The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

The Triangular Dart Flap: A Reconstructive Option for Soft Tissue Defects.

INTRODUCTION: Reconstruction of soft tissue defects after skin cancer excision remains a challenge. Options for reconstruction are numerous, including primary repair, local tissue rearrangement, and skin grafts, among others. In this series, the authors present a novel technique: The triangular dart flap. This is a single-stage tissue rearrangement that uses the redundant tissue of the dog-ear to aid in the closure of these wounds. METHODS: A retrospective review was conducted of all patients undergoing local tissue rearrangements by the senior author from 2009 to 2018. Factors were collected and analyzed, including age, size and cause of defect, comorbidities, smoking history, and postoperative complications. RESULTS: Twenty-four patients underwent reconstruction with a triangular dart flap for repair of malignant defects. Mean defect size was 7.3 cm2 (0.8-20 cm2), and mean repair size was 29.7 cm2 (6-80 cm2). Initial pathology included basal cell carcinoma (45.8%), melanoma in situ (29.2%), and squamous cell carcinoma (16.7%), among others. Location varied widely among face and extremities. Anesthesia was predominantly local only (79.1%). There were no major complications, and 5 (20.8%) minor complications. CONCLUSIONS: The triangular dart flap is a novel single-stage procedure, generally performed under local anesthesia only, for correction of Mohs defects. By using the redundant tissue of dog-ears to better approximate the wound edges, a tension-free primary closure can be achieved in sensitive areas, such as the nasal tip.

Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.

BACKGROUND: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed. METHODS: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines. RESULTS: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis. CONCLUSIONS: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC.

Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators.

Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.

Timing of Free Flaps for Traumatic Wounds of the Lower Extremity: Have Advances in Perioperative Care Changed the Treatment Algorithm?

BACKGROUND: Despite the landmark study by Godina 30 years ago, opinions still vary within the literature about the management of complex traumatic wounds in the lower extremity. We present a large series of lower extremity reconstructions with vascularized free tissue and examine the perioperative factors that influenced the success of these cases. METHODS: We reviewed 88 patients with free flap reconstruction of traumatic lower extremity wounds over 8 years. Primary outcomes were flap infections, flap loss, total flap-specific complications, and total recipient site complications. Independent variables specific to perioperative care including time to flap coverage, injury classification, exposed or infected hardware, prior osteomyelitis, use of wound vacuum-assisted closure (VAC) therapy, and concurrent polytrauma were investigated to establish their influence on primary outcomes. Each independent variable was assessed using Chi-square or Fisher's exact test and was included in a logistic regression analysis to establish significance. RESULTS: Of the 88 patients, 8 had flap loss, 8 had flap infections, and a total of 23 had primary adverse outcomes. Timing of the reconstruction, VAC use, injury classification, prior hardware or wound status, or presence of polytrauma had no statistically significant impact on the primary outcomes. Injury classification/severity on total recipient site complications (p = 0.051) and flap-specific complications (p = 0.073) trended toward significance; however, subgroup analysis did not achieve significance. Logistic regression of any recipient site complication including all independent variables similarly showed no significance. CONCLUSION: Although the original study by Godina suggests early coverage is critical to optimize outcomes, in the modern era of advanced wound care, our study adds to a growing body of evidence that supports the de-emphasis of the 72-hour reconstruction interval. Our current management is focused on more effectively coordinating efficient peritraumatic and perioperative care on an individualized basis in the often very complicated polytrauma patient.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

The Sternum-Nipple Distance is Double the Nipple-Inframammary Fold Distance in Macromastia.

BACKGROUND: Reduction mammaplasty is one of the most commonly performed plastic surgery operations. For a majority of techniques, the most common long-term complication is pseudoptosis. It has previously been proposed that upper breast suspensory ligaments (SL) are weaker than lower breast SL. We tested this hypothesis through anthropometry of the proxies for upper and lower SL strength: the sternal notch-nipple (SN-N) distance and the nipple-inframammary fold (N-IMF) distance, respectively. METHODS: An institutional review board-approved retrospective review of patients undergoing reduction mammoplasty in an academic faculty practice between 2008 and 2015 was conducted. Patient demographics included age, race, and body mass index (BMI); patient comorbidities included smoking status, diabetes, and hypertension. Breast anthropometric measurements included SN-N and N-IMF. Sternal notch-nipple was used as the primary metric of the upper SL strength, whereas N-IMF was used as the primary metric of the lower SL strength. Intraoperative details included reduction technique and resection mass. Postoperative complications were recorded, including nipple areola complex necrosis and hematoma. Linear regression analysis was performed with the primary endpoint of the relationship between SN-N and N-IMF distance in macromastia. RESULTS: Data from 208 patients, totaling 400 individual breast measurements, were collected. The mean SN-N length was 35.1 cm, mean N-IMF length was 16.0 cm, and mean resection weight was 1094 g. Linear regression found that N-IMF distance could be predicted as 45% of the SN-N distance (N-IMF = 0.454 * SN-N). This was a strong relationship, demonstrated by univariate analysis of SN-N and N-IMF (R, 0.624; P < 0.001). A Wise pattern was used in 89.9% of cases; an inferior pedicle was used in 83.7% of cases. Nipple areola complex necrosis occurred in 15 breasts (3.75%). Sternal notch-nipple (R, 0.127; P = 0.011) and N-IMF (R, 0.119; P = 0.017) were both predictive of nipple areola complex necrosis (Table 4). CONCLUSIONS: In our series, the N-IMF distance increased 0.45 cm for every 1 cm increase in the SN-N distance. This relationship strengthens our primary hypothesis that the lower pole ligaments stretch at a significantly slower rate than the upper pole ligaments. Taking this into consideration, we suggest that surgeons seeking to minimize pseudoptosis rates should favor techniques that minimally disrupt the lower SL.

A member of the Phosphate transporter 1 (Pht1) family from the arsenic-hyperaccumulating fern Pteris vittata is a high-affinity arsenate transporter.

Pteris vittata exhibits enhanced arsenic uptake, but the corresponding mechanisms are not well known. The prevalent form of arsenic in most soils is arsenate, which is a phosphate analog and a substrate for Phosphate transporter 1 (Pht1) transporters. Herein we identify and characterize three P. vittata Pht1 transporters. Pteris vittata Pht1 cDNAs were isolated and characterized via heterologous expression in Saccharomyces cerevisiae (yeast) and Nicotiana benthamiana leaves. Expression of the PvPht1 loci in P. vittata gametophytes was also examined in response to phosphate deficiency and arsenate exposure. Expression of each of the PvPht1 cDNAs complemented the phosphate uptake defect of a yeast mutant. Compared with yeast cells expressing Arabidopsis thaliana Pht1;5, cells expressing PvPht1;3 were more sensitive to arsenate, and accumulated more arsenic. Uptake assays with yeast cells and radiolabeled (32)P revealed that PvPht1;3 and AtPht1;5 have similar affinities for phosphate, but the affinity of PvPht1;3 for arsenate is much greater. In P. vittata gametophytes, PvPht1;3 transcript levels increased in response to phosphate (Pi) deficiency and arsenate exposure. PvPht1;3 is induced by Pi deficiency and arsenate, and encodes a phosphate transporter that has a high affinity for arsenate. PvPht1;3 probably contributes to the enhanced arsenate uptake capacity and affinity exhibited by P. vittata.

Ligand and pathogen specificity of the Atlantic salmon serum C-type lectin.

BACKGROUND: An Atlantic salmon (Salmo salar) C-type lectin (SSL) binds to mannose and related sugars as well as to the surface of Aeromonas salmonicida. To characterize this lectin as a pathogen recognition receptor in salmon, aspects of its interaction with molecules and with intact pathogens were investigated. METHODS: SSL was isolated using whole-yeast-affinity and mannan-affinity chromatography. The binding of SSL to the two major surface molecules of A. salmonicida, lipopolysaccharide (LPS) and A-layer protein was investigated by western blotting and enzyme-linked immunosorbent assays. Microbial binding specificity of SSL was examined by whole cell binding assays using a range of species. Carbohydrate ligand specificity of SSL was examined using glycan array analysis and frontal affinity chromatography. RESULTS: SSL showed binding to bacteria and yeast including, Pseudomonas fluorescens, A. salmonicida, A. hydrophila, Pichia pastoris, and Saccharomyces cerevisiae, but there was no detectable binding to Yersinia ruckeri. In antimicrobial assays, SSL showed no activity against Escherichia coli, Bacillus subtilis, S. cerevisiae, or A. salmonicida, but it was found to agglutinate E. coli. The major surface molecule of A. salmonicida recognized by SSL was shown to be LPS and not the A-layer protein. LPS binding was mannose-inhibitable. Glycans containing N-acetylglucosamine were shown to be predominant ligands. CONCLUSION: SSL has a distinct ligand preference while allowing recognition of a wide variety of related carbohydrate structures. GENERAL SIGNIFICANCE: SSL is likely to function as a wide-spectrum pattern recognition protein.

Interleukin-1ß mediates macrophage-induced impairment of insulin signaling in human primary adipocytes.

Adipose tissue expansion during obesity is associated with increased macrophage infiltration. Macrophage-derived factors significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. Identification of the major factors that mediate detrimental effects of macrophages on adipocytes may offer potential therapeutic targets. IL-1ß, a proinflammatory cytokine, is suggested to be involved in the development of insulin resistance. This study investigated the role of IL-1ß in macrophage-adipocyte cross-talk, which affects insulin signaling in human adipocytes. Using macrophage-conditioned (MC) medium and human primary adipocytes, we examined the effect of IL-1ß antagonism on the insulin signaling pathway. Gene expression profile and protein abundance of insulin signaling molecules were determined, as was the production of proinflammatory cytokine/chemokines. We also examined whether IL-1ß mediates MC medium-induced alteration in adipocyte lipid storage. MC medium and IL-1ß significantly reduced gene expression and protein abundance of insulin signaling molecules, including insulin receptor substrate-1, phosphoinositide 3-kinase p85α, and glucose transporter 4 and phosphorylation of Akt. In contrast, the expression and release of the proinflammatory markers, including IL-6, IL-8, monocyte chemotactic protein-1, and chemokine (C-C motif) ligand 5 by adipocytes were markedly increased. These changes were significantly reduced by blocking IL-1ß activity, its receptor binding, or its production by macrophages. MC medium-inhibited expression of the adipogenic factors and -stimulated lipolysis was also blunted with IL-1ß neutralization. We conclude that IL-1ß mediates, at least in part, the effect of macrophages on insulin signaling and proinflammatory response in human adipocytes. Blocking IL-1ß could be beneficial for preventing obesity-associated insulin resistance and inflammation in human adipose tissue.

Postoperative Day 1 Discharge in Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction.

With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge. Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected. Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group (P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations (P = 0.023) and bilateral operations (P = 0.01). No major complications occurred in those discharged on POD1. Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge.

Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer.

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-ß1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

Discovery of pyrrolidine-based ß-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

The Virtual Interview Experience: Advantages, Disadvantages, and Trends in Applicant Behavior.

Residency programs and applicants were forced to hold virtual interviews during the 2020-2021 application cycle. Inability to evaluate a program and/or applicant in person has intangible drawbacks. However, there are obvious advantages: cost, convenience, and comfort. Do the advantages outweigh the disadvantages? How have applicant behaviors changed to learn about programs in a virtual-only interview process? Methods: A survey was distributed to 302 applicants to a single plastic surgery residency program during the 2020 application cycle. Demographics, social media presence and utilization, and experience with the virtual application and interview process were analyzed. A 2018 survey from our institution was compared with a subset of questions for longitudinal analysis. Results: Seventy-six respondents (25.2%) completed the survey. Most applicants (88.2%) spent less than $1000 during the interview and application cycle. Over half (56.6%) did not receive letters of recommendation from outside their home program. A significant minority (27.6%) of applicants attended more than one interview in a single day. Compared to 2018, applicants in 2021 were significantly more likely to access alternative digital resources (forums/discussion boards, social media, and podcasts) when learning about programs. Average number of interviews remains in the range of pre-COVID studies, but the percentage of interviews attended increased. Conclusions: Applicants spent substantially less money on interviews and relied on alternative digital sources to learn about residency programs. This study objectively quantifies the advantages of virtual interviews. Disadvantages include inability to assess "fit" and lack of nonverbal communication.

Bilateral Diffuse Pseudoangiomatous Stromal Hyperplasia Necessitating Mastectomy.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon, benign breast lesion often diagnosed incidentally and frequently mistaken for fibroadenoma given similar radiographic appearance. Histopathology classically reveals diffuse, dense fibrous stromal background with a complex network of spindle cells forming slit-like spaces, giving it the appearance of angiomatous proliferation. Surgical excision is generally not necessary. Here we present two unusual cases of PASH: an adolescent patient with bilateral rapid onset of symptoms, and a premenopausal patient with bilateral, diffuse, recurrent PASH. Both required mastectomy. We aim to highlight the variable nature of presentation and briefly review current management options.

Investigation and management of iron deficiency anaemia in a specialist palliative care setting and the role of intravenous iron: a descriptive analysis of hospice data.

Background: Anaemia is common in hospice populations and associated with significant symptom burden. Guidelines recommend investigating for and treating iron deficiency (ID), but there is little evidence of this practice in palliative care populations. This report describes the results of investigations for and subsequent management of ID in a UK hospice. Methods: This is a descriptive study of routine clinical data. Laboratory and clinical records were reviewed retrospectively for 12 months following the implementation, in August 2018, of routine investigation for ID amongst patients with clinically relevant anaemia in whom treatment would be considered. Absolute (AID) and functional iron deficiency (FID) were diagnosed using established definitions and treatments recorded. Results: Iron status was evaluated in 112 cases, representing 25/110 (22.7%) of those with mild, 46/76 (60.5%) moderate and 41/54 (75.9%) severe anaemia. Twenty-eight (25%) were defined as having AID, 48 (42.8%) FID and 36 (32%) no ID. There was a significant difference between groups in symptoms triggering haemoglobin check and diagnosis, with a higher proportion of patients with classic symptoms of anaemia and gastrointestinal malignancy in those with AID. Intravenous iron was given on 12 occasions in the hospice with no major adverse events. Subjective symptom benefit in 7 cases and a statistically significant increase in overall mean haemoglobin were observed. Conclusions: This report describes the outcome of investigations for iron deficiency in patients with clinically significant anaemia in a UK hospice. Results indicate iron deficiency is common and can be safely treated with intravenous iron replacement, within current guidelines, in a hospice setting. Further research should define the optimum use of this approach in palliative care patients.

Many patients supported by hospices have anaemia. This means there is a reduction in the molecule, haemoglobin, which carries oxygen in the blood. Symptoms can include tiredness and shortness of breath. In severe cases, patients may be given a blood transfusion, however this carries significant risks and blood is a limited resource. Anaemia can be caused by a lack of iron. Iron deficiency can be treated with iron tablets or injections. However, iron tablets can have a lot of side effects and patients generally have to go to hospital for iron injections. There is little information about how important this is for anaemia that we see in hospices and how it should be treated. We looked at the results of tests for iron deficiency done at a UK hospice in day-to-day practice. The hospice started doing these tests for appropriate patients with anaemia after it was recommended in recent guidelines. Out of the tests performed, a quarter showed iron deficiency. There were a higher number of patients with typical symptoms of anaemia and patients with a cancer of the gut in the group with iron deficiency. We also looked at treatment given for iron deficiency. Twelve were given iron injections at the hospice, which hasn't been reported before. This study was not designed to investigate how well this worked but there were no major side effects. It also seemed to improve blood counts and help symptoms in most. Overall, this study showed that we were able to test for iron deficiency at the hospice, we found it often and, in certain patients, were able to treat it with iron injections at the hospice. Research in the future should look at how we could best use this approach. It should also look at the effectiveness of iron injections in hospice patients.

Social media impact in the Match: A survey of current trends in the United States.

BACKGROUND: Applicants to integrated plastic and reconstructive surgery (PRS) residency in the United States spend exorbitant amounts of time and money throughout the interview process. Outside of first-hand experience through a visiting rotation, applicants utilize various resources in learning about a program. Today's applicants are "Millennials," the demographic cohort raised during the information age and proficient with digital technology. The authors evaluated whether programs have a presence on social media, and whether applicants are following these accounts. METHODS: An online survey was sent to applicants to a single integrated plastic surgery program evaluating basic demographics, social media utilization, and sources of information accessed throughout the residency application process. A manual search of popular social media platforms (Instagram, Facebook, and Twitter) was performed in October 2019. Accounts affiliated with integrated PRS programs were identified and analyzed. RESULTS: Eighty-four of 222 applicants (37.8%) completed the survey. Ninety-six percent of applicants were within the Millennial demographic. Ninety-six percent of applicants had some form of social media presence, with Facebook (90%) and Instagram (87%) being the most popular platforms. Seventy-three percent of applicants reported following a PRS residency social media account. As of October 2019, 59 integrated residency programs (73%) have active Instagram accounts. CONCLUSIONS: Applicants still rely on the program website when researching potential residencies, but social media is being rapidly adopted by programs. Program social media accounts should be used as a dynamic form of communication to better inform applicants of program strengths and weaknesses.

Comparative Cancer Cell Signaling in Muscle-Invasive Urothelial Carcinoma of the Bladder in Dogs and Humans.

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in humans, but also in dogs that represent a naturally occurring model for this disease. Dogs are immunocompetent animals that share risk factors, pathophysiological features, clinical signs and response to chemotherapeutics with human cancer patients. This review summarizes the fundamental pathways for canine MIUC initiation, progression, and metastasis, emerging therapeutic targets and mechanisms of drug resistance, and proposes new opportunities for potential prognostic and diagnostic biomarkers and therapeutics. Identifying similarities and differences between cancer signaling in dogs and humans is of utmost importance for the efficient translation of in vitro research to successful clinical trials for both species.

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes.

To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy.

The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD-and the current state of the available compounds in clinical development.