't Hooft suppression and holographic entropy

Recent works have related the bulk first law of black hole mechanics to the first law of entanglement in a dual CFT. These are first order relations, and receive corrections for finite changes. In particular, the latter is naively expected to be accurate only for small changes in the quantum state. But when Newton's constant is small relative to the AdS scale, the former holds to good approximation even for classical perturbations that contain many quanta. This suggests that -- for appropriate states -- corrections to the first law of entanglement are suppressed by powers of $N$ in CFTs whose correlators satisfy 't Hooft large-$N$ power counting. We take first steps toward verifying that this is so by studying the large-$N$ structure of the entropy of spatial regions for a class of CFT states motivated by those created from the vacuum by acting with real-time single-trace sources. We show that $1/N$ counting matches bulk predictions, though we require the effect of the source on the modular hamiltonian to be non-singular. The magnitude of our sources is $\epsilon N$ with $\epsilon$ fixed-but-small as $N\rightarrow \infty$. Our results also provide a perturbative derivation -- without relying on the replica trick -- of the subleading Faulkner-Lewkowycz-Maldacena correction to the Ryu-Takayagi and Hubeny-Rangamani-Takayanagi conjectures at all orders in $1/N$.Comment: 24 pages, no figures. v2: minor changes to agree with published versio

Clinical and Pathologic Factors In Breast Cancer Patients with Bone Metastases Undergoing Surgery for Pathologic and Impending Fractures

Introduction: Metastatic lesions to bone carry a poor prognosis. Bone lesions can be responsible for significant morbidity in patients, including pathologic or impending fractures that may require emergent surgical evaluation. Objective: We evaluated the clinical and pathologic features associated with breast cancer patients with bone metastases who underwent surgery for pathologic or impending fractures. Methods: A retrospective chart review of 20 breast cancer patients with bone metastases who underwent surgery from the Bone Biorepository Bank at Sidney Kimmel Cancer Center was performed. We evaluated their clinical and pathologic characteristics and performed Fisher’s Exact Testing to explore potential associations. Results: 90% and 15% of patients received systemic chemotherapy and bone directed radiation prior to surgery, respectively. The average time between diagnosis to surgery was 6.21 years and the average patient age was 63 years. 60% of the tumor specimens demonstrated medium or high tumor burden. Similarly, 70% of the tumor specimens demonstrated a medium or high stromal proliferative response. On Fisher’s Exact Test, while both stromal proliferative response and tumor burden trended towards an association, this was not found to be statistically significant. Discussion: Breast cancer patients undergoing surgery for boney metastasis were noted to have a wide range of ages and time from diagnosis to surgery. While there was a higher percentage of patients with tumors of high and medium tumor burden and stromal proliferative response, this trend was not found to be statistically significant. Future studies with larger sample sizes are required to determine the relationship between these features

Effect of conjugated bile salts on antibiotic susceptibility of bile salt-tolerant Lactobacillus and Bifidobacterium isolates.

Virtually every antibiotic may cause in vivo alterations in the number, level, and composition of the indigenous microbiotae. The degree to which the microbiotae are disturbed depends on many factors. Although bile may augment antibiotic activity, studies on the effect of bile on the antibiotic susceptibility of indigenous and exogenous probiotic microorganisms are lacking. It was against this background that the antibiotic susceptibility of 37 bile salt-tolerant Lactobacillus and 11 Bifidobacterium isolates from human and other sources was determined in the presence of 0.5% wt/wt oxgall (conjugated bile salts). Oxgall did not affect the intrinsic resistance of lactobacilli to metronidazole (5 microg), vancomycin (30 microg), and cotrimoxazole (25 microg), whereas it resulted in a complete loss of resistance to polymyxin B (300 microg) and the aminoglycosides gentamicin (10 microg), kanamycin (30 microg), and streptomycin (10 microg) for most strains studied (P < 0.001). Oxgall did not affect the intrinsic resistance of bifidobacteria to metronidazole and vancomycin, whereas polymyxin B and co-trimoxazole resistance was diminished (P < 0.05) and aminoglycoside resistance was lost (P < 0.001). Seven lactobacilli, but no bifidobacteria strain, showed unaltered intrinsic antibiotic resistance profiles in the presence of oxgall. Oxgall affected the extrinsic susceptibility of lactobacilli and bifidobacteria to penicillin G (10 microg), ampicillin (10 microg), tetracycline (30 microg), chloramphenicol (30 microg), erythromycin (15 microg), and rifampicin (5 microg) in a source- and strain-dependent manner. Human strain-drug combinations of lactobacilli (P < 0.05) and bifidobacteria (P < 0.01) were more likely to show no change or decreased susceptibility compared with other strain-drug combinations. The antimicrobial activity spectra of polymyxin B and the aminoglycosides should not be considered limited to gram-negative bacteria but extended to include gram-positive genera of the indigenous and transiting microbiotae in the presence of conjugated bile salts. Those lactobacilli (7 of 37) that show unaltered intrinsic and diminished extrinsic antibiotic susceptibility in the presence of oxgall may possess greater upper gastrointestinal tract transit tolerance in the presence of antibiotics

Antibiotic susceptibility of potentially probiotic Lactobacillus species.

In recent years, the time-honored reputation of lactobacilli as promoters of gastrointestinal and female urogenital health has been qualified. This has occurred due to a rare association with human infection in the presence of certain predisposing factors and their potential to act as a source of undesirable antibiotic resistance determinants to other members of the indigenous microbiota. This necessitates greater caution in their selection for use in microbial adjunct nutrition and disease management (prophylaxis and therapy). It was against this background that 46 Lactobacillus strains from human and dairy sources were assayed for susceptibility to 44 antibiotics. All strains were resistant to a group of 14 antibiotics, which included inhibitors of cell wall synthesis (cefoxitin [30 microg] and aztreonam [30 microg]), protein synthesis (amikacin [30 microg], gentamicin [10 microg], kanamycin [30 microg], and streptomycin [10 microg]), nucleic acid synthesis (norfloxacin [10 microg], nalidixic acid [30 microg], sulphamethoxazole [100 microg], trimethoprim [5 microg], co-trimoxazole [25 microg], and metronidazole [5 microg]), and cytoplasmic membrane function (polymyxin B [300 microg] and colistin sulphate [10 microg]). All strains were susceptible to tetracycline (30 microg), chloramphenicol (30 microg), and rifampicin (5 microg). Four human strains and one dairy strain exhibited atypical resistance to a penicillin, bacitracin (10 microg), and/or nitrofurantoin (300 microg). One human strain was also resistant to erythromycin (15 microg) and clindamycin (2 microg). These resistances may have been acquired due to antibiotic exposure in vivo, but conclusive evidence is lacking in this regard. Seven microorganism-drug combinations were evaluated for beta-lactamase activity using synergy and nitrocefin tests. The absence of activity suggested that cell wall impermeability appeared responsible for beta-lactam resistance. The occurrence of a minority of lactobacilli with undesirable, atypical resistance to certain antibiotics demonstrates that not all strains are suitable for use as probiotics or bacteriotherapeutic agents. The natural resistance of lactobacilli to a wide range of clinically important antibiotics may enable the development of antibiotic/probiotic combination therapies for such conditions as diarrhea, female urogenital tract infection, and infective endocarditis

Dysregulated methylation at imprinted genes in prostate tumor tissue detected by methylation microarray.

BACKGROUND: Imprinting is an important epigenetic regulator of gene expression that is often disrupted in cancer. While loss of imprinting (LOI) has been reported for two genes in prostate cancer (IGF2 and TFPI2), disease-related changes in methylation across all imprinted gene regions has not been investigated. METHODS: Using an Illumina Infinium Methylation Assay, we analyzed methylation of 396 CpG sites in the promoter regions of 56 genes in a pooled sample of 12 pairs of prostate tumor and adjacent normal tissue. Selected LOI identified from the array was validated using the Sequenom EpiTYPER assay for individual samples and further confirmed by expression data from publicly available datasets. RESULTS: Methylation significantly increased in 52 sites and significantly decreased in 17 sites across 28 unique genes (P \u3c 0.05), and the strongest evidence for loss of imprinting was demonstrated in tumor suppressor genes DLK1, PLAGL1, SLC22A18, TP73, and WT1. Differential expression of these five genes in prostate tumor versus normal tissue using array data from a publicly available database were consistent with the observed LOI patterns, and WT1 hypermethylation was confirmed using quantitative DNA methylation analysis. CONCLUSIONS: Together, these findings suggest a more widespread dysregulation of genetic imprinting in prostate cancer than previously reported and warrant further investigation

Triarylmethyl Cation-Catalyzed Three-Component Coupling for the Synthesis of Unsymmetrical Bisindolylmethanes [post-print]

An efficient synthesis of unsymmetrical bisindolylmethanes has been accomplished using triarylmethyl cations to catalyze the reaction of N-arylimines with two different indoles. Optimization of the organocatalyst by tuning cation stability allows for excellent single addition selectivity when coupled with p-nitrophenyl imines. The optimal catalyst is commercially available, and the reaction minimizes waste and environmental impact by employing a one-to-one ratio of starting materials. The intermediates can be isolated or used in situ in a one-pot two-step reaction to generate unsymmetrical bisindolylmethanes in high yields. The reaction tolerates a broad range of imines with the highest yields observed for electron-poor and neutral imines. A wide range of indole nucleophiles are also successfully employed allowing for the creation of a large variety of unsymmetrical bisindolylmethanes

T-Cell Redirecting Bispecific Antibodies: A Review of a Novel Class of Immuno-Oncology for Advanced Prostate Cancer

Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation

A Scoping Review Protocol to Elucidate Outcomes Following Abiraterone Versus Enzalutamide for Prostate Cancer

INTRODUCTION: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making. METHOD AND ANALYSIS: The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation. ETHICS AND DISSEMINATION: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227