Hypoxia, Neutrophils, and the Colon Tumor Inflammatory Response

In 1863, Rudolf Virchow proposed that tumors arise from sites of chronic inflammation. This concept was largely ignored throughout the majority of the next century as the genetic basis of cancer was explored. However, it has become well appreciated that inflammation and cancer are intimately linked. For example, chronic inflammation of the intestine in the form of Inflammatory Bowel Disease (IBD) predisposes to the development of colon cancer. Although the vast majority of colon tumors do not arise from sites of chronic inflammation, sporadic colon tumors elicit an inflammatory response that is essential for tumor growth, progression, and evasion of anti-tumor immunity. Hypoxia is a well-characterized feature of nearly all solid tumors and promotes stabilization of the hypoxia inducible transcription factors (HIF-1α and HIF-2α) with known roles in modulating tumor-associated inflammation. We have previously reported that intestinal epithelial HIF-2α is an important driver of the acute inflammatory response in colitis. The present work describes a novel axis by which intestinal epithelial HIF-2α serves as a critical link between inflammation and cancer of the colon. Mechanistically, our work shows a crucial role for intestinal epithelial HIF-2α in regulation of the immune microenvironment of colon tumors through recruitment of intra-tumoral neutrophils. Neutrophils are granulocytic myeloid cells of the innate immune system that are the first responders to sites of infection to limit microbes. Neutrophils are highly infiltrated in nearly all solid tumors including colon cancer. We showed that neutrophil influx was due to direct HIF-2α-dependent regulation of the potent neutrophil chemokine CXCL1. These data identify a novel role for HIF-2α in modulation of the tumor immune microenvironment of inflammation-driven colon tumors and suggest therapeutic potential. Our data suggested an important role for neutrophils in the maintenance of colon tumors. However, the importance of neutrophils in the initiation of colon tumorigenesis is largely unknown. Using mice with constitutive genetic depletion of neutrophils, the present work demonstrates an essential role for neutrophils in restricting colon tumor growth and progression in both inflammation-driven and sporadic colon tumor models. Neutrophil depletion correlated with robust expansion of colon-tumor associated microbiota and tumor-associated B-cells, both of which had important roles in neutrophil-deficient colon tumorigenesis. Together, our data suggest divergent roles for neutrophils in the initiation and maintenance of colon tumors. The work presented in this thesis also shows an important role for the transcription factor, myc-associated zinc finger (MAZ) in colitis and colon cancer. MAZ is an inflammation induced transcription factor that has a previously identified role as a HIF-2α transcriptional cofactor. We show that MAZ is highly active in human colitis and colon cancer. The present work delineates a critical function for MAZ in the inflammatory progression of colitis and colon cancer through regulation of oncogenic STAT3 signaling. Collectively, these studies shed new light onto the inflammatory progression of colon cancer and propose potential therapeutic targets.PHDMol & Integrtv Physiology PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155241/1/trinerda_1.pd

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2alpha-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC

The potential of sports facilities for involvement in the blue-green infrastructure of the city of Pilsen

Venkovní sportovní areály mají nezanedbatelný potenciál pro zapojení do modro-zelené infrastruktury a to především v ohledu hospodaření s dešťovou vodou města Plzně. Přispívají k zlepšení mikroklimatu území pomocí retence srážkové vody a také její evapotranspirace. Pokud jsou systematicky propojeny s přírodními plochami v okolí, mohou se zapojit do sítě MZI a pomoci s adaptací měst na změny klimatu. To souvisí s jejich rozdílným potenciálem podle typu využití prostoru v okolí. V bakalářské práci provádím výzkum, ve kterém inventarizací vybraných sportovních areálů v katastrálním území Plzně hodnotím pomocí různými parametrů potenciál k zapojení do modro-zelené infrastruktury města Plzně.ObhájenoOutdoor sports facilities have a significant potential for involvement in the blue-green infrastructure, especially in terms of stormwater management in the city of Pilsen. They contribute to the improvement of the microclimate of the area through the retention of rainwater and also its evapotranspiration. If they are systematically connected with natural areas nearby, can be included to the network of blue-green infrastructure and help with cities adaptation to climate change. This is related to their different potential according to the type of use space in the area space. In my Bachelor's thesis I do reseach in which I make an inventory of selected sports facilities in the cadastral area of Pilsen and evaluate them by using of various parameters the potential for involvement in the blue-green infrastructure of the city of Pilsen

Hypoxic Regulation of Neutrophils in Cancer

Neutrophils have been well-characterized for their role in the host anti-microbial response. However, it is now appreciated that neutrophils have a critical role in tumorigenesis and tumor progression in the majority of solid tumors. Recent studies have indicated a critical role for hypoxia in regulating neutrophil function in tumors. Furthermore, neutrophil-specific expression of hypoxia-inducible transcription factors may represent a novel therapeutic target for human cancer. In this review, we highlight the function of neutrophils in cancer and the role of the neutrophil hypoxic response in regulating the neoplastic progression of cancer

The Lack of a Physical Exam During New Patient Telehealth Visits Does Not Impact Plans for Office and Operating Room Procedures

ObjectiveTo understand how the lack of a physical examination during new patient video visits can impact urological surgery planning during the COVID-19 pandemic.MethodsWe retrospectively reviewed 590 consecutive urology patients who underwent new patient video visits from March through May 2020 at a single academic center. Our primary outcome was procedural plan concordance, the proportion of video visit surgical plans that remained the same after the patient was seen in-person, either in clinic or on day of surgery. Median days between video and in-person visits were compared between concordant and discordant cases using the Mann-Whitney U test; P < .05 was significant.ResultsOverall, 195 (33%) were evaluated by new patient video visits and had a procedure scheduled, of which, 186 (95%) had concordant plans after in-person evaluation. Further, 99% of plans for in-office procedures and 91% for operating room procedures were unchanged. Four patients (2.1%) had surgical plans altered after changes in clinical course, two (1%) due to additional imaging, and three (1.5%) based on genitourinary examination findings. Days between video visit and in-person evaluation did not differ significantly in concordant cases (median 37.5 [IQR, 16 - 80.5]) as compared to discordant cases (median 58.0 [IQR, 20 - 224]; P = .12).ConclusionsMost surgical plans developed during new patient video visits remain unchanged after in-person examination. However, changes in clinical course or updated imaging can alter operative plans. Likewise, certain urologic conditions (eg, penile cancer) rely on the genitourinary examination to dictate surgical approach