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Abstract Background Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. Methods In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. Results Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. Conclusions Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.

We give an analog of exceptional polynomials in the matrix‐valued setting by considering suitable factorizations of a given second‐order differential operator and performing Darboux transformations. Orthogonality and density of the exceptional sequence are discussed in detail. We give an example of matrix‐valued exceptional Laguerre polynomials of arbitrary size. [ABSTRACT FROM AUTHOR]

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 ([BCL-X.sub.L]), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by [BCL-X.sub.L] inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers., Apoptosis, or programmed cell death, is a conserved and regulated process that is the primary mechanism for the removal of aged, damaged and unnecessary cells. The ability to block apoptotic [...]

Summary: Thermococcales, a major order of archaea inhabiting the iron‐ and sulfur‐rich anaerobic parts of hydrothermal deep‐sea vents, have been shown to rapidly produce abundant quantities of pyrite FeS2 in iron–sulfur‐rich fluids at 85°C, suggesting that they may contribute to the formation of 'low temperature' FeS2 in their ecosystem. We show that this process operates in Thermococcus kodakarensis only when zero‐valent sulfur is directly available as intracellular sulfur vesicles. Whether in the presence or absence of zero‐valent sulfur, significant amounts of Fe3S4 greigite nanocrystals are formed extracellularly. We also show that mineralization of iron sulfides induces massive cell mortality but that concomitantly with the formation of greigite and/or pyrite, a new generation of cells can grow. This phenomenon is observed for Fe concentrations of 5 mM but not higher suggesting that above a threshold in the iron pulse all cells are lysed. We hypothesize that iron sulfides precipitation on former cell materials might induce the release of nutrients in the mineralization medium further used by a fraction of surviving non‐mineralized cells allowing production of new alive cells. This suggests that biologically induced mineralization of iron‐sulfides could be part of a survival strategy employed by Thermococcales to cope with mineralizing high‐temperature hydrothermal environments. [ABSTRACT FROM AUTHOR]

Burkholderia sp. Nafp2/4‐1b (=SARCC‐3049) is a plant growth–promoting rhizobacteria (PGPR) initially isolated from the rhizosphere of pristine grassland in South Africa, and its ability to enhance growth was previously evaluated on maize (Zea mays L.). Here, the bacterium was tested with the aim of investigating its role in improving the nodulation and growth of the forage legume lucerne (Medicago sativa L.) when it is co‐inoculated with the rhizobial symbionts of this legume in the glasshouse. When the co‐inoculation resulted in a statistically significant (P = 0·05) increase in the number of nodules and improved plant biomass compared with single inoculation, we sequenced and analysed its genome to gain a better understanding of the genetic determinants responsible for the observed PGPR traits. The Illumina HiSeq 2500‐sequenced genome resulted in 92 scaffolds, with an N50 of 322 407 bp, a total draft genome size of 7 788 045 bp and GC content of 66·2%. Analysis of the genome sequence confirmed the presence of a number of essential genes that code for various PGPR traits. The main plant beneficial genes associated with PGPR traits in Burkholderia sp. Nafp2/4‐1b include pyoverdine siderophores biosynthesis gene (PvdF); acdS that codes for 1‐aminocyclopropane‐1‐carboxylate (ACC) deaminase; the tryptophan synthase genes involved in auxin biosynthesis (TSA1, TSB1) and the pqqABCDE operon related to phosphate solubilization. This study generated valuable information on the potential of the PGPR Burkholderia sp. strain Nafp2/4‐1b as an effective commercial inoculant, which warrants further formulation and field application studies before developing it into a low cost, environmentally safe and effective biofertilizer. [ABSTRACT FROM AUTHOR]

Background: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges.Methods: In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines.Results: Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance.Conclusions: Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance. [ABSTRACT FROM AUTHOR]

The Bcl-2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non-Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl-2 family inhibitors alone or in combination with standard-of-care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response. [ABSTRACT FROM AUTHOR]

In order to discover novel immunomodulators for application in treating autoimmune diseases, a stable Jurkat transfectant was constructed in which luciferase reporter gene is driven by a full-length IL-2 promotor. A chemical library was screened to identify compounds that inhibited luciferase expression in Jurkat transfectants stimulated with PMA and ionomycin. A class of compounds (bis-trifluoromethyl pyrazole, BTPs) was identified from this screen. BTPs were shown to inhibit anti-CD3 and anti-CD28 antibody-induced IL-2 secretion, mixed lymphocyte reaction, and Con A-induced T cell proliferation in normal human peripheral blood T cells. In addition, mRNA levels of IL-4, IL-5, IL-9, IL-10, IL-13, IL-15, and IFN-γ were markedly inhibited by BTPs in peripheral blood mononuclear cells stimulated by Con A as determined by multi-probe RNA protection assay. Furthermore, IL-2, IL-4, IL-5, and IFN-γ secretion by Hut 78 cells or CD3+ T cells stimulated with PMA plus ionomycin or anti-CD3 antibody plus PMA were inhibited in a concentration-dependent manner by BTPs. Therefore, BTPs inhibit a wide spectrum of cytokine production including TH1 and TH2 type cytokines. Taken together, these compounds may be useful for treating autoimmune diseases and organ transplant rejection. [Copyright &y& Elsevier]

Relatively little has been published about upper lateral cartilage abnormalities, trauma, and management in rhinoplastic literature. In this paper we would like to present a relatively common problem seen either by trauma or as a result of rhinoplasty. The upper lateral cartilages are a pair of triangular cartilages, one on each side of the dorsum, which comprise the upper cartilaginous vault with the septum and can be avulsed due to direct trauma. This results in loss of their attachments and resultant healing in a new angulated position. The middle third of the nose, being relatively mobile is less susceptible to trauma than the upper third which is rigid and comprised of bone, and that frequently is the reason for less incidence of avulsion of the upper lateral cartilages compared to fractured nasal bones. The surgical treatment of the structures adjacent to the upper lateral cartilage during the process of rhinoplasty severs many attachments of these cartilages and frequently causes them to be free floating. This may not be recognized and not treated. Lack of appropriate realignment in the normal anatomical position may heal the cartilage in a distorted angulated position. Irrespective of etiology, when distortions of the upper lateral cartilage occur, they may cause significant concavity and "hollowed out" appearance on the side of the avulsion which functionally may impede the nasal airway by encroachment and/or "flutter valve" effect. During inspiration this unsupported upper lateral cartilage may interfere with anatomy, physiology and efficiency of the internal nasal valve function. Avulsion of the upper lateral cartilage is a definite entity and should be recognized and treated appropriately to realign the lateral cartilage in its normal anatomical position for a functional as well as a good cosmetic result. [ABSTRACT FROM AUTHOR]

Different types of alloplastic implants are currently being utilized in performing mentoplasty. A review of the literature points out the number of prostheses that have been used. Each type of material has inherit physical properties which determine its characteristics for use as a chin implant. The type of implant and method selected in chin augmentation depends upon accurate preoperative evaluation and full understanding of the properties of alloplastic substances. Five hundred and thirty-nine cases of chin augmentation utilizing different materials and methods were reviewed over a nine year period. The limitations of mentoplasty as well as the advantages, disadvantages, and in selected cases, the indications for the use of a particular implant are discussed. [ABSTRACT FROM AUTHOR]

The advantages of the Fomon technique modifications in rhinoplasty are outlined. The importance of these adaptations is emphasized. [ABSTRACT FROM AUTHOR]

Satisfactory treatment of alopecia following rhytidectomy is discussed using the punch graft technique. In spite of the presence of scar tissue following rhytidectomy, this procedure has been quite successful because of the rich blood supply in that area. [ABSTRACT FROM AUTHOR]

A method of chin augmentation employing a newer synthetic material (Proplast) is presented. The characteristics and biocompatibility of Proplast are detailed. Technical considerations and results of short term clinical trials in 20 patients are discussed. One implant necessitated removal secondary to trauma four months after surgery. All other implants including over 30 additional cases have been without incident. [ABSTRACT FROM AUTHOR]

The infrabrow lift is presented as a specific method to correct skin redundancy between the eyebrow and upper lid. Indications are outlined which differentiate this technique from the suprabrow surgical approach. The surgical technique is discussed. Esthetic results have proven most satisfactory. [ABSTRACT FROM AUTHOR]