IU Indianapolis ScholarWorks :: Browsing by Author "Konger, Raymond L."

Browsing by Author "Konger, Raymond L."

Now showing 1 - 10 of 19

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor
(American Association for Cancer Research, 2014-12-01) Sahu, Ravi P.; Ocana, Jesus A.; Harrison, Kathleen A.; Ferracini, Matheus; Touloukian, Christopher E.; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C.; Althouse, Sandra K.; Perkins, Susan M.; Speicher, Paul J.; Tyler, Douglas S.; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.
Cigarette smoke exposure mediated generation of Platelet-activating factor agonists induces systemic immunosuppression
(Office of the Vice Chancellor for Research, 2012-04-13) Sahu, Ravi P.; Turner, Matthew J.; Konger, Raymond L.; Travers, Jeffrey B.
The ubiquitous environmental pollutant cigarette smoke (CS) is known to exert immodulatory effects. CS also acts as a potent pro-oxidative stressor. Several studies including ours have characterized the importance of various pro-oxidative stressors including UVB to inhibit host immunity and an importance of the platelet-activating factor (1-alkyl-2-acetyl-glycerophosphocholine; PAF), a potent lipid mediator in this process. PAF is produced enzymatically in a tightly-controlled process. In addition, oxidative stressors can act directly on glycerophosphocholines (GPC) to produce oxidized GPC which are potent PAF-R agonists. The present studies employed model systems consisting of PAF-receptor (PAF-R)-expressing (KBP) and–deficient (KBM) cells and mice (wild type [WT] and Pafr-/-) to determine whether CS exposure could generate PAF-R agonists in blood and whether it could suppress contact hypersensitivity reactions in a PAF-R-dependent manner. We show that lipid extracts derived from the blood of CS-treated WT mice resulted in immediate intracellular calcium (Ca2+2+mice. This inhibitory effect of CS in WT mice were similar to those induced by a PAF-R agonist, CPAF or histamine. Furthermore, this inhibition of CHS by CS in WT mice was blocked by antioxidants vitamin C and N-acetyl cysteine. These findings indicate that CS exposure induces systemic immunosuppression in a PAF-R-dependent manner. These studies provide the first evidence that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF agonists through lipid oxidation.) mobilization response only in KBP cells. However, no Camobilization response was detected with lipid extracts from non-smoked (sham) mice both in KBP and KBM cells. In addition, lipid extracts only from CS-treated mice induced an increase in IL-8 secretion in KBP cells indicating that CS generates systemic PAF-R agonists. CS exposure also inhibited contact hypersensitivity to the allergen dinitrofluorobenzene (DNFB) selectively in WT but not inPafr-/-
Comparison of the acute ultraviolet photoresponse in congenic albino hairless C57BL/6J mice relative to outbred SKH1 hairless mice
(Wiley, 2016-09) Konger, Raymond L.; Derr-Yellin, Ethel; Hojati, Delaram; Lutz, Cathleen; Sundberg, John P.; Pathology and Laboratory Medicine, School of Medicine
Hairless albino Crl:SKH1-Hrhr mice are commonly utilized for studies in which hair or pigmentation would introduce an impediment to observational studies. Being an outbred strain, the SKH1 model suffers from key limitations that are not seen with congenic mouse strains. Inbred and congenic C57BL/6J mice are commonly utilized for modified genetic mouse models. We compare the acute UV-induced photoresponse between outbred SKH1 mice and an immune competent, hairless, albino C57BL/6J congenic mouse line [B6.Cg-Tyrc-2J Hrhr/J]. Histologically, B6.Cg-Tyrc-2J Hrhr/J skin is indistinguishable from that of SKH1 mice. The skin of both SKH1 and B6.Cg-Tyrc-2J Hrhr/J mice exhibited a reduction in hypodermal adipose tissue, the presence of utricles and dermal cystic structures, the presence of dermal granulomas, and epidermal thickening. In response to a single 1500 J/m2 UVB dose, the edema and apoptotic response was equivalent in both mouse strains. However, B6.Cg-Tyrc-2J Hrhr/J mice exhibited a more robust delayed sunburn reaction, with an increase in epidermal erosion, scab formation, and myeloperoxidase activity relative to SKH1 mice. Compared with SKH1 mice, B6.Cg-Tyrc-2J Hrhr/J also exhibited an aberrant proliferative response to this single UV exposure. Epidermal Ki67 immunopositivity was significantly suppressed in B6.Cg-Tyrc-2J Hrhr/J mice at 24 hours post-UV. A smaller non-significant reduction in Ki67 labeling was observed in SKH1 mice. Finally, at 72 hours post-UV, SKH1 mice, but not B6.Cg-Tyrc-2J Hrhr/J mice, exhibited a significant increase in Ki67 immunolabeling relative to non-irradiated controls. Thus, B6.Cg-Tyrc-2J Hrhr/J mice are suitable for photobiology experiments.
Data-driven imaging of tissue inflammation using RGB-based hyperspectral reconstruction toward personal monitoring of dermatologic health
(Optical Society of America, 2017-10-26) Kim, Taehoon; Visbal-Onufrak, Michelle A.; Konger, Raymond L.; Kim, Young L.; Pathology and Laboratory Medicine, School of Medicine
Sensitive and accurate assessment of dermatologic inflammatory hyperemia in otherwise grossly normal-appearing skin conditions is beneficial to laypeople for monitoring their own skin health on a regular basis, to patients for looking for timely clinical examination, and to primary care physicians or dermatologists for delivering effective treatments. We propose that mathematical hyperspectral reconstruction from RGB images in a simple imaging setup can provide reliable visualization of hemoglobin content in a large skin area. Without relying on a complicated, expensive, and slow hyperspectral imaging system, we demonstrate the feasibility of determining heterogeneous or multifocal areas of inflammatory hyperemia associated with experimental photocarcinogenesis in mice. We envision that RGB-based reconstructed hyperspectral imaging of subclinical inflammatory hyperemic foci could potentially be integrated with the built-in camera (RGB sensor) of a smartphone to develop a simple imaging device that could offer affordable monitoring of dermatologic health.
Dietary Polyphenols in Cancer Chemoprevention: Implications in Pancreatic Cancer
(MDPI, 2020-07-23) Thyagarajan, Anita; Forino, Andrew S.; Konger, Raymond L.; Sahu, Ravi P.; Pathology and Laboratory Medicine, School of Medicine
Naturally occurring dietary agents present in a wide variety of plant products, are rich sources of phytochemicals possessing medicinal properties, and thus, have been used in folk medicine for ages to treat various ailments. The beneficial effects of such dietary components are frequently attributed to their anti-inflammatory and antioxidant properties, particularly in regards to their antineoplastic activities. As many tumor types exhibit greater oxidative stress levels that are implicated in favoring autonomous cell growth activation, most chemotherapeutic agents can also enhance tumoral oxidative stress levels in part via generating reactive oxygen species (ROS). While ROS-mediated imbalance of the cellular redox potential can provide novel drug targets, as a consequence, this ROS-mediated excessive damage to cellular functions, including oncogenic mutagenesis, has also been implicated in inducing chemoresistance. This remains one of the major challenges in the treatment and management of human malignancies. Antioxidant-enriched natural compounds offer one of the promising approaches in mitigating some of the underlying mechanisms involved in tumorigenesis and metastasis, and therefore, have been extensively explored in cancer chemoprevention. Among various groups of dietary phytochemicals, polyphenols have been extensively explored for their underlying chemopreventive mechanisms in other cancer models. Thus, the current review highlights the significance and mechanisms of some of the highly studied polyphenolic compounds, with greater emphasis on pancreatic cancer chemoprevention.
Epidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponse
(Impact Journals, 2017-09-18) Konger, Raymond L.; Derr-Yellin, Ethel; Travers, Jeffrey B.; Ocana, Jesus A.; Sahu, Ravi P.; Pathology and Laboratory Medicine, School of Medicine
It is known that ultraviolet B (UVB) induces PPARγ ligand formation while loss of murine epidermal PPARγ (Pparg-/-epi) promotes UVB-induced apoptosis, inflammation, and carcinogenesis. PPARγ is known to suppress tumor necrosis factor-α (TNF-α) production. TNF-α is also known to promote UVB-induced inflammation, apoptosis, and immunosuppression. We show that Pparg-/-epi mice exhibit increased baseline TNF-α expression. Neutralizing Abs to TNF-α block the increased photo-inflammation and photo-toxicity that is observed in Pparg-/-epi mouse skin. Interestingly, the increase in UVB-induced apoptosis in Pparg-/-epi mice is not accompanied by a change in cyclobutane pyrimidine dimer clearance or in mutation burden. This suggests that loss of epidermal PPARγ does not result in a significant alteration in DNA repair capacity. However, loss of epidermal PPARγ results in marked immunosuppression using a contact hypersensitivity (CHS) model. This impaired CHS response was significantly alleviated using neutralizing TNF-α antibodies or loss of germline Tnf. In addition, the PPARγ agonist rosiglitazone reversed UVB-induced systemic immunosuppression (UV-IS) as well as UV-induced growth of B16F10 melanoma tumor cells in syngeneic mice. Finally, increased B16F10 tumor growth was observed when injected subcutaneously into Pparg-/-epi mice. Thus, we provide novel evidence that epidermal PPARγ is important for cutaneous immune function and the acute photoresponse.
Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin
(MDPI, 2021-08-11) Konger, Raymond L.; Derr-Yellin, Ethel; Zimmers, Teresa A.; Katona, Terrence; Xuei, Xiaoling; Liu, Yunlong; Zhou, Hong-Ming; Simpson, Ed Ronald, Jr.; Turner, Matthew J.; Pathology and Laboratory Medicine, School of Medicine
Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.
Evidence for a non-stochastic two-field hypothesis for persistent skin cancer risk
(Nature, 2020-11-05) Konger, Raymond L.; Ren, Lu; Sahu, Ravi P.; Derr-Yellin, Ethel; Kim, Young L.; Dermatology, School of Medicine
With recurring carcinogen exposures, individual tumors develop in a field of genetic mutations through a stepwise process of clonal expansion and evolution. Once established, this “cancer field” persists in the absence of continued carcinogen exposures, resulting in a sustained risk for cancer development. Using a bioimaging approach, we previously demonstrated that a dermal premalignant field characterized by inflammatory angiogenesis persists following the cessation of ultraviolet light exposures and accurately predicts future overlying epidermal tumor formation. Following ultraviolet light treatments, others have observed that patches of p53 immunopositive cells persist stochastically throughout the epidermal stem cell population. However, these studies were done by random biopsies, introducing sampling bias. We now show that, rather than being randomly distributed, p53+ epidermal cells are enriched only in areas overlying this multi-focal dermal field. Moreover, we also show that the dermal field is characterized by a senescent phenotype. We propose that persistence of the overlying epithelial cancerization field in the absence of exogenous carcinogens or promoters requires a two-field composite consisting of a dermal senescent field driving the persistence of the overlying epidermal cancer field. These observations challenge current models that suggest that persistence of cancer risk in the absence of continued carcinogen exposures is simply a function of stochastically arranged, long-lived but dormant epithelial clonal stem cells mutants. The model proposed here could provide new insights into how cancer risk persists following cessation of carcinogenic exposures.
Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth
(American Society for Biochemistry and Molecular Biology, 2016-10-14) Lakhter, Alexander J.; Hamilton, James; Konger, Raymond L.; Brustovetsky, Nickolay; Broxmeyer, Hal E.; Naidu, Samisubbu R.; Microbiology and Immunology, School of Medicine
Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.
Large area, label-free imaging of extracellular matrix using telecentricity
(SPIE, 2017-01) Onufrak, Michelle A. Visbal; Konger, Raymond L.; Kim, Young L.; Pathology and Laboratory Medicine, School of Medicine
Subtle alterations in stromal tissue structures and organizations within the extracellular matrix (ECM) have been observed in several types of tissue abnormalities, including early skin cancer and wounds. Current microscopic imaging methods often lack the ability to accurately determine the extent of malignancy over a large area, due to their limited field of view. In this research we focus on the development of simple mesoscopic (i.e. between microscopic and macroscopic) biomedical imaging device for non-invasive assessment of ECM alterations over a large, heterogeneous area. In our technology development, a telecentric lens, commonly used in machine vision systems but rarely used in biomedical imaging, serves as a key platform to visualize alterations in tissue microenvironments in a label-free manner over a clinically relevant area. In general, telecentric imaging represents a simple, alternative method for reducing unwanted scattering or diffuse light caused by the highly anisotropic scattering properties of biological tissue. In particular, under telecentric imaging the light intensity backscattered from biological tissue is mainly sensitive to the scattering anisotropy factor, possibly associated with the ECM. We demonstrate the inherent advantages of combining telecentric lens systems with hyperspectral imaging for providing optical information of tissue scattering in biological tissue of murine models, as well as light absorption of hemoglobin in blood vessel tissue phantoms. Thus, we envision that telecentric imaging could potentially serve for simple site-specific, tissue-based assessment of stromal alterations over a clinically relevant field of view in a label-free manner, for studying diseases associated with disruption of homeostasis in ECM.

Browsing by Author "Konger, Raymond L."

Results Per Page

Sort Options