Rational design of peptide derivatives for inhibition of MyD88‐mediated toll‐like receptor signaling in human peripheral blood mononuclear cells and epithelial cells exposed to Francisella tularensis

Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88‐mediated toll‐like receptor (TLR) signaling by Francisella tularensis. Fifty‐three tripeptide derivatives were synthesized to mimic a key BB‐loop region involved in toll‐like/interleukin‐1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF‐α, IFN‐γ, IL‐6, and IL‐1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F. tularensis. From 53 compounds synthesized and tested, ten compounds were identified as effective inhibitors of F. tularensisLPS‐induced cytokines. Compound stability testing in the presence of human liver microsomes and human serum resulted in the identification of tripeptide derivative 7 that was a potent, stable, and drug‐like small molecule. Target corroboration using a cell‐based reporter assay and competition experiments with MyD88 TIR domain protein supported that the effect of 7 was through MyD88 TIR domain interactions. Compound 7 also attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis at a multiplicity of infection of 1:5. Small molecules that target TIR domain interactions in MyD88‐dependent TLR signaling represent a promising strategy toward host‐directed adjunctive therapeutics for inflammation associated with biothreat agent‐induced sepsis.     

Extensively remodeled,fractured cetacean tympanic bullae show that whales can survive traumatic injury to the ears

Underwater human activities and anthropogenic noise in our oceans may be a major source of habitat degradation for marine life. This issue was highlighted by the opening of the United States Eastern Seaboard for seismic oil and gas exploration in 2014, which generated massive media coverage and widespread concern that seismic surveys could kill or deafen whales. We discovered 11 new specimens of fractured and healed cetacean ear bones, out of a survey of 2127 specimens housed in museum collections. This rare condition has been previously reported only in two specimens of blue whales (Balaenoptera musculus) from the early 1900s, summarized by Fraser & Purves ( 1953 ). All of our new specimens are represented by species for which this condition had never been reported previously, including both baleen and toothed whales. The baleen whale specimens (Balaenoptera physalus, Balaenoptera borealis, Balaenoptera acutorostrata) were collected during Canadian commercial whaling operations in the Atlantic Ocean in the 1970s; the specimens include ear bones with well‐healed fractures, demonstrating that baleen whales are capable of overcoming traumatic injury to the ears. The toothed whale specimens (Delphinus sp., Berardius bairdii) were found dead on beaches in 1972 and 2001, respectively, with less remodeled fractures. Thus, ear injuries may be more lethal to the echolocating toothed whales, which rely on hearing for navigation and foraging. We explore several hypotheses regarding how these injuries could have occurred, and conclude that the most parsimonious explanations appear to be both direct and indirect effects of lytic processes from disease or calcium depletion, or damage from external pressure waves. Although further research is required to confirm whether the fractures resulted from natural or human‐induced events, this study underscores the importance of museum collections and the work of stranding networks in understanding the potential effects of modern human activities on marine mammal health.     

Optimizing antibiotic prescribing: collective approaches to managing a common-pool resource

BackgroundAntimicrobial resistance (AMR) is one of the greatest threats in 21st century medicine. AMR has been characterized as a social dilemma. A familiar version describes the situation in which a collective resource (in this case, antibiotic efficacy) is exhausted due to over-exploitation. The dilemma arises because individuals are motivated to maximize individual payoffs, although the collective outcome is worse if all act in this way.ObjectivesWe aim to outline the implications for antimicrobial stewardship of characterizing antibiotic overuse as a social dilemma.SourcesWe conducted a narrative review of the literature on interventions to promote the conservation of resources in social dilemmas.ContentThe social dilemma of antibiotic over-use is complicated by the lack of visibility and imminence of AMR, a loose coupling between individual actions and the outcome of AMR, and the agency relationships inherent in the prescriber role. We identify seven strategies for shifting prescriber behaviour and promoting a focus on the collectively desirable outcome of conservation of antibiotic efficacy: (1) establish clearly defined boundaries and access rights; (2) raise the visibility and imminence of the problem; (3) enable collective choice arrangements; (4) conduct behaviour-based monitoring; (5) use social and reputational incentives and sanctions; (6) address misalignment of goals and incentives; and (7) provide conflict resolution mechanisms.ImplicationsWe conclude that this theoretic analysis of antibiotic stewardship could make the problem of optimizing antibiotic prescribing more tractable, providing a theory base for intervention development.     

Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Philadelphia chromosome–like (Ph-like) acute lymphoblastic leukemia (ALL) is a subset of high-risk B cell ALLs. A large proportion of Ph-like ALL cases carry activating kinase mutations that could potentially allow them to be targeted by tyrosine kinase inhibitors. Ph-like ALL is not an uncommon entity, especially among adults, with a frequency exceeding 20%, including in older patients (>60 years old) with ALL. Ph-like ALL is associated with inferior outcomes across all ages, and studies have consistently shown a higher incidence of persistent postinduction minimal residual disease in patients carrying Ph-like ALL compared with other subgroups of ALL, and this translates into inferior leukemia-related outcomes. The inferior outcome of conventional chemotherapy for Ph-like ALL in adults raises the fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters. Here we present and discuss several scenarios in which adults with Ph-like ALL underwent or were considered for HCT in CR1 for various reasons. Although the decision to proceed with HCT was clear and indisputable in some of these situations, in others we struggled with the decision to transplant in CR1 because of the lack of published data regarding the efficacy of allogeneic HCT as consolidation for Ph-like ALL. We emphasize the urgent need for developing well-designed studies to address this important question.     

Association between polycyclic aromatic hydrocarbon-DNA adduct levels in maternal and newborn white blood cells and glutathione S-transferase P1 and CYP1A1 polymorphisms.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants; a number are carcinogenic. Metabolic polymorphisms may modulate susceptibility to PAH-induced DNA damage and carcinogenesis. This study investigates the relationship between PAH-DNA adduct levels (in maternal and newborn WBCs) and two polymorphisms: (a) an MspI RFLP in the 3' noncoding region of cytochrome P4501A1 (CYP1A1); and (b) an A-->G transition in nucleotide 313 of glutathione S-transferase P1 (GSTP1), resulting in an ile105val substitution. CYP1A1 catalyzes the bioactivation of PAH; the CYP1A1 MspI RFLP has been associated with cancer of the lung. GSTP1 catalyzes the detoxification of PAH; the val allele has greater catalytic efficiency toward PAH diol epoxides. The study involves 160 mothers and their newborns from Poland. Regression models controlled for maternal smoking and other confounders. No association was seen between maternal adduct levels and either polymorphism, separately or combined. However, adduct levels were higher among newborns with the CYP1A1 MspI restriction site (heterozygotes and homozygotes combined) compared with newborns lacking the restriction site (P = 0.06). Adducts were higher among GSTP1 ile/val and ile/ile newborns compared with GSTP1 val/val newborns (P = 0.08). Adduct levels were 4-fold higher among GSTP1 ile/ile newborns having the CYP1A1 restriction site compared with GSTP1 val/val newborns who lacked the CYP1A1 restriction site (P = 0.04). This study demonstrates a significant combined effect of phase I and phase II polymorphisms on DNA damage from PAHs in fetal tissues. It illustrates the importance of considering interindividual variation in assessing risks of transplacental exposure to PAHs.     

Unusual findings in the inguinal canal: a report of four cases

Masses in the inguinal canal other than hernias are rare occurrences, and their preoperative diagnosis requires a high index of suspicion. A soft, partly reducible groin mass in a 3-month-old boy proved to be a cystic lymphangioma within the inguinal canal. A 15-month-old female who presented with an irreducible inguinal mass was found to have a neuroblastoma metastasis in the groin. An irreducible groin mass in a 6-year-old female proved to be an inguinal canal epidermal inclusion cyst. A 14-year-old female presented with a painful groin swelling that represented an incarcerated hemorrhagic ovarian cyst. An awareness of the wide spectrum of entities other than the standard bowel, testicle, and ovary in the inguinal canal can help to identify uncommon pathologies preoperatively. Accepted: 6 January 1998     

Metabolism of 4′-thio-β- -arabinofuranosylcytosine in CEM cells

Because of the excellent in vivo activity of 4′-thio-β- -arabinofuranosylcytosine (T-araC) against a variety of human solid tumors, we have studied its metabolism in CEM cells to determine how the biochemical pharmacology of this compound differs from that of β- -arabinofuranosylcytosine (araC). Although there were many quantitative differences in the metabolism of T-araC and araC, the basic mechanism of action of T-araC was similar to that of araC: it was phosphorylated to T-araC-5′-triphosphate (T-araCTP) and inhibited DNA synthesis. The major differences between these two compounds were: (i) T-araC was phosphorylated to active metabolites at 1% the rate of araC; (ii) T-araCTP was 10- to 20-fold more potent as an inhibitor of DNA synthesis than was the 5′-triphosphate of araC (araCTP); (iii) the half-life of T-araCTP was twice that of araCTP; (iv) the catalytic efficiency of T-araC with cytidine deaminase was 10% that of araC; and (v) the 5′-monophosphate of araC was a better substrate for deoxycytidine 5′-monophosphate deaminase than was the 5′-monophosphate of T-araC. Of these differences in the metabolism of these two compounds, we propose that the prolonged retention of T-araCTP is a major factor contributing to the activity of T-araC against solid tumors. The data in this study represent another example of how relatively small structural changes in nucleoside analogs can profoundly affect the biochemical activity.     

Basaloid squamous carcinoma metastatic to renal-cell carcinoma: Fine-needle aspiration cytology of tumor-to-tumor metastasis

We describe an unusual case of a basaloid squamous-cell carcinoma (BSCC) of the tonsil in a 56-yr-old man that metastasized to a primary renal-cell carcinoma (RCC) and the lung. The diagnosis of the second primary, the RCC, was based on fine-needle aspiration (FNA) cytology. A subsequent nephrectomy specimen revealed BSCC metastatic to RCC, clear-cell type. Retrospective analysis of the FNA of the renal mass revealed classic RCC morphology and, in addition, another cytologically distinctive pattern characterized by occasional sheets of cohesive neoplastic cells with hyperchromatic nuclei and nuclear molding representative of BSCC. The cytologic features of a subsequent FNA of the lung were characteristic of metastatic BSCC. Our retrospective analysis of cytologic material from the renal mass underscores the importance of raising the possibility of tumor-to-tumor metastasis when distinctly different morphologic features are seen in an otherwise typical cytology of a neoplasm in patients with an already known or suspected second primary. To our knowledge, this case report is the first one documenting metastasis of BSCC to RCC. Diagn. Cytopathol. 1997;17:379–382. © 1997 Wiley-Liss, Inc.