Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Munchausen's syndrome.

Establishment and Characterization of Seven Dunning Rat Prostatic Cancer Cell Lines and Their Use in Developing Methods for Predicting Metastatic Abilities of Prostatic Cancers

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer. Citation Format: Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F. Greenwald, Coyin Oh, Juliann Shih, James M. McFarland, Bang Wong, Jesse S. Boehm, Rameen Beroukhim, Todd R. Golub. Patient-derived xenografts undergo mouse-specific tumor evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1028.

Abstract 1028: Patient-derived xenografts undergo mouse-specific tumor evolution

The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process.

https://www.mdpi.com/1422-0067/21/12/4449/pdf

Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis

Metastatic disease is the principal cause of prostate-cancer-related mortality. Our ability to accurately recapitulate the spread of prostate cancer to bone - the most common site of metastasis - is critical to the development of novel metastasis-directed therapies. Several translational models of prostate cancer bone metastasis have been developed, including animal models, cell line injection models, 3D in vitro models, bone implant models, and patient-derived xenograft models. The use of these models has led to numerous advances in elucidating the molecular mechanisms of metastasis and innovations in targeted therapy. Despite this progress, current models are limited by a failure to holistically reproduce each individual element of the metastatic cascade in prostate cancer bone metastasis. In addition, factors such as accurate recapitulation of immunobiological events and improvements in tumour heterogeneity require further consideration. Knowledge gained from historical and currently used models will improve the development of next-generation models. An introspective appraisal of current preclinical models demonstrating bone metastases is warranted to narrow research focus, improve future translational modelling, and expedite the delivery of urgently needed metastasis-directed treatments.

Translational models of prostate cancer bone metastasis

Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper.

/pdf/drosophila-melanogaster-as-a-function-based-high-throughput-338s9008vf.pdf

Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients

Munchausen Syndrome by Proxy (MSBP) is a psychiatric disorder characterised by the adoption of bizarre behavioural-patterns by caregivers in which diseases or disorders are fabricated in individuals, usually children, for purposes which span feelings of superiority derived from deceit of persons deemed superior to the caregiver, or attention seeking. The patient under discussion was a 6 year old male brought to the hospital by his mother with complaints of repetitive and unceasing passing of stones per urethra. Upon inspection of stone specimens brought in by the parents and physical examination, the stones in question were observed to be common stones, with no reason to suggest a urolithiatic origin, leading to the suspicion of MSBP. Further questioning of both the mother and father revealed more information regarding the cause of her child's illness and strongly suggested that the stones were being physically inserted into the child's urethra by the mother--often in the father's absence--after administration of sedative-hynotic drugs.

Münchausen syndrome by proxy: the overlooked diagnosis

Ureteral triplication is a rare congenital anomaly of the urinary tract. Since the first description by Warny in 1870, approximately 100 known cases have been reported in the literature, often accompanied by a variety of associated anomalies in contralateral kidney. This report presents a case of ureteral triplication with contralateral duplication and vesicoureteral reflux (VUR) of the upper moiety on the triplicate side. The patient was a 10 year old male who presented with a history of recurrent urinary tract infections and right loin pain. ACT urogram was performed which showed a triplicate right ureter with gross hydroureter of the upper moiety. There was a duplex system present on the left side. The patient underwent right upper pole heminephroureterectomy. Keywords: Hydronephrosis, vesicoureteric reflux, ureteral, duplication, triplication

/pdf/ureteral-triplication-and-contralateral-duplication-with-3d590s15ae.pdf

Aymon Naushad Ali

Papers

Translational models of prostate cancer bone metastasis

Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients

Münchausen syndrome by proxy: the overlooked diagnosis

Ureteral triplication and contralateral duplication with vesicoureteral reflux