Hearing impairment is the most prevalent sensory disease in humans and can have dramatic effects on the development, and preservation, of our cognitive abilities and social interactions. Currently 20 % of the world\'s population suffer from a form of hearing impairment; this is predicted to rise to 25 % by 2050. Despite this staggering disease load, and the vast damage it inflicts on the social, medical and economic fabric of humankind, our ability to predict, or prevent, the loss of hearing is very poor indeed. We here make the case for a paradigm shift in our approach to studying deafness. By exploiting more forcefully the molecular-genetic conservation between human hearing and hearing in morphologically distinct models, such as the fruit fly Drosophila melanogaster, we believe, a deeper understanding of hearing and deafness can be achieved. An understanding that moves beyond the surface of the \'deafness genes\' to probe the underlying bedrock of hearing, which is shared across taxa, and partly shared across modalities. When it comes to understanding the workings (and failings) of human sensory function, a simple fruit fly has a lot to offer and a fly eye might sometimes be a powerful model for a human ear. Particularly the use of fly avatars, in which specific molecular (genetic or proteomic) states of humans (e.g. specific patients) are experimentally reproduced, in order to study the corresponding molecular mechanisms (e.g. specific diseases) in a controlled yet naturalistic environment, is a tool that promises multiple unprecedented insights. The use of the fly - and fly avatars - would benefit humans and will help enhance the power of other scientific models, such as the mouse.

Since the second half of the twentieth century, many important discoveries in the field of behavioral psychopharmacology have been made using operant conditioning cages. These cages provide objective data collection and have revolutionized behavioral research. Unfortunately, in the rush towards automation, many mistakes may have been made that could have been avoided by observing experimental animals. The study described in this paper is an excellent example of how important additional behavioral observation can be for interpreting instrumental data. In this study, we evaluated the effects of single injections of 3 different doses of agomelatine (5, 10, and 40 mg/kg) on feedback sensitivity in rats. To this end, we tested 40 animals in the instrumental probabilistic reversal learning task in a Latin square design. The highest applied dose of agomelatine, prima facie, reduced the sensitivity of rats to negative feedback - an effect that can be considered antidepressant. However, additional behavioral observation dramatically changed the interpretation of the results and revealed that the perceived effect of agomelatine on sensitivity to negative feedback can actually be attributed to drug-induced drowsiness.

RNA-sequencing (RNA-seq) technology has led to a surge of neuroscience research using animal models to probe the complex molecular mechanisms underlying brain function and behavior, including substance use disorders. However, findings from rodent studies often fail to be translated into clinical treatments. Here, we developed a novel pipeline for narrowing candidate genes from preclinical studies by translational potential and demonstrated its utility in 2 RNA-seq studies of rodent self-administration. This pipeline uses evolutionary conservation and preferential expression of genes across brain tissues to prioritize candidate genes, increasing the translational utility of RNA-seq in model organisms. Initially, we demonstrate the utility of our prioritization pipeline using an uncorrected P-value. However, we found no differentially expressed genes in either dataset after correcting for multiple testing with false discovery rate (FDR < 0.05 or <0.1). This is likely due to low statistical power that is common across rodent behavioral studies, and, therefore, we additionally illustrate the use of our pipeline on a third dataset with differentially expressed genes corrected for multiple testing (FDR < 0.05). We also advocate for improved RNA-seq data collection, statistical testing, and metadata reporting that will bolster the field\'s ability to identify reliable candidate genes and improve the translational value of bioinformatics in rodent research.

Additive genetic variance, VA, is the key parameter for predicting adaptive and neutral phenotypic evolution. Changes in demography (e.g. increased close-relative inbreeding) can alter VA, but how they do so depends on the (typically unknown) gene action and allele frequencies across many loci. For example, VA increases proportionally with the inbreeding coefficient when allelic effects are additive, but smaller (or larger) increases can occur when allele frequencies are unequal at causal loci with dominance effects. Here, we describe an experimental approach to assess the potential for dominance effects to deflate VA under inbreeding. Applying a powerful paired pedigree design in Drosophila serrata, we measured 11 wing traits on half-sibling families bred via either random or sibling mating, differing only in homozygosity (not allele frequency). Despite close inbreeding and substantial power to detect small VA, we detected no deviation from the expected additive effect of inbreeding on genetic (co)variances. Our results suggest the average dominance coefficient is very small relative to the additive effect, or that allele frequencies are relatively equal at loci affecting wing traits. We outline the further opportunities for this paired pedigree approach to reveal the characteristics of VA, providing insight into historical selection and future evolutionary potential.

Although acute cardiac tamponade is one of the major problems in clinical practice, a suitable animal model is still lacking. We tried to create acute cardiac tamponade in macaques by echo-guided catheter manipulation. A 13-year-old male macaque was anesthetized, and a long sheath was inserted into the left ventricle via the left carotid artery under the guidance of transthoracic echocardiography. The sheath was then inserted into the orifice of the left coronary artery to perforate the proximal site of the left anterior descending branch. A cardiac tamponade was successfully created. Injection of diluted contrast agent into the pericardial space via a catheter made it possible to clearly distinguish between the hemopericardium and the surrounding tissues on postmortem computed tomography. This procedure did not need an X-ray imaging system during catheterization. Our present model would help us examine the intrathoracic organs in the presence of acute cardiac tamponade.

BACKGROUND: Osteosarcoma (OS) is an aggressive malignant bone tumour with high mortality. A poor prognosis is noted in patients with distal metastases or multidrug resistance. As an emerging antitumor strategy, photodynamic therapy (PDT) mediated by visible and near infrared light has attracted intensive attention given its target selectivity, remote controllability, minimal or non-invasive features. However, PDT also has obvious limitations. Specifically, due to the limited penetration of light, it is mainly used in the clinical treatment of superficial malignant tumours, such as musculoskeletal sarcomas and melanoma, but it has not been applied to the clinical treatment of deep malignant bone tumours except for a very small number of experiments on deep canine OS models.
METHODS: We searched for studies that focused on the effectiveness and safety of PDT for OS based on in vitro experiments and animal models in the last decade. A systematic search was conducted using electronic databases, including PubMed, ClinicalTrials.gov, and the Cochrane Library.
METHODS: (1) original research articles about PDT for OS; (2) articles in English; (3) in vitro or animal model research; and (4) detailed information, including cell name, fluence, irradiation wavelength, time of incubation with PS, duration between PS treatment and irradiation, and duration between irradiation and viability assays.
METHODS: (1) study was a review/systemic review article, patent, letter, or conference abstract/paper; (2) articles were not published in English; (3) studies containing overlapping or insufficient data.
RESULTS: We identified 201 publications, and 44 articles met the inclusion criteria and were included in the synthesis. Unfortunately, there are no relevant clinical reports of the use of PDT in the treatment of human OS. In these studies, 8 studies only employed in vivo experiments to evaluate the efficiency of PDT in an OS animal model, 19 studies exclusively performed in vitro viability assays of cells treated with PDT under different conditions, and 17 studies included in vitro cell experiments and in vivo animal OS models to evaluate the effect of PDT on OS in vivo and in vitro. All studies have shown that PDT is cytotoxic to OS cells or can inhibit the growth of OS in heterologous or homologous animal OS models but exhibits minimal cytotoxicity at a certain range of dosages.
CONCLUSIONS: Based on this systematic review, PDT can eradicate OS cells in cell culture and there is some evidence for efficacy in animal models. However, the ability for PDT to control human OS is unclear, the animal and human reports do not show evidence of human OS control, they just do show feasibility. The major issues concerning the potential for treatment of osteosarcoma with PDT are that adequate light should be transmitted to tumor loci and if the disease is caught before metastasis and irradiation of tumor sites is feasible, curative potential is there. Otherwise, PDT may be mainly palliative. To determine whether PDT can safely and efficiently be used in the clinical treatment of OS, many preclinical orthotopic animal OS models and OS models of multiple systemic metastases must be performed and interstitial PDT or intraoperative PDT may be a good and potential candidate for human OS treatment. If these problems can be well solved, PDT may be a potentially effective strategy for the treatment of OS patients.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a potentially fatal infectious disease requiring long treatment duration with multiple antibiotics and against which there is no reliable cure. Among the factors that have hampered the development of adequate drug regimens is the lack of an animal model that reproduces the NTM lung pathology required for studying antibiotic penetration and efficacy. Given the documented similarities between tuberculosis and NTM immunopathology in patients, we first determined that the rabbit model of active tuberculosis reproduces key features of human NTM-PD and provides an acceptable surrogate model to study lesion penetration. We focused on clarithromycin, a macrolide and pillar of NTM-PD treatment, and explored the underlying causes of the disconnect between its favorable potency and pharmacokinetics and inconsistent clinical outcome. To quantify pharmacokinetic-pharmacodynamic target attainment at the site of disease, we developed a translational model describing clarithromycin distribution from plasma to lung lesions, including the spatial quantitation of clarithromycin and azithromycin in mycobacterial lesions of two patients on long-term macrolide therapy. Through clinical simulations, we visualized the coverage of clarithromycin in plasma and four disease compartments, revealing heterogeneous bacteriostatic and bactericidal target attainment depending on the compartment and the corresponding potency against nontuberculous mycobacteria in clinically relevant assays. Overall, clarithromycin\'s favorable tissue penetration and lack of bactericidal activity indicated that its clinical activity is limited by pharmacodynamic, rather than pharmacokinetic, factors. Our results pave the way toward the simulation of lesion pharmacokinetic-pharmacodynamic coverage by multidrug combinations to enable the prioritization of promising regimens for clinical trials.

The ongoing COVID-19 pandemic caused by infection with SARS-CoV-2 has created an urgent need for animal models to enable study of basic infection and disease mechanisms and for development of vaccines, therapeutics, and diagnostics. Most research on animal models for COVID-19 has been directed toward rodents, transgenic rodents, and non-human primates. The primary focus has been on the angiotensin-converting enzyme 2 (ACE2), which is a host cell receptor for SARS-CoV-2. Among investigated species, irrespective of ACE2 spike protein binding, only mild (or no) disease has occurred following infection with SARS-CoV-2, suggesting that ACE2 may be necessary for infection but is not sufficient to determine the outcome of infection. The common trait of all species investigated as COVID models is their healthy status prior to virus challenge. In contrast, the vast majority of severe COVID-19 cases occur in people with chronic comorbidities such as diabetes, obesity, and/or cardiovascular disease. Healthy pigs express ACE2 protein that binds the viral spike protein but they are not susceptible to infection with SARS-CoV-2. However, certain pig breeds, such as the Ossabaw pig, can reproducibly be made obese and show most aspects of the metabolic syndrome, thus resembling the more than 80% of the critically ill COVID-19 patients admitted to hospitals. We urge considering infection with porcine respiratory coronavirus of metabolic syndrome pigs, such as the obese Ossabaw pig, as a highly relevant animal model of severe COVID-19.

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UNASSIGNED: Non-islet cell tumor hypoglycemia is a rare paraneoplastic syndrome associated with tumors. Although it mainly occurs in solid tumors of mesenchymal and epithelial origin, but rarely also in hematopoietic and neuroendocrine origin.
UNASSIGNED: We describe a 65-year-old man with a muscle-invasive bladder urothelial carcinoma, which rapidly progressed against systemic chemotherapy consisting of gemcitabine and cisplatin. Notably, the patient developed hypoglycemia at the terminal stage of the disease. Pathological diagnosis was giant cell urothelial carcinoma, which was strongly positive for insulin-like growth factor-II in immunohistochemistry. We established patient-derived xenograft from insulin-like growth factor-II producing bladder urothelial carcinoma that caused non-islet cell tumor hypoglycemia. Although we evaluated the efficacy of the neutralizing antibody, there was no statistically significant inhibitory effect on tumor growth.
UNASSIGNED: To the best of our knowledge, this is the first report of insulin-like growth factor-II-producing urothelial carcinoma that have been recapitulated in a patient-derived xenograft model.