Treatment with novel topoisomerase inhibitors in Ewing sarcoma models reveals heterogeneity of tumor response.

Introduction: The topoisomerase 1 (TOP1) inhibitor irinotecan is a standard-of-care agent for relapsed Ewing sarcoma (EWS), but its efficacy is limited by chemical instability, rapid clearance and reversibility, and dose-limiting toxicities, such as diarrhea. Indenoisoquinolines (IIQs) represent a new class of clinical TOP1 inhibitors designed to address these limitations.

Methods: In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS.

Author Correction: ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer.

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Tumor Suppression by Anti-Fibroblast Activation Protein Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor therapy that utilizes an antibody-photo-absorbing conjugate activated by near-infrared light.

Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope.

Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell.

Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis.

Background: Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases.

Methods: RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases.

Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins.

Background: Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics.

Methods: Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice.

The effect of aerosolized bacterial lysate on experimentally induced pneumonia in calves.

Bovine respiratory disease (BRD) often occurs during specific periods of increased susceptibility when stress, viral infection, or reduced air quality are thought to suppress respiratory defences. The innate immune system is rapidly responsive and broadly protective and could be a target for preventing BRD during these periods of increased susceptibility. This study tested the hypothesis that stimulation of pulmonary innate immune responses by aerosol delivery of a lysate of killed and bacteria would protect calves against pneumonia.

Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers.

Antibody-based therapies designed for human use frequently fail to cross-react with the murine isoform of their target. Because of this problem, preclinical studies of antibody-based mesothelin (Msl)-targeted therapeutics in immunocompetent systems have been limited by the lack of suitable mouse models. Here, we describe two immunocompetent humanized mesothelin transgenic mouse lines that can act as tolerant hosts for C57Bl/6-syngeneic cell lines expressing the human isoform of mesothelin.

Soft tissue sarcoma at the site of a previous laparoscopic-assisted gastropexy in a dog.

An 8-year-old, spayed female, Doberman pinscher dog was presented to the Ontario Veterinary College Health Sciences Center for evaluation of a large subcutaneous mass on the right cranial ventral abdomen. Computed tomography localized a 6 × 7 cm soft tissue mass to the site of a laparoscopic-assisted gastropexy performed 3 years earlier. Body wall resection with wide surgical margins was performed.

TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.

Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon.

Effect of aerosolized bacterial lysate on development of naturally occurring respiratory disease in beef calves.

Background: Bovine respiratory disease (BRD) is a major problem affecting beef cattle after arrival to feedlots. Alternatives to antibiotics are needed for prevention.

Hypothesis: Stimulation of pulmonary innate immune responses at the time of arrival to a feedlot reduces the occurrence and severity of BRD.

Naturally Acquired Mouse Kidney Parvovirus Infection Produces a Persistent Interstitial Nephritis in Immunocompetent Laboratory Mice.

Mouse kidney parvovirus (MKPV), also known as murine chapparvovirus (MuCPV), is an emerging, highly infectious agent that has been isolated from laboratory and wild mouse populations. In immunocompromised mice, MKPV produces severe chronic interstitial nephropathy and renal failure within 4 to 5 months of infection. However, the course of disease, severity of histologic lesions, and viral shedding are uncertain for immunocompetent mice.

Pulmonary and systemic responses to aerosolized lysate of Staphylococcus aureus and Escherichia coli in calves.

Background: Constitutive and inducible defenses protect the respiratory tract from bacterial infection. The objective of this study was to characterize the response to an aerosolized lysate of killed bacteria, as a basis for studying the regulation and in vivo effects of these inducible innate immune responses.

Results: Bacterial lysate consisting of heat-killed and sonicated Staphylococcus aureus and Escherichia coli was aerosolized to 6 calves and systemic and pulmonary innate immune and inflammatory responses were measured in the first 24 h relative to baseline.

Host Tolerance to Infection with the Bacteria that Cause Bovine Respiratory Disease.

Calves vary considerably in their pathologic and clinical responses to infection of the lung with bacteria. The reasons may include resistance to infection because of pre-existing immunity, development of effective immune responses, or infection with a minimally virulent bacterial strain. However, studies of natural disease and of experimental infections indicate that some calves develop only mild lung lesions and minimal clinical signs despite substantial numbers of pathogenic bacteria in the lung.

Effect of tracheal antimicrobial peptide on the development of Mannheimia haemolytica pneumonia in cattle.

Bacterial pneumonia causes significant economic loss to the beef industry and occurs at times of stress and viral infection. Administering antibiotics to at-risk calves is often used to prevent the disease, but alternatives to mass treatment with antibiotics are needed. Tracheal antimicrobial peptide (TAP), a β-defensin naturally produced by bovine airways, has bactericidal activity against the pathogens that cause pneumonia in cattle.

Development of an aerosolized Mannheimia haemolytica experimental pneumonia model in clean-catch colostrum-deprived calves.

Mannheimia haemolytica is an important cause of bovine respiratory disease (BRD). BRD is usually a multifactorial disease with host factors and viral infections influencing pathogenesis. Previous studies that have attempted to experimentally induce pneumonia using aerosolized M.

Observational Study Design in Veterinary Pathology, Part 2: Methodology.

Observational studies are a basis for much of our knowledge of veterinary pathology, yet considerations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offered advice on planning and carrying out an observational study. Part 2 of the series focuses on methodology.

Observational Study Design in Veterinary Pathology, Part 1: Study Design.

Observational studies are the basis for much of our knowledge of veterinary pathology and are highly relevant to the daily practice of pathology. However, recommendations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offer advice on planning and conducting an observational study with examples from the veterinary pathology literature.

Deserving citizenship? Exploring migrants' experiences of the 'citizenship test' process in the United Kingdom.

Since the early 2000s several European countries have introduced language and citizenship tests as new requirements for access to long-term residence or naturalization. The content of citizenship tests has been often presented as exclusionary in nature, in particular as it is based on the idea that access to citizenship has to be 'deserved'. In this paper, we aim to explore the citizenship tests 'from below', through the focus on the experience of migrants who prepare and take the 'Life in the UK' test, and with particular reference to how they relate to the idea of 'deservingness'.

Bovine neutrophils in health and disease.

Bovine neutrophils have similarities to those of other species with respect to mechanisms of their activation and migration into tissue, modulation of immune responses and the balance between microbial killing and host tissue damage. However, bovine neutrophils have biochemical and functional differences from those of other species, which may yield insights about the comparative biology of neutrophils. Neutrophils play protective and harmful roles in the infectious diseases of cattle that occur at times of transition: respiratory disease in beef calves recently arrived to feedlots and mastitis and other diseases of postparturient dairy cows.

Diagnosis and Management of Polycythemia Vera in a Ferret ().

A 5-y-old female ferret (Mustela putorius furo) was evaluated for diarrhea, anorexia, and lethargy for 1 wk. Only mild dehydration was detected on physical examination. CBC analysis revealed marked erythrocytosis with an unremarkable plasma biochemistry panel; follow-up CBC analyses revealed a consistent primary erythrocytosis.

Laser-induced breakdown spectroscopy for elemental characterization of calcitic alterations on cave walls.

Cave walls are affected by different kinds of alterations involving preservative issues in the case of ornate caves, in particular regarding the rock art covering the walls. In this context, coralloids correspond to a facies with popcorn-like aspect belonging to the speleothem family, mostly composed of calcium carbonate. The elemental characterization indicates the presence of elements that might be linked to the diagenesis and the expansion of the alterations as demonstrated by prior analyses on stalagmites.

Multi-block analysis coupled to laser-induced breakdown spectroscopy for sorting geological materials from caves.

In this study, multi-block analysis was applied for the first time to LIBS spectra provided by a portable LIBS system (IVEA Solution, France) equipped with three compact Czerny-Turner spectrometers covering the spectral ranges 200-397nm, 398-571nm and 572-1000nm. 41 geological samples taken from a laboratory-cave situated in the "Vézère valley", an area rich with prehistoric sites and decorated caves listed as a UNESCO world heritage in the south west of France, were analyzed. They were composed of limestone and clay considered as underlying supports and of two types of alterations referred as moonmilk and coralloid.