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The theory of cancer immunoediting, which describes the dynamic interactions between tumors and host immune cells that shape the character of each compartment, is foundational for understanding cancer immunotherapy. Few models exist that facilitate in-depth study of each of the three canonical phases of immunoediting: elimination, equilibrium, and escape. Here, we utilized NPK-C1, a transplantable prostate tumor model that we found recapitulated the three phases of immunoediting spontaneously in immunocompetent animals. Given that a significant portion of NPK-C1 tumors reliably progressed to the escape phase, we were able to delineate cell types and mechanisms differentially prevalent in equilibrium versus escape phases. Using high-dimensional flow cytometry, we found that activated CD4+ effector T cells were enriched in regressing tumors, highlighting a role for CD4+ T cells in antitumor immunity. CD8+ T cells were also important for NPK-C1 control, specifically, central memory–like cytotoxic CD8+ T cells. Regulatory T cells (Treg), as a whole, were counterintuitively enriched in regressing tumors; however, high-dimensional analysis revealed their significant phenotypic diversity, with a number of Treg subpopulations enriched in progressing tumors. In the myeloid compartment, we found that iNOS+ dendritic cell (DC)–like cells are enriched in regressing tumors, whereas CD103+ DCs were associated with late-stage tumor progression. In total, these analyses of the NPK-C1 model provide novel insights into the roles of lymphoid and myeloid populations throughout the cancer immunoediting process and highlight a role for multidimensional, flow-based analyses to more deeply understand immune cell dynamics in the tumor microenvironment.

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance. Using lineage tracing and molecular profiling, Abate-Shen and colleagues identify a Ras and Myc co-activation signature that predicts metastasis and castration resistance in localized prostate cancer.

Introducción: La Hiperplasia Prostática Benigna (HPB) es una patología frecuente en pacientes mayores de 40 años. El uso de medicamentos como tamsulosina y finasterida disminuyen considerablemente los síntomas obstructivos e irritativos, por lo que solo un pequeño porcentaje amerita tratamiento quirúrgico. Entre los efectos secundarios que tiene el tratamiento farmacológico se encuentra la disfunción eréctil, la cual puede afectar la calidad de vida de quienes lo utilizan y también la funcionalidad del subsistema conyugal. El objetivo principal es determinar si existe asociación entre disfunción eréctil y funcionalidad del subsistema conyugal en pacientes con hiperplasia prostática benigna. Material y métodos: Estudio observacional, transversal y descriptivo que se llevó a cabo en 143 pacientes con diagnóstico de HPB que reciben tratamiento con tamsulosina y finasterida, seleccionados a través de muestreo no probabilístico por casos consecutivos. Para el grado de disfunción eréctil se utilizó el cuestionario IIEF-5 y para el grado de funcionalidad del subsistema conyugal la escala de Chávez[1]Velasco. El análisis de los resultados se llevó a cabo mediante estadística descriptiva y para la asociación de las variables dependiente e independiente Chi cuadrada, con un IC del 95% y una significancia estadística ≤ 0.05. Resultados: El rango de edad fue de 45 a 65 años, 73% casados, el resto en unión libre. 135 presentaron algún grado de disfunción eréctil y 73 disfunción del subsistema conyugal. Conclusiones: Existe una asociación positiva entre disfunción eréctil y funcionalidad del subsistema conyugal (p=0.027).

RESUMENINTRODUCCIÓNLos ganglioneuromas son tumores muy poco frecuentes, de comportamiento benigno, que derivan de la cresta neural. Su diagnóstico es generalmente incidental y de presentación clínica silente. Se localizan con mayor frecuencia en el retroperitoneo y mediastino, rara vez presentandose en la glándula suprarrenal (1/1 000 000 en la población general). REPORTE DE CASO Masculino de 56 años de edad, asintomático, quien es referido a valoración por hematuria microscópica. Al realizar Tomografía contrastada se encuentra tumoración suprarrenal izquierda de 4 cm, homogénea, con atenuación 4 cm y retardo en el lavado tumoral, el tratamiento terapéutico y diagnóstico más adecuado, es la adrenalectomía laparoscópica.

Background The theory of cancer immunoediting, which describes the dynamic interactions between tumors and host immune cells that shape the character of each compartment, is foundational for understanding cancer immunotherapy. Few models exist that facilitate in-depth study of each of the three canonical phases of immunoediting: elimination, equilibrium, and escape. Here, we perform high dimensional longitudinal immune profiling of NPK-C1, a transplantable prostate tumor model that recapitulates the three phases of immunoediting spontaneously in immunocompetent C57BL/6 animals. Methods We generated a 28-color immune phenotyping panel to interrogate the NPK-C1 microenvironment using a Cytek Aurora spectral flow cytometer. We analyzed NPK-C1 tumors on days 10, 15, 20 and 24 post-implantation, representing elimination, equilibrium, early escape, and late escape phases, respectively. These data were analyzed by both traditional gating and with an optimized dimensionality reduction and unsupervised clustering workflow. We additionally performed in vivo depletion studies of T cell and granulocyte subsets at early and late time points to determine if these bulk populations are required for immunoediting during elimination and equilibrium/escape. Results We found that a cluster of activated CD4 effector T cells were enriched early during elimination phase and were overrepresented in NPK-C1 tumors which regress rather than progress to escape. CD4 in vivo depletion studies validated a functional role for CD4 T cells in suppressing NPK-C1 progression at these phases. Additionally, a central memory-like cytotoxic CD8 T cell cluster was enriched in regressing NPK-C1 tumors, and CD8 depletion allowed NPK-C1 progression throughout immunoediting. Regulatory T cells (Tregs) as a whole were counterintuitively enriched in regressing tumors, however high dimensional analysis revealed their significant phenotypic diversity, with a number of Treg subpopulations enriched in progressing tumors. In the myeloid compartment, we found that iNOS+ DC-like cells were enriched in regressing tumors, while CD103+ DCs were counterintuitively associated with late stage tumor progression. Conclusions These data introduce a new model – NPK-C1 – to study immunoediting and suggest both CD8 and CD4 T cells are required to suppress tumor outgrowth throughout each phase of cancer immunoediting, while myeloid populations exhibit significant phenotypic and functional diversity throughout this process. Further, our identification of unique sub-populations of myeloid and T cells correlating with either regression or progression to escape highlights a role for multi-dimensional flow-based analyses to more deeply understand immune cell dynamics in the tumor microenvironment. Ethics Approval All experiments and procedures for this study were approved by the Columbia University Medical Center Institutional Animal Care and Use Committee (IACUC)

Precision oncology therapies are significantly hindered by the emergence of genetically or epigenetically-distinct cellular sub-populations, presenting either pre-existing or acquired drug resistance. For example, patients affected by advanced prostate cancer (PC), which is initially driven by aberrant activation of androgen receptor (AR) signals, often respond to Androgen Deprivation Therapy (ADT). Unfortunately, long-term treatment leads to the emergence of ADT-resistant tumors, termed Castration Resistant Prostate Cancer (CRPC), and poor outcome. Next-generation AR inhibitors extend CRPC patient survival, but frequently lead to the emergence of an even more aggressive Neuroendocrine PC (NEPC) phenotype, with exceedingly poor prognosis. Progression to NEPC is often determined by epigenetic-mediated reprogramming, rather than genomic alterations, resulting in cell-adaptive resistance, driven by aberrant activation of a handful of Master Regulator (MR) proteins. Consequently, better and more mechanistic understanding of cell-adaptive resistance is necessary to develop effective therapeutic strategies for CRPC. To address this challenge, we devised an RNA-based, high-throughput methodology, to systematically elucidate drug resistance mechanisms with single-cell resolution, and we applied it to study diverse, clonal populations that emerge following long-term treatment of PC LnCAP cells with next-generation AR inhibitors. Specifically, we identified Master Regulator (MR) proteins leading to the emergence of drug resistance, as well as clinically-available inhibitors able to reversing their activity, which were experimentally validated. We used PLATE-Seq, a low-cost, high-throughput RNA-Seq technology to profile more than 80 clonal, ADT-resistant populations, with single-cell resolution, and the VIPER algorithm to elucidate the MR proteins that mechanistically regulate their cell-adaptation programs. Our analysis revealed distinct cell-adaptive responses, associated with profound epigenetic reprogramming of prostate cancer cells. We used OncoTreat to prioritize a list of more than 400 FDA-approved and late-stage investigational drugs. Sensitivity to predicted drugs was confirmed in vitro and in vivo studies, in xenograft models derived from ADT- resistant clones are underway. We propose that this framework may represent a relevant advance to the study of cell-adaptive mechanism of drug resistance. Critically, this methodology is not limited to prostate cancer and can be applied to study arbitrary drug-resistance phenotypes. Citation Format: Prem Subramaniam, Alessandro Vasciaveo, Juan Arriaga, Jordan Kesner, Cory Abate-Shen, Andrea Califano. Targeting cell-adaptive mechanisms of drug resistance in lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1421.

Millions of individuals in United States are affected by Prostate Cancer (PCa), with tens of thousands dying every year, as therapeutic options for more advanced stages are not yet curative. A lack of suitable models of human cancer and inter-patient tumor heterogeneity often hinder the drug discovery process. In fact, the lost-in-translation phenomenon is one of the major causes of failure for compounds in the transitioning process from the workbench to the clinic. These limitations implicate considerable costs for the society in terms of both financial assets and human lives. To accelerate the drug discovery process, we devised and experimentally validated OncoLoop, a data-driven framework for the identification of clinically-relevant compounds that can be validated in preclinical models that optimally match patient-specific tumor dependencies. Specifically, we generated a set of Genetically-Engineered Mouse Models (GEMMs) of prostate cancer that recapitulate a wide variety of established prostate-cancer driver mutations. Their RNA profiles were then used to reverse-engineer a murine prostate cancer regulatory network, which was used to assess the activity profile of thousands of GEMM-specific regulatory proteins using the VIPER algorithm. We then assessed the match between the GEMM repertoire and several human prostate cancer databases–including from The Cancer Genome Atlas (TCGA) and Stand-Up To Cancer (SU2C) consortia–based on GEMM vs. patient Master Regulator (MR) protein conservation. This allowed selecting an optimally matched GEMM model, for virtually every patient in these databases, to serve as an in vivo surrogate model for screening patient-relevant drugs (i.e., a patient avatar). We then leveraged large-scale perturbational databases, comprising RNASeq profiles of 2 prostate cancer cell lines treated with >400 drugs, to prioritize drugs presenting the greatest ability to reverse MR protein activity in both the patient and in its optimally-matched GEMM, using the OncoTreat algorithm (Alvarez, et al. Nat Genet 2018). This formed a closed loop between each patient, its optimally matched GEMM and the drug(s) inferred to invert the activity of MR proteins in both the patient and the GEMM. OncoLoop selection of candidate drugs was validated in vivo. Notably, four out of five drugs were validated in the GEMM, including two inducing complete abrogation of tumor growth and two inducing significant tumor size reduction. In summary, we propose that given a patient's tumor biopsy, OncoLoop can identify an optimal GEMM model for in vivo validation and dramatically reduce the combinatorial search space of candidate drugs to a handful that may be effectively tested in that model. OncoLoop can be applied to any other cancer for which clinically-relevant tumor models are available. Citation Format: Alessandro Vasciaveo, Min Zou, Juan Arriaga, Andrea Califano, Cory Abate-Shen. OncoLoop: Closing the loop between patient-centered drug discovery and preclinical testing in precision-oncology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 822.

Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell-intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression. Cross-species master regulator analyses comparing this mouse signature with a comparable human signature identifies conserved drivers of metastatic progression with demonstrable clinical and functional relevance. In particular, nuclear receptor binding SET Domain Protein 2 (NSD2) is robustly expressed in lethal prostate cancer in humans, while its silencing inhibits metastasis of mouse allografts in vivo. We propose that cross-species analysis can elucidate mechanisms of metastasis progression, thus providing potential additional therapeutic opportunities for treatment of lethal prostate cancer., Identifying cell intrinsic mechanisms promoting metastasis are necessary to develop new cancer therapeutics. Here they do cross-species computational analysis and identify nuclear receptor binding SET domain Protein 2 (NSD2) as a driver of prostate cancer metastasis.

Recent genomic sequencing analyses have unveiled the spectrum of genomic alterations that occur in primary and advanced prostate cancer, raising the question of whether the corresponding genes are functionally relevant for prostate tumorigenesis, and whether such functions are associated with particular disease stages. In this review, we describe genetically engineered mouse models (GEMMs) of prostate cancer, focusing on those that model genomic alterations known to occur in human prostate cancer. We consider whether the phenotypes of GEMMs based on gain or loss of function of the relevant genes provide reliable counterparts to study the predicted consequences of the corresponding genomic alterations as occur in human prostate cancer, and we discuss exceptions in which the GEMMs do not fully emulate the expected phenotypes. Last, we highlight future directions for the generation of new GEMMs of prostate cancer and consider how we can use GEMMs most effectively to decipher the biological and molecular mechanisms of disease progression, as well as to tackle clinically relevant questions.

The overarching intent of this manuscript is to heighten awareness to the concept of commitment escalation as it bears on a failing family business. Specifically, drawing on the concept of emotional ownership, together with self-justification arguments, we a) identify factors considered to be most forceful in contributing to the presence of commitment escalation and thus, resistance to change in a failing family business (i.e., emotional ownership, feeling of responsibility, investment of capital, temporal distance from the founder’s business, individualism/collectivism), and b) model these related factors in a form that can serve heuristically to stimulate future empirical research capable of testing for the construct validity of commitment escalation in a family business context. We present potential items that may be useful for future scholars in measuring our constructs of interest as they relate to a failing family business.

Since the Food and Drug Administration (FDA), USA granted its approval to use the da Vinci Robotic Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA, USA) for gynecological practice, it has been documented that the advantages of robotics apply well to urogynecologic procedures. The two most common operative techniques in this area are Burch’s procedure for stress urinary incontinence and sacrocolpopexy for correct the pelvic organs prolapse. During both procedures, complications can arise. The most common in retropubic cystourethropexy are injuries to the urinary organs during dissection and suture fixation; vascular damage, ureteral entrapment, and obturator nerve damage can occur, furthermore others less frequent that have been reported. Regarding to sacrocolpopexy, vascular injuries to promontory and iliac vessels may occur, mesh erosion and migration is an important issue and rarely but osteomyelitis can befall. It is mandatory to understand the anatomy of the Retzius and presacral spaces to avoid the mentioned complications, as well to be prepared to control and repair of the injuries in these procedures, with patience and efficiency. Proved skills in laparoscopic and robotic suturing is mandatory for the appropriate performance of urogynecologic procedures. In this chapter, the complications reported and how to resolve them are described.

Commercializing new technologies implies a process of adding value for different stakeholders in specific industries. This case study offers the opportunity to evaluate potential global markets in the early stages of technological innovation development. The process of commercializing new technologies is seen from the perspective of small and medium-sized enterprises (SMEs) – the subject of the case is an SME that is trying to take a position in the promising and growing market of digital imaging for medical purposes in the USA. After several years of remarkable achievements, the entrepreneur must decide on the next steps in order to finish his product and take it to the market.

The primary metastatic site of prostate cancer is the bone, which is associated with high morbidity and mortality. Despite this fact, very few genetically engineered mouse models recapitulate this phenotype, hindering our ability to model and understand the molecular drivers of bone metastasis. Our laboratory has generated a highly metastatic mouse model of castration-resistant prostate cancer based on the monoallelic loss of function of Nkx3.1, biallelic deletion of Pten, and oncogenic mutation of Kras in the prostate, termed the NPK model. By tracking these tumors with a bright fluorescent reporter, we now show that these tumors metastasize to bone with a penetrance of ~45% and display a bone distribution similar to that of human cancer. This model has thus allowed us to comprehensively profile the molecular alterations of bone metastatic lesions compared to the primary tumor and other metastatic sites. We found that differential gene expression profiles comparing bone metastases with primary tumors differ from those comparing lung metastases with primary tumors, suggesting that different biologic principles underlie metastasis to these two organ sites. Furthermore, gene-expression profiling demonstrated significant overlap with human bone metastases at the gene, master regulator, and pathway levels. Even though expression of the androgen receptor (AR) is maintained in the primary tumor and most lung metastases, bone lesions are AR-, without evidence of neuroendocrine (NE) differentiation, pointing to an AR-, NE- prostate cancer subtype, which is increasingly frequent in human prostate cancer. These results lay the groundwork for understanding the molecular drivers and pathways that are important for bone metastatic spread and may hopefully aid in selecting appropriate molecular targets to combat the metastatic disease. Citation Format: Juan Martin Arriaga, Cory Abate-Shen. A genetically engineered mouse model of de novo bone metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B01.

The urologist is a specialist in the diseases of the urinary tract, which includes the kidneys, ureters, bladder, and urethra, all present in both men and women. Therefore, the urologist works with both men and women. This specialist also deals with men’s genital diseases—specifically those that affect the penis, testicles, or prostate—and those related to the male sexual function.

Micro-enterprises, with fewer than ten employees, are responsible for most new jobs in emerging economies. Unfortunately, low-income entrepreneurs frequently lack enough entrepreneurial competency to survive and expand. The research presented in this chapter aims to evaluate the importance of entrepreneurial development agencies at the base of the pyramid. Structural equation modelling with survey data from enterprises participating in an entrepreneurship education process in Mexico provides evidence of the positive and significant impact of entrepreneurial development agencies on performance, with the mediating effect of market-product innovation and market orientation.

The complete removal of the stone is the ultimate goal in management, a result that might not be attained even after several sessions of percutaneous nephrolithotomy (PCNL) and/or extracorporeal shockwave lithotripsy (SWL) and/or retrograde intrarenal surgery (ureteroscopy). The objective of this study is to assess our technique of anatrophic nephrolithotomy, with decreased renal ischemia and reduced patient morbidity.From 2007 to 2010, we performed eight anatrophic laparoscopic nephrolithotomies in adult patients with staghorn renal calculus. The mean patient age was 49 years (range 35-62 y). The mean stone size was 53 mm (range 35-70 mm). All patients had complex renal calculi, with stones occupying more than 80% of the caliceal system. In all cases, a Double-J stent was placed before surgery. After clamping the hilum, the incision was made laterally and longitudinally through full thickness of cortex using a laparoscopic scalpel. A running cortical suture was performed with Hem-o-lok reinforcement. Renal function was assessed in three patients, using renography with technetium-99m-diethylenetriaminepentacetic acid (99mTc-DTPA), before and 3 months after the surgery.Procedures for all patients were completed laparoscopically. The mean operative time was 142.5 minutes, and the mean warm ischemia time was 20.8 minutes. The estimated blood loss was 315 mL. The hospital stay average was 3.5 days. Only one patient had a complication--a vascular fistula with permanent postoperative hematuria. This patient subsequently underwent successful endovascular embolization. Residual stones were identified in 37% of cases (three patients) during follow-up imaging at 15 days. There were minimal changes on serum creatinine values.Laparoscopic surgery is feasible when anatrophic nephrolithotomy is indicated. This technique minimizes the barriers of an open flank incision, while achieving excellent stone-free rates. This minimally invasive technique should be considered for complex stones that would necessitate multiple renal access tracks and secondary procedures.