What are Board-Certified Plastic Surgeons Posting on Instagram?

BACKGROUND: Plastic surgeons increasingly use social media to market their practices and educate prospective patients. Previous studies have investigated plastic surgery content on Instagram from the angle of hashtags and most popular plastic surgeons. However, very little is understood about what plastic surgeons themselves post on Instagram and what plastic surgery content average users engage with. OBJECTIVES: The aim of this study was to analyze Instagram posts from accounts related to plastic surgeons in the USA to establish suggestions for growing one's practice with this powerful platform to reach patients. METHODS: Board-certified plastic surgeons from all US regions that were active from February 1, 2023 to April 12, 2023 were randomly chosen. Their Instagram accounts were accessed for post analysis. For procedural posts, engagement statistics and multiple variables were collected. Dixon's outlier test was used to determine outliers in the data. ANCOVA and Tukey analysis was used to determine whether procedure type influenced engagement. RESULTS: 120 surgeon accounts were identified with 2157 posts analyzed, yielding notable differences in posts among regions. Most posts were aesthetic procedures (94.4%) and of female patients (90.3%). Surgical procedures were also predominant (86.1%). In addition, Reels had higher engagement than photograph posts. Users engaged with Body procedures at the highest rate. CONCLUSIONS: This cross-sectional analysis shows plastic surgeons tend to overwhelmingly post female patients, aesthetic procedures, and surgical content. These insights may be used to guide social media content and improve the effectiveness of Instagram as a tool for marketing or education. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Perceptions of Surgical Drains among Breast Reconstruction Patients and Health Care Staff: A Qualitative Survey Study.

BACKGROUND: Surgical drains are a key component for recovery in breast reconstruction procedures. However, they are often cumbersome and carry a risk of infection with prolonged use. We aimed to develop a more thorough understanding of patient and health care provider perspectives on surgical drains, to inform future efforts in improving the breast reconstruction patient experience. METHODS: Twenty-nine breast reconstruction patients and eight plastic surgery providers were recruited to complete surveys focused on surgical drains. Likert scales ranging from 1 to 5 were developed to gauge how bothersome drains felt, as well as concern for infection. Ordinal variable and categorical multiple-choice analyses were applied as appropriate. RESULTS: Fifteen (51.7%) patients underwent implant-based breast reconstruction, and 14 (48.3%) patients underwent autologous breast reconstruction. The most common duration of drain placement was 2 weeks (N = 13). The surgical site infection (SSI) rate requiring antibiotics was 28% (N = 8). On a scale of 1 to 5, both patients (median = 3) and providers (median = 2.5) viewed drains as bothersome. Patients were "frequently" concerned about infection risk (median = 3). Other high-frequency patient concerns included general pain and discomfort. CONCLUSION: Surgical drains are a common component of breast reconstruction procedures and are viewed as cumbersome by both patients and providers. Patients expressed concerns about drain site pain, discomfort, and tugging on clothing. Patients and providers both believed that drains could contribute to SSI. Overall, these data provide insight to drive future improvements in the patient drain experience.

Red Blood Cells Derived from Whole Blood Treated with Riboflavin and UV Light Maintain Adequate Cell Quality through 21 Days of Storage.

BACKGROUND: The Mirasol system for whole blood (WB) is a non-toxic, non-mutagenic pathogen reduction technology (PRT) that treats WB units with riboflavin (vitamin B2) and ultraviolet (UV) light to alter nucleic acids, thereby reducing pathogen infectivity and inactivating white blood cells. This study evaluates the quality of red blood cells (RBCs) derived from WB treated with the Mirasol system. STUDY DESIGN AND METHODS: Paired units of WB were collected from 61 healthy donors. One unit per donor was treated with riboflavin and UV light and the other was used as an untreated control. RBCs were processed from the WB units and stored in AS-3 at 1-6°C for 21 days and sampled for in vitro analyses of RBC quality parameters. RESULTS: Several statistically significant differences were observed between test and control units, but values were overall within normal clinical ranges. After leukoreduction, the residual leukocyte count and RBC recovery met FDA requirements. The RBC units derived from treated WB maintained haemolysis below 1% through 21 days of storage. CONCLUSION: RBCs derived from WB treated with the Mirasol system meet accepted FDA guidelines for RBC quality through 21 days of storage at 1-6°C.

Predictors of outcome among patients on extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: There is a lack of data regarding clinical variables associated with successful bridge to lung transplantation (LT) using extracorporeal membrane oxygenation (ECMO) support. METHODS: We reviewed the institutional database for patients supported with veno-venous (VV) or veno-arterial ECMO as a bridge to LT (n=25; mean age: 50.6±14.2 years). We recorded clinical and laboratory variables, findings on echocardiogram and development of organ dysfunction along with hospital and one-year survival. Variables were compared between patients successfully bridged to LT versus those who were not. RESULTS: The most common diagnostic group was interstitial lung disease (18/25, 72%). VV-ECMO was used in the majority (84%). Fifteen patients (60%) were successfully bridged to LT, and the majority were alive at 1 year (14/15, 93.3%). The presence of right ventricular systolic dysfunction on pre-ECMO echocardiogram was associated with increased risk of unsuccessful bridging (OR, 95% CI: 2.67, 1.01-6.99, P=.041). While on ECMO, trough albumin levels <2.5 gm%, peak blood urea nitrogen levels >35 mg/dL and positive fluid balance were also associated with failure to bridge to LT. CONCLUSIONS: Among patients awaiting LT, the presence of RV systolic dysfunction before ECMO initiation along with worsening renal functions, low albumin levels, and volume overload is associated with poor outcomes.

Assessing physician-parent communication during emergency medical procedures in children: an observational study in a low-literacy Latino patient population.

OBJECTIVE: Effective physician-patient communication is critical to the clinical decision-making process. We studied parental recall of information provided during an informed consent discussion process before performance of emergency medical procedures in a pediatric emergency department of an inner-city hospital with a large bilingual population. METHODS: Fifty-five parent/child dyads undergoing emergency medical procedures were surveyed prospectively in English/Spanish postprocedure for recall of informed consent information. Exact logistic regression was used to predict the ability to name a risk, benefit, and alternative to the procedure based on a parent's language, education, and acculturation. RESULTS: Among English-speaking parents, there tended to be higher proportions that could name a risk, benefit, or alternative. Our regression models showed overall that the parents with more than a high school education tended to have nearly 5 times higher odds of being able to name a risk. CONCLUSIONS: A gap in communication may exist between physicians and patients (or parents of patients) during the consent-taking process, and this gap may be impacted by socio-demographic factors such as language and education level.

Isolation and analyses of lamina propria lymphocytes from mouse intestines.

Investigating intestinal immune responses is critical to understanding local and systemic immunity. However, obtaining resident intestinal immune cells with high cell viability can be challenging. Here, we provide an optimized protocol to isolate lamina propria lymphocytes from the small and large intestines, including lymphocyte activation for cytokine expression analysis and techniques for surface and intracellular antibody staining and flow cytometry. This protocol can be used for isolating and analyzing tissue-resident immune cells from other tissues with specified modifications. For complete details on the use and execution of this protocol, please refer to Kim et al. (2022).

Reproducible and opposing gut microbiome signatures distinguish autoimmune diseases and cancers: a systematic review and meta-analysis.

BACKGROUND: The gut microbiome promotes specific immune responses, and in turn, the immune system has a hand in shaping the microbiome. Cancer and autoimmune diseases are two major disease families that result from the contrasting manifestations of immune dysfunction. We hypothesized that the opposing immunological profiles between cancer and autoimmunity yield analogously inverted gut microbiome signatures. To test this, we conducted a systematic review and meta-analysis on gut microbiome signatures and their directionality in cancers and autoimmune conditions. METHODOLOGY: We searched PubMed, Web of Science, and Embase to identify relevant articles to be included in this study. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements and PRISMA 2009 checklist. Study estimates were pooled by a generic inverse variance random-effects meta-analysis model. The relative abundance of microbiome features was converted to log fold change, and the standard error was calculated from the p-values, sample size, and fold change. RESULTS: We screened 3874 potentially relevant publications. A total of 82 eligible studies comprising 37 autoimmune and 45 cancer studies with 4208 healthy human controls and 5957 disease cases from 27 countries were included in this study. We identified a set of microbiome features that show consistent, opposite directionality between cancers and autoimmune diseases in multiple studies. Fusobacterium and Peptostreptococcus were the most consistently increased genera among the cancer cases which were found to be associated in a remarkable 13 (+0.5 log fold change in 5 studies) and 11 studies (+3.6 log fold change in 5 studies), respectively. Conversely, Bacteroides was the most prominent genus, which was found to be increased in 12 autoimmune studies (+0.2 log fold change in 6 studies) and decreased in six cancer studies (-0.3 log fold change in 4 studies). Sulfur-metabolism pathways were found to be the most frequent pathways among the member of cancer-increased genus and species. CONCLUSIONS: The surprising reproducibility of these associations across studies and geographies suggests a shared underlying mechanism shaping the microbiome across cancers and autoimmune diseases. Video Abstract.

Identification of novel small molecule antimicrobials targeting Mycoplasma bovis.

OBJECTIVES: To screen novel small molecule compounds for inhibition of Mycoplasma bovis growth and to characterize their activity in terms of dose-dependency and ability to function in milk. METHODS: Using a tetrazolium salt cytotoxicity assay, 480 natural compounds were screened to determine which of the small molecules have the potential to become therapeutic options for M. bovis prevention and treatment. The dose response was determined in broth culture and in fresh quarter milk for a subset of compounds shown to be capable of inhibiting M. bovis growth. RESULTS: Data suggest that 32 of the 480 compounds tested were able to inhibit growth of M. bovis using a tetrazolium salt assay. Methanesulphonic acid, 3-[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyloxy](1S,3R,4R,5R)-1,4,5-trihydroxycyclohexane carboxylic acid, S-carboxymethyl-l-cysteine, l-aspartic acid, dihydrotachysterol, eriodictyol and (+)-α-tocopherol acid succinate were selected for further concentration-dependent studies and testing in fresh quarter milk. Each compound demonstrated a dose response in broth culture and at 3 h and 24 h in fresh quarter milk. CONCLUSIONS: Small molecule natural compounds are capable of inhibiting the growth of M. bovis in both a pleuropneumonia-like organism (PPLO) medium and in fresh quarter milk. Results suggest that the compounds are mycoplasmastatic in a dose-dependent manner. By inhibiting M. bovis, small molecule natural compounds offer the potential for prophylactic or therapeutic use on organic and natural farms as a viable alternative to traditional antimicrobial agents.

A Denver Refugee Clinic Blood Lead Level Analysis in Refugee Females of Reproductive Age, 13-45 years, 2014-2019.

The objective was to determine if refugee females of reproductive age (FRA) are at risk of having elevated blood lead levels (BLL). A retrospective quality improvement project conducted at a Denver community health center (9/2014-3/2019) evaluated BLLs from initial domestic medical examinations (DME) in 312 FRA refugees (13-45 years). Associations between elevated BLL and demographic factors were explored using multivariable regression analysis. Of 312 FRA refugees, BLLs ranged from < 2.0 to 26.2 mcg/dL, 5% had elevated BLLs. Of pregnant refugees (49), 4% had elevated BLLs. Afghani country of origin was positively associated with elevated BLLs, adjusting for age (FRA: Prevalence Ratio 6.90 [2.68-17.77], p < 0.0001). Afghani FRA refugees, irrespective of pregnancy and breast-feeding status, should have BLL testing at DME. Nationally representative evaluations of FRA refugees are needed to determine if BLL screening should be expanded to all FRA refugees, irrespective of pregnancy or breast-feeding status.

A nonradioactive plate-based assay for stimulators of nonspecific DNA nicking by HIV-1 integrase and other nucleases.

Retroviral integrase enzymes have a nonspecific endonuclease activity that is stimulated by certain compounds, suggesting that integrase could be manipulated to damage viral DNA. To identify integrase stimulator (IS) compounds as potential antiviral agents, we have developed a nonradioactive assay that is suitable for high-throughput screening. The assay uses a 49-mer oligonucleotide that is 5'-labeled with a fluorophore, 3'-tagged with a quencher, and designed to form a hairpin that mimics radioactive double-stranded substrates in gel-based nicking assays. Reactions in 384-well plates are analyzed on a real-time PCR machine after a single heat denaturation and subsequent cooling to a point between the melting temperatures of unnicked substrate and nicked products (no cycling is required). Under these conditions, unnicked DNA reforms the hairpin and quenches fluorescence, whereas completely nicked DNA yields a large signal. The assay was linear with time, stimulator concentration, and amount of integrase, and 20% concentrations of the solvent used for many chemical libraries did not interfere with the assay. The assay had an excellent Z' factor, and it reliably detected known IS compounds. This assay, which is adaptable to other nonspecific nucleases, will be useful for identifying additional IS compounds to develop the novel antiviral strategy of stimulating integrase to destroy retroviral DNA.

Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development.

PURPOSE: Deregulation of phosphatidylinositol 3-kinase/Akt and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathways occurs in melanoma and breast cancer, deregulating normal cellular apoptosis and proliferation. Therapeutic cocktails simultaneously targeting these pathways could promote synergistically acting tumor inhibition. However, agents with manageable toxicity and mechanistic basis for synergy need identification. The purpose of this study is to evaluate the preclinical therapeutic efficacy and associated toxicity of combining sorafenib with nanoliposomal ceramide. EXPERIMENTAL DESIGN: Effects of sorafenib and nanoliposomal ceramide as single and combinatorial agents were examined on cultured cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assays and CalcuSyn software used to assess synergistic or additive inhibition. Western blotting measured cooperative effects on signaling pathways. Rates of proliferation, apoptosis, and angiogenesis were measured in size- and time-matched tumors to identify mechanistic basis for inhibition. Toxicity was evaluated measuring animal weight, blood toxicity parameters, and changes in liver histology. RESULTS: Sorafenib and nanoliposomal ceramide synergistically inhibited cultured cells by cooperatively targeting mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling. A 1- to 2-fold increase in cellular apoptosis and 3- to 4-fold decrease in cellular proliferation were observed following combination treatment compared with single agents, which caused synergistically acting inhibition. In vivo, an approximately 30% increase in tumor inhibition compared with sorafenib treatment alone and an approximately 58% reduction in tumor size compared with nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity. CONCLUSIONS: This study shows that nanoliposomal ceramide enhances effectiveness of sorafenib causing synergistic inhibition. Thus, a foundation is established for clinical trials evaluating the efficacy of combining sorafenib with nanoliposomal ceramide for treatment of cancers.

CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers.

CREB mediates effects of cyclic AMP on cellular gene expression. Ubiquitous CREB target genes are induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell-specific genes by targeting CBP/p300 to promoter-distal enhancer regions. Subsequent increases in histone acetylation facilitate recruitment of the coactivators CRTC2 and BRD4, leading to release of RNA polymerase II over the target gene body. Indeed, CREB-induced hyperacetylation of chromatin over superenhancers promoted beta cell-restricted gene expression, which is sensitive to inhibitors of CBP/p300 and BRD4 activity. Neurod1 appears critical in establishing nucleosome-free regions for recruitment of CREB to beta cell-specific enhancers. Deletion of a CREB-Neurod1-bound enhancer within the Lrrc10b-Syt7 superenhancer disrupted the expression of both genes and decreased beta cell function. Our results demonstrate how cross talk between signal-dependent and lineage-determining factors promotes the expression of cell-type-specific gene programs in response to extracellular cues.

The impact of pharmacists' input to reduce serotonin syndrome drug interactions in an Australian hospital.

BACKGROUND: Drug interactions contribute significantly to adverse-related events and hospital admissions. Example of common drug interactions includes combinations of medications that induces serotonin syndrome. Pharmacists are well placed in the multidisciplinary team to alert prescribers of these drug interactions and offer an alternative management. OBJECTIVE: The objective is to evaluate the effectiveness of pharmacists' input in preventing patients being discharged on clinically relevant drug interactions that have the potential to cause serotonin syndrome in an Australian hospital. METHOD: A retrospective cross-sectional audit of patients' case notes who were prescribed a combination of drugs likely to induce serotonin syndrome on admission were examined over a 3-month period. A predefined list of serotonin syndrome-inducing drugs of severity 1 and 2 was used to search for patients on these drug combinations on admission. The severities of the drug combinations were classified as per the Monthly Index of Medical Specialties drug interactions guide. Subsequent pharmacists' interventions were recorded on discharge to observe any change in prescribing practice. Descriptive statistics were used to analyze the data. P values were obtained using the Student's t-test and Fisher's exact tests. RESULTS: A total of 144 patients over 3 months were identified to have been prescribed a combination of drugs with a potential to cause serotonin syndrome during admission. Of these patients, 79 and 21% were prescribed combination of serotonergic drugs that were classified as severity 1 and 2, respectively, according to Monthly Index of Medical Specialties. A total of 56% (n = 81) of the audited patients were discharged with no serotonin syndrome-inducing drug combinations and 44% (n = 63) were discharged on serotonin syndrome-inducing drug combinations of severity 1 or 2. Pharmacist input has led to a significant reduction (relative risk reduction 44%; P < 0.0001) in the total number of patients who were discharged on severity 1 and 2 serotonin syndrome-inducing drug combinations. There were 87 patients (60%) who had a pharmacist input during admission. In this subset of the cohort, 36% (n = 31) of patients were discharged on serotonin syndrome-inducing drug combinations (combined both severity 1 and 2) compared with 56% (n = 32) in those who did not get a pharmacist input, P = 0.017. In addition, 64% (n = 56) of patients in this group were discharged on no serotonin syndrome-inducing drug combinations compared with 44% (n =  25) in the nonpharmacist group, P = 0.017. CONCLUSION: The audit highlights the pharmacists' role in significantly reducing clinically relevant drug interaction in patients prescribed serotonin syndrome-inducing drug combination in a single-center Australian hospital on discharge.

Development of a fresh cadaver model for instruction of ultrasound-guided breast biopsy during the surgery clerkship: pre-test and post-test results among third-year medical students.

BACKGROUND: The aim of our study was to determine if a fresh cadaver model is a viable method for teaching ultrasound (US)-guided breast biopsy of palpable breast lesions. METHODS: Third-year medical students were assessed both preinstruction and postinstruction on their ability to perform US-guided needle aspiration or biopsy of artificially created masses using a 10-item checklist. RESULTS: Forty-one third-year medical students completed the cadaver laboratory as part of the surgery clerkship. Eight items on the checklist were found to be significantly different between pre-testing and post-testing. The mean preinstruction score was 2.4, whereas the mean postinstruction score was 7.10 (P < .001). CONCLUSIONS: Fresh cadaver models have been widely used in medical education. However, there are few fresh cadaver models that provide instruction on procedures done in the outpatient setting. Our model was found to be an effective method for the instruction of US-guided breast biopsy among medical students.

Introducing a Fresh Cadaver Model for Ultrasound-guided Central Venous Access Training in Undergraduate Medical Education.

INTRODUCTION: Over the past decade, medical students have witnessed a decline in the opportunities to perform technical skills during their clinical years. Ultrasound-guided central venous access (USG-CVA) is a critical procedure commonly performed by emergency medicine, anesthesia, and general surgery residents, often during their first month of residency. However, the acquisition of skills required to safely perform this procedure is often deficient upon graduation from medical school. To ameliorate this lack of technical proficiency, ultrasound simulation models have been introduced into undergraduate medical education to train venous access skills. Criticisms of simulation models are the innate lack of realistic tactile qualities, as well as the lack of anatomical variances when compared to living patients. The purpose of our investigation was to design and evaluate a life-like and reproducible training model for USG-CVA using a fresh cadaver. METHODS: This was a cross-sectional study at an urban academic medical center. An 18-point procedural knowledge tool and an 18-point procedural skill evaluation tool were administered during a cadaver lab at the beginning and end of the surgical clerkship. During the fresh cadaver lab, procedure naïve third-year medical students were trained on how to perform ultrasound-guided central venous access of the femoral and internal jugular vessels. Preparation of the fresh cadaver model involved placement of a thin-walled latex tubing in the anatomic location of the femoral and internal jugular vein respectively. RESULTS: Fifty-six third-year medical students participated in this study during their surgical clerkship. The fresh cadaver model provided high quality and lifelike ultrasound images despite numerous cannulation attempts. Technical skill scores improved from an average score of 3 to 12 (p<0.001) and procedural knowledge scores improved from an average score of 4 to 8 (p<0.001). CONCLUSION: The use of this novel cadaver model prevented extravasation of fluid, maintained ultrasound-imaging quality, and proved to be an effective educational model allowing third-year medical students to improve and maintain their technical skills.

Predictors of serious bacterial infections in pediatric burn patients with fever.

To determine predictors of serious bacterial infections in pediatric burn patients with fever (core temp ≥38.5°C), the authors conducted a retrospective review of medical records of pediatric (0-18 years) patients admitted to the Arizona Burn Center between 2008 and 2011 with greater than 5% TBSA and inpatient hospitalization for ≥72 hours. The study group comprised patients with a febrile episode during their inpatient stay. Serious bacterial infection (the primary outcome variable) was defined as: bacteremia, urinary tract infection, meningitis (blood, urine, or cerebrospinal fluid culture positive for a pathogen respectively), pneumonia, line, and wound infection. A generalized estimating equation analysis was done to predict the presence or absence of serious bacterial infection. Of 1082 pediatric burn patients hospitalized during the study period, 353 met the study eligibility criteria. A total of 108 patients (30.6%) had at least one fever episode (fever group). No difference in demographic characteristics was noted between the fever and no-fever groups; significant differences were observed for: third-degree TBSA, second-degree TBSA, total operating room visits, length of stay, Injury Severity Score, and death. A total of 47.2% of the patients had one or more episodes of fever with serious bacterial infection. In a generalized estimating equation predictive model, presence of a central line, second-, and third-degree TBSA were predictive of serious bacterial infection in burn patients with fever. In this study, individual clinical variables such as tachypnea and tachycardia were not predictive of serious bacterial infections, but the presence of a central line, and larger TBSA were significant predictors of serious bacterial infections. Younger age (P =.08) and ventilator support (P =.057) also approached significance as predictors of serious bacterial infections.

Development and use of ceramide nanoliposomes in cancer.

Integration of C6-ceramide into stealth pegylated nanoliposomes has led to the development of a promising preclinical therapeutic alone and in combination with other agents for treatment of cancer. Ceramide itself has been implicated as a bioactive lipid second messenger mediating cell senescence, cell cycle arrest, and apoptosis. Recent lipidomic analyses have demonstrated that specific ceramide species are differentially metabolized in individual cancers. Therapeutics that increase ceramide levels in cancer tissues have shown increased cell death and tumor inhibition. However, the use of ceramide itself as therapeutic has been problematic due to its inherent hydrophobicity and insolubility, therefore limiting the application for intravenous administration. Pegylated nanoliposomes eliminate this issue and are able to enhance the intracellular delivery of ceramide to cancer cells.

Evaluation of a system to screen for stimulators of non-specific DNA nicking by HIV-1 integrase: application to a library of 50,000 compounds.

BACKGROUND: In addition to activities needed to catalyse integration, retroviral integrases exhibit non-specific endonuclease activity that is enhanced by certain small compounds, suggesting that integrase could be stimulated to damage viral DNA before integration occurs. METHODS: A non-radioactive, plate-based, solution phase, fluorescence assay was used to screen a library of 50,080 drug-like chemicals for stimulation of non-specific DNA nicking by HIV-1 integrase. RESULTS: A semi-automated workflow was established and primary hits were readily identified from a graphic output. Overall, 0.6% of the chemicals caused a large increase in fluorescence (the primary hit rate) without also having visible colour that could have artifactually caused this result. None of the potential stimulators from this moderate-size library, however, passed a secondary test that included an inactive integrase mutant that assessed whether the increased fluorescence depended on the endonuclease activity of integrase. CONCLUSIONS: This first attempt at identifying integrase stimulator compounds establishes the necessary logistics and workflow required. The results from this study should encourage larger scale high-throughput screening to advance the novel antiviral strategy of stimulating integrase to damage retroviral DNA.

Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer.

Poor prognosis cancers, such as pancreatic cancer, represent inherent challenges for ceramide-based nanotherapeutics due to metabolic pathways, which neutralize ceramide to less toxic or pro-oncogenic metabolites. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a bioactive lipid that is pro-apoptotic to many cancer cells, but not to normal cells. In this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide (Lip-C6) with either gemcitabine or an inhibitor of glucosylceramide synthase. We first assessed the biological effect of Lip-C6 in PANC-1 cells, a gemcitabine-resistant human pancreatic cancer cell line, and found that low doses alone did not induce cell toxicity. However, cytotoxicity was achieved by combining Lip-C6 with either non-toxic sub-therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Furthermore, these combinations with Lip-C6 cooperatively inhibited PANC-1 tumor growth in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine did not. Furthermore, by including PDMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS3, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we have demonstrated that nanoliposomal ceramide can be an effective anti-pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization.