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Cell death can be initiated through activation of the extrinsic and intrinsic apoptotic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, preferentially triggers the extrinsic apoptotic pathway by binding as a trimer to two closely related cell surface death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Receptor trimerization leads to the formation of the death-inducing signaling complex (DISC) to recruit and activate downstream caspases that ultimately leads to apoptotic cell death. Because TRAIL signaling induces apoptosis, several TRAIL receptor agonists have been developed for the treatment of cancer. ABBV-621 is a novel, second generation TRAIL receptor agonist that is an engineered fusion protein consisting of an IgG1-Fc linked to a single chain trimer of TRAIL subunits resulting in a total of six death receptor binding sites per molecule to maximize receptor clustering that is currently being tested in Phase I clinical trials (NCT03082209). To expand upon the potential therapeutic utility of ABBV-621, we tested the combinatorial activity of ABBV-621 with numerous standard-of-care (SoC) therapeutics and targeted agents in diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines. Thein vitroresults led to selection of agents to combine with ABBV-621 forin vivostudies. In DLBCL cell line-derived xenograft (CDX) preclinical models, we observed combination activity of ABBV-621 with pevonedistat (PEV) a selective NEDD8 inhibitor. Additionally, synergistic activity was observed with ABBV-621 with either bendamustine (BED) or rituximab (RTX) alone, or BED/RTX together. In AML, we observed compelling combination activity of ABBV-621 with PEV in cell line-derived xenograft (CDX) models. In MM, combination of ABBV-621 plus bortezomib (BTZ) resulted in deeper anti-tumorigenic activity than either agent alone in several CDX models. The pre-clinical data presented here support expanding the indications and settings where ABBV-621 may have utility. A clinical trial assessing the activity of ABBV-621 in combination with bortezomib and dexamethasone in R/R MM patients is planned. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Disclosures Smith: AbbVie:Current Employment, Current equity holder in publicly-traded company.Jin:AbbVie:Current Employment, Current equity holder in publicly-traded company.Chen:AbbVie:Current Employment, Current equity holder in publicly-traded company.Zhang:AbbVie:Current Employment, Current equity holder in publicly-traded company.Huska:AbbVie:Current Employment, Current equity holder in publicly-traded company.Widomski:AbbVie:Current Employment, Current equity holder in publicly-traded company.Bontcheva:AbbVie:Current Employment, Current equity holder in publicly-traded company.Buchanan:AbbVie:Current Employment, Current equity holder in publicly-traded company.Morgan-Lappe:AbbVie:Current Employment, Current equity holder in publicly-traded company.Phillips:AbbVie:Current Employment, Current equity holder in publicly-traded company.Tahir:AbbVie:Current Employment, Current equity holder in publicly-traded company.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3383-5) contains supplementary material, which is available to authorized users.

Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.

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.

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1–Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-γ) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED 50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

This study examined psychosocial correlates of immune function and illness in 89 male first-year US Air Force Academy cadets. A psychosocial questionnaire was administered to cadets prior to their arrival at the academy and was readministered during cadet orientation and during the stressful environment of Basic Cadet Training (BCT). Immune responsiveness was analyzed by PHA-, PMA-, or anti-CD3-stimulated thymidine uptake in mononuclear leucocytes. Illness episodes were assessed via medical chart review and self-reported symptoms. There were significant increases in distress levels as cadets entered BCT. No psychosocial measure assessed prior to arrival at the academy predicted level of PHA-, PMA-, and anti-CD3-stimulated thymidine uptake or risk of illness. However, hostility levels reported during BCT predicted risk of illness in the four weeks following psychosocial assessment (odds ratio = 7.1; 95% confidence interval: 1.4-36.1). Elevated response to environmental stressors and lower well-being levels also predicted impending illness, but only in the cohort of cadets who had not contracted food poisoning prior to assessment during BCT (OR = 9.3, CI = 1.9-46.7; OR = 0.09, CI = 0.02-0.53). These results suggest that self-report measures of hostility, response to environmental stressors and well-being may be useful predictors of impending illness episodes in males encountering high stress environments.

Revision rhinoplasty can present difficult and challenging problems, which maximally test the skill and judgment of the facial plastic surgeon. We conducted a retrospective study of 1221 consecutive rhinoplasties, of which 170 were revision procedures. The rate of revision of our own procedures is 5.3%. Postrhinoplastic deformities are divided anatomically into the upper, middle, and lower thirds of the nose. The largest category of deformities occur in the lower thirds of the nose, in which bossa are the most common problem. Overall, pollybeak is the most common deformity in 33% of the procedures performed, followed by bossa in 26%, and excessive dorsal removal in 24%. We analyzed the causes and selected management of these cases.

All authors are employees of AbbVie and participated in the design, conduct, and interpretation of these studies. AbbVie and Genentech provided financial support for these studies and participated in the review and approval of this publication. The BCL-2-selective inhibitor ABT-199 has demonstrated efficacy in numerous preclinical models of hematologic malignancies without causing thrombocytopenia, a dose-limiting toxicity associated with the BCL-2/BCL-XL inhibitor navitoclax (Souers et al. 2013. Nat. Med. 19, 202-208). ABT-199 has also demonstrated clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) (Seymour et al. 2014. J. Clin. Oncol. 32, 448s; Davids et al. 2014. J. Clin. Oncol. 32, 544s). Despite these encouraging early clinical data, some subjects do not respond to ABT-199 or progress while on treatment. Pre-clinical models indicate that both intrinsic and acquired resistance may be a consequence of MCL-1 expression. Consequently, we have explored potent and selective small molecule inhibitors of CDK9, a kinase known to maintain the expression of MCL-1 through its role in p-TEFb-mediated transcription. Inhibition of CDK9 resulted in the rapid loss in RNA polymerase II phosphorylation (Serine 5) and MCL-1 expression that was closely followed by the induction of apoptosis in MCL-1-dependent cell lines, a cellular response that could be rescued by overexpression of BCL-2. Substantial synergy was observed between CDK9 inhibitors and ABT-199 in a number of hematologic cell lines with intrinsic or acquired resistance to ABT-199. Direct inhibition of MCL-1 with the small molecule BH3 mimetic A-1210477 was also highly synergistic with ABT-199, further validating the utility of co-inhibiting MCL-1 and BCL-2 function simultaneously in ABT-199 resistant tumors. Importantly, the CDK9 inhibitor-ABT-199 combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in xenograft models of non-Hodgkin’s lymphoma (NHL) and acute myelogenous leukemia (AML). These data indicate that CDK9 inhibitors may be highly efficacious when used in combination with ABT-199 for the treatment of hematologic malignancies. Disclosures Chen: Abbvie: Employment, Equity Ownership. Jin:Abbvie: Employment, Equity Ownership. Tapang:abbvie: Employment, Equity Ownership. Tahir:abbvie: Employment, Equity Ownership. Smith:abbvie: Employment, Equity Ownership. Xue:abbvie: Employment, Equity Ownership. Zhang:abbvie: Employment, Equity Ownership. Gao:abbvie: Employment, Equity Ownership. Tong:abbvie: Employment, Equity Ownership. Clark:abbvie: Employment, Equity Ownership. Ricker:abbvie: Employment, Equity Ownership. Penning:abbvie: Employment, Equity Ownership. Albert:abbvie: Employment, Equity Ownership. Phillips:abbvie: Employment, Equity Ownership. Souers:abbvie: Employment, Equity Ownership. Leverson:abbvie: Employment, Equity Ownership.

Multiple environmental factors asociated with space flight can increase the risk of infectious illness among crewmembers thereby adversely affecting crew health and mission success. Host defences can be impaired by multiple physiological and psychological stressors including: sleep deprivation, disrupted circadian rhythms, separation from family, perceived danger, radiation exposure, and possibly also by the direct and indirect effects of microgravity. Relevant human immunological data from isolated or stressful environments including spaceflight will be reviewed. Long-duration missions should include reliable hardware which supports sophisticated immunodiagnostic capabilities. Future advances in immunology and molecular biology will continue to provide therapeutic agents and biologic response modifiers which should effectively and selectively restore immune function which has been depressed by exposure to environmental stressors.

Comparing the bones that make up each side of the nose by anthropometry reveals asymmetries caused by both developmental and traumatic processes, which precludes performing osteotomies using a set procedure. The frontal process of the maxilla is a key structure in narrowing the bony contours of the nose to correct the “open roof syndrome” (incomplete closure of the roof of the nose) after hump removal. It must be included in many instances in order to achieve a satisfactory infracture. This is especially important in the management of a large or asymmetric frontal process. Furthermore, osteotomies should be placed sufficiently lateral to the nasal bones to prevent the aesthetically unpleasing complication of the so-called step deformity. The questionable efficacy of osteotomies in rhinoplasty on the non-Caucasian nose is also briefly considered in this article.

Rhinoplasty is one of the most challenging surgical procedures. Surgeons should strive to obtain maximum aesthetic and functional results with minimal operative intervention. Excessive surgery often results in unwarranted impairment of nasal function. The obstructive or sensory complications of rhinoplasty can occur in the early or late postoperative periods. The most common functional sequelae of rhinoplasty, and their causes, prevention and therapy, are discussed.

A modification of an absorbent, non-adherent material (Telfa) is described for use as an anterior nasal packing. The ideal nasal packing should fulfill certain criteria. It should be easy to introduce and remove, contour to the nasal cavity to exert a tamponade effect, and should not prolapse or react unfavorably with the mucous membranes of the nose. The advantages of Telfa as a nasal packing is discussed and compared to previously described materials in this regard. During the past three years this pack has been used in over 800 patients for anterior epistaxis, septal and rhinoplastic surgery. The results have been extremely satisfactory, and the authors suggest their use in these cases.

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.

Often in rhinoplasty, adequate osteotomies and mobilization of the nasal bones fail to close the dorsum--leaving an open roof deformity. Preexisting conditions and certain anatomical relationships contribute to this problem. The various methods of correcting the deformity are discussed and the author's approach presented.

• Double lateral osteotomy has proved to be useful in the management of broad, thick, and heavy maxillary processes. The technique of performing two lateral osteotomies and the indications for its application are described. The results obtained from cadaver dissection and clinical experience with this technique are discussed. ( Arch Otolaryngol 103:344-348, 1977)

The functional sequelae of rhinoplastic surgery are emphasized and the functional and anatomical causes of postoperative nasal obstruction are discussed. A maneuver to improve the airway and decrease the incidence of postoperative nasal obstruction is presented.

The difficulties in obtaining an adequate result in the Negroid nose have been elucidated by other authors. Paucity of lobular cartilage; the flat dorsum; short columella; wide flaring nares; and skin that tends to keloid formation have led many surgeons to attempt radical surgical techniques to obtain rather limited results. To circumvent the complications in the more radical procedures, a more conservative concept of an entirely intranasal operation without external skin incisions is outlined. This technique consists of tip rotation and lobular cartilage trimming; the use of a non-absorbable basal bunching suture, and the placement of a dorsal implant without performing osteotomies. A comparison with other techniques is made, as well as surgical aims, limitations and a discussion of results. Pertinent illustrations and photographs are presented.

The concept of rhinoplasty of the mature nose is presented. As an isolated procedure or in conjunction with other facial plastic procedures, shortening the length of a drooping nose can give the effect of a more youthful appearance. The anatomy and physiology of the nose as it ages is discussed and if understood by the surgeon, these patients need no longer be rejected because of their age. Technical consideration are important, and the use of the modified rim incision, high septal transfixion and lobule rotation is suggested. An analysis of 30 cases over a noe year period is documented to support this thesis.

• Many materials have been used for augmentation mentoplasty with varying degrees of success. In our experience with the silicone bag-gel implant in 50 cases over the past 18 months the results have been quite satisfactory and there were no untoward complications. ( Arch Otolaryngol 103:292-293, 1977)

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.

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.

The advantages of the Fomon technique modifications in rhinoplasty are outlined. The importance of these adaptations is emphasized.

Recognition of plasma cell tumors of the upper respiratory system and particularly of the accessory nasal sinuses has increased since attention has been called to their incidence by New, 1 Claiborn, 2 Jackson 3 and others. The otolaryngologist finds these tumors of particular interest because of their occurrence in the upper respiratory tract and, especially, in the maxillary sinuses. The plasma cell tumor is generally considered to arise from the bone marrow although many cases of extraosseous origin have been reported. The classic multiple myeloma is thought to be a disease of the bone marrow or of the blood-forming structures generally, and, while the plasma cell tumors seem to be a phase in the developmental history of multiple myeloma, the cause and nature of these tumors are not definitely known and their exact relationship to multiple myeloma 4 is not clear. If the plasma cell tumor should be regarded as