implantation blastocyst: epiblast (Epi), primitive endoderm (PrE), and trophectoderm (TE). Here, we aim to understand whether these three cell types can be induced from fibroblasts by one combination of transcription factors. By utilizing a sophisticated fluorescent knockin reporter system, we identified a combination of five transcription factors, Gata3, Eomes, Tfap2c, Myc, and Esrrb, that can reprogram fibroblasts into induced pluripotent stem cells (iPSCs), induced trophoblast stem cells (iTSCs), and induced extraembryonic endoderm stem cells (iXENs), concomitantly. In-depth transcriptomic, chromatin, and epigenetic analyses provide insights into the molecular mechanisms that underlie the reprogramming process toward the three cell types. Mechanistically, we show that the interplay between Esrrb and Eomes during the reprogramming process determines cell fate, where high levels of Esrrb induce a XEN-like state that drives pluripotency and high levels of Eomes drive trophectodermal fate.

Leptin can clearly induce apoptosis in human PCa cell lines. These findings could lead to development of new leptin agonists with enhanced pro-apoptotic effects and targeted for use in human PCa.

Critical limb ischemia (CLI) is the most severe presentation of peripheral arterial disease. We developed cell-based therapy entailing intra-arterial injection of autologous venous endothelial cells (ECs) modified to express angiopoietin 1, combined with autologous venous smooth muscle cells (SMCs) modified to express vascular endothelial growth factor. This combination promoted arteriogenesis in animal models and was safe in patients with limiting claudication. In an open-label, phase Ib study, we assessed the safety and efficacy of this therapy in CLI patients who failed or were unsuitable for surgery or intravascular intervention. Of 23 patients enrolled, 18 with rest pain or non-healing ulcers (Rutherford categories 4 and 5) were treated according to protocol, and 5 with significant tissue loss (Rutherford 6) were treated under compassionate treatment. Patients were assigned randomly to receive 1 × 10 or 5 × 10 (EC-to-SMC ratio, 1:1) of the cell combination. One-year amputation-free survival rate was 72% (13/18) for Rutherford 4 and 5 patients; all 5 patients with Rutherford 6 underwent amputation. Of the 12 with unhealing ulcers at dosing, 6 had complete healing and 2 others had >66% reduction in ulcer size. Outcomes did not differ between the dose groups. No severe adverse events were observed related to the therapy.

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

Background/Aim: In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long followup. Patients and Methods: Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine. Results: Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5-and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews. Hairy cell leukemia (HCL) is an uncommon indolent B-cell lymphoproliferative disorder occurring in 3/1,000,000 patients (1). It was first described by Bouroncle et al. in 1958 as "leukemic reticuloendotheliosis"(2) and only later was the term HCL first used describing the characteristic 'hairy' surface features of the leukemia cells. Clinically, the disorder is characterized by pancytopenia, splenomegaly and recurrent infections (3). It is more common in men (4:1 men/women ratio), with a median age at diagnosis of 55 years (4). Diagnosis of HCL is usually made by histopathology after bone marrow biopsy and in combination with a characteristic flow cytometric profile showing CD19 + , CD20 + , CD11c + , CD25 + , CD103 + , CD123 + , CD200 + , CD27 − , and light chain restriction (3). In 2011, molecular studies by Tiacci et al. showed that almost all cases of HCL were associated with a 6423

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Hyperandrogenism is characterized clinically by hirsutism, acne, androgens-dependent alopecia and elevated serum concentrations of androgens (testosterone and androstenedione). Polycystic ovary syndrome is the most frequent cause of hyperandrogenism. Nevertheless, the differential diagnosis includes androgen-secreting tumors of the ovary or adrenal gland. Although rare, it is important to consider this diagnosis in patients with serum testosterone concentrations greater than 7 nmol/l. A 35-year-old woman who presented with hirsutism, amenorrhea and acanthosis nigricans is described. The endocrine abnormalities included a serum testosterone concentration of 9 nmol/l and overt type II diabetes mellitus. Imaging studies, including magnetic resonance imaging and Doppler ultrasonography, did not disclose a secreting tumor. After cyproterone acetate was prescribed the serum testosterone concentration returned to normal. The recent application of modern, high-resolution diagnostic ultrasonography and magnetic resonance imaging enabled a morphologically based diagnosis in a case of severe hyperandrogenism, with no need for invasive procedures. The therapeutic response to antiandrogens is reassuring.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.