Robert R Klein

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Journals/Publications

• Crawford, M., Elliott, A., Klein, R., Lee, M., Reynolds, C., & Riaz, T. (2024). Disseminated Histoplasmosis in an Immunocompetent Patient from Southern Arizona. Journal of Fungi, 10(11), 756.
• Jordan, R., Aly, F. Z., Irhayyim, A., Mukhtar, F., & Klein, R. (2024). Prevalence of Non 16/18 High Risk Human Papilloma Virus as a Quality Metric in Gynecological Cytology. Diagnostic Cytopathology, 52(7), 377-380.
• Bauman, J. E., Saba, N. F., Roe, D., Bauman, J. R., Kaczmar, J., Bhatia, A., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Giri, A., Burtness, B., Centuori, S., Caulin, C., Klein, R., Saboda, K., Obara, S., & Chung, C. H. (2023). Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 41(22), 3851-3862.
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  Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.
• Frost, K. L., Jilek, J. L., Sinari, S., Klein, R. R., Billheimer, D., Wright, S. H., & Cherrington, N. J. (2023). Renal Transporter Alterations in Patients with Chronic Liver Diseases: Nonalcoholic Steatohepatitis, Alcohol-Associated, Viral Hepatitis, and Alcohol-Viral Combination. Drug metabolism and disposition: the biological fate of chemicals, 51(2), 155-164.
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  Alterations in hepatic transporters have been identified in precirrhotic chronic liver diseases (CLDs) that result in pharmacokinetic variations causing adverse drug reactions (ADRs). However, the effect of CLD on the expression of renal transporters is unknown despite the overwhelming evidence of kidney injury in CLD patients. This study determines the transcriptomic and proteomic expression profiles of renal drug transporters in patients with defined CLD etiology. Renal biopsies were obtained from patients with a history of CLD etiologies, including nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (ALD), viral hepatitis C (HCV), and combination ALD/HCV. A significant decrease in organic anion transporter (OAT)-3 was identified in NASH, ALD, HCV, and ALD/HCV (1.56 ± 1.10; 1.01 ± 0.46; 1.03 ± 0.43; 0.86 ± 0.57 pmol/mg protein) relative to control (2.77 ± 1.39 pmol/mg protein). Additionally, a decrease was shown for OAT4 in NASH (24.9 ± 5.69 pmol/mg protein) relative to control (43.8 ± 19.9 pmol/mg protein) and in urate transporter 1 (URAT1) for ALD and HCV (1.56 ± 0.15 and 1.65 ± 0.69 pmol/mg protein) relative to control (4.69 ± 4.59 pmol/mg protein). These decreases in organic anion transporter expression could result in increased and prolonged systemic exposure to drugs and possible toxicity. Renal transporter changes, in addition to hepatic transporter alterations, should be considered in dose adjustments for CLD patients for a more accurate disposition profile. It is important to consider a multiorgan approach to altered pharmacokinetics of drugs prescribed to CLD patients to prevent ADRs and improve patient outcomes. SIGNIFICANCE STATEMENT: Chronic liver diseases are known to elicit alterations in hepatic transporters that result in a disrupted pharmacokinetic profile for various drugs. However, it is unknown if there are alterations in renal transporters during chronic liver disease, despite strong indications of renal dysfunction associated with chronic liver disease. Identifying renal transporter expression changes in patients with chronic liver disease facilitates essential investigations on the multifaceted relationship between liver dysfunction and kidney physiology to offer dose adjustments and prevent adverse drug reactions.
• Frost, K. L., Jilek, J. L., Thompson, A. D., Klein, R. R., Sinari, S., Torabzedehkorasani, E., Billheimer, D. D., Schnellmann, R. G., & Cherrington, N. J. (2022). Increased Renal Expression of Complement Components in Patients With Liver Diseases: Nonalcoholic Steatohepatitis, Alcohol-Associated, Viral Hepatitis, and Alcohol-Viral Combination. Toxicological sciences : an official journal of the Society of Toxicology, 189(1), 62-72.
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  Inflammatory liver diseases, including nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (ALD), hepatitis C virus (HCV), and ALD/HCV, account for nearly 2 million deaths annually. Despite increasing evidence that liver dysfunction impacts renal physiology, there is limited supportive clinical information, due to limited diagnosis of liver disease, complexity in liver disease etiology, and inadequacy of renal function tests. Human kidney biopsies with liver and renal pathology were obtained from patients with nonalcoholic fatty liver disease (NAFLD), NASH, ALD, HCV, and ALD/HCV (n = 5-7). Each liver disease showed renal pathology with at least 50% interstitial nephritis, 50% interstitial fibrosis, and renal dysfunction by estimated glomerular filtration rate (NAFLD 36.7 ± 21.4; NASH 32.7 ± 15.0; ALD 16.0 ± 11.0; HCV 27.6 ± 11.5; ALD/HCV 21.0 ± 11.2 ml/min/1.73 m2). Transcriptomic analysis identified 55 genes with expression changes in a conserved direction in response to liver disease. Considering association with immune regulation, protein levels of alpha-2-macroglobulin, clusterin, complement C1q C chain (C1QC), CD163, and joining chain of multimeric IgA and IgM (JCHAIN) were further quantified by LC-MS/MS. C1QC demonstrated an increase in NASH, ALD, HCV, and ALD/HCV (42.9 ± 16.6; 38.8 ± 18.4; 39.0 ± 13.5; 40.1 ± 20.1 pmol/mg protein) relative to control (19.2 ± 10.4 pmol/mg protein; p ≤ 0.08). Renal expression changes identified in inflammatory liver diseases with interstitial pathology suggest the pathogenesis of liver associated renal dysfunction. This unique cohort overcomes diagnostic discrepancies and sample availability to provide insight for mechanistic investigations on the impact of liver dysfunction on renal physiology.
• Hau, R. K., Klein, R. R., Wright, S. H., & Cherrington, N. J. (2022). Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier. Drug metabolism and disposition: the biological fate of chemicals, 50(6), 770-780.
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  The blood-testis barrier (BTB) is formed by basal tight junctions between adjacent Sertoli cells (SCs) of the seminiferous tubules and acts as a physical barrier to protect developing germ cells in the adluminal compartment from reproductive toxicants. Xenobiotics, including antivirals, male contraceptives, and cancer chemotherapeutics, are known to cross the BTB, although the mechanisms that permit barrier circumvention are generally unknown. This study used immunohistological staining of human testicular tissue to determine the site of expression for xenobiotic transporters that facilitate transport across the BTB. Organic anion transporter (OAT) 1, OAT2, and organic cation transporter, novel (OCTN) 1 primarily localized to the basal membrane of SCs, whereas OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. Concentrative nucleoside transporter (CNT) 2 localized to Leydig cells (LCs), PMCs, and SC apicolateral membranes. Organic cation transporter (OCT) 1, OCT2, and OCT3 mostly localized to PMCs and LCs, although there was minor staining in developing germ cells for OCT3. Organic anion transporting polypeptide (OATP) 1A2, OATP1B1, OATP1B3, OATP2A1, OATP2B1, and OATP3A1-v2 localized to SC basal membranes with diffuse staining for some transporters. Notably, OATP1C1 and OATP4A1 primarily localized to LCs. Positive staining for multidrug and toxin extrusion protein (MATE) 1 was only observed throughout the adluminal compartment. Definitive staining for CNT1, OAT3, MATE2, and OATP6A1 was not observed. The location of these transporters is consistent with their involvement in the movement of xenobiotics across the BTB. Altogether, the localization of these transporters provides insight into the mechanisms of drug disposition across the BTB and will be useful in developing tools to overcome the pharmacokinetic and pharmacodynamic difficulties presented by the BTB. SIGNIFICANCE STATEMENT: Although the total mRNA and protein expression of drug transporters in the testes has been explored, the localization of many transporters at the blood-testis barrier (BTB) has not been determined. This study applied immunohistological staining in human testicular tissues to identify the cellular localization of drug transporters in the testes. The observations made in this study have implications for the development of drugs that can effectively use transporters expressed at the basal membranes of Sertoli cells to bypass the BTB.
• Li, Z., Woodhead, G. J., Rouse, A. R., Klein, R., Larson, M. C., & Gmitro, A. F. (2023). Multispectral confocal endomicroscopy in lung biopsy guidance. Journal of Optical Microsystems, 3(1). doi:10.1117/1.JOM.3.1.011002
• Klein, R., Aly, F. Z., Irhayyim, A., & Knapik, J. (2021). Negative Loop Electrosurgical Excision Procedure (LEEP) Following Cervical Biopsy Diagnosis of High Grade Squamous Intraepithelial Lesion. International Journal of Clinical and Experimental Pathology. International Journal of Clinical and Experimental Pathology 14(12), December 2021; published online 15 December 2021., 14(12), 1148-1154.
• Aly, F. Z., Mostofizadeh, S., Jawaid, S., Knapik, J., Mukhtar, F., & Klein, R. (2020). Effect of Single Operator Cholangioscopy on Accuracy of Bile Duct Cytology. Diagnostic Cytopathology, 48(12), 1230-1236. doi:https://doi.org/10.1002/dc.24553
• Becker, J., & Klein, R. (2020). 4D Dynamic Contrast-enhanced MRI for Pre-operative Localization in Patients with Primary Hyperparathyroidism. American Journal of Neuroradiology.
• Gilman, K., Camden, J., Klein, R., Zhang, Q., Weisman, G., & Limesand, K. H. (2019). P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation.. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology. doi:10.1152/ajpregu.00192.2018
• Eshghi, A., Klein, R., Eshghi, N., & Kuo, P. H. (2018). F-FDG PET/CT for the Evaluation of Primary Eosinophilic Granuloma of the Hypothalamus. Journal of nuclear medicine technology, 46(3), 290-291.
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  A 21-y-old man who presented with polyuria and polydipsia was discovered to have diabetes insipidus due to eosinophilic granuloma of the hypothalamus. F-FDG PET/CT, which was performed as a metastatic work-up, revealed an intensely F-FDG-avid hypothalamic mass and no other sites of disease.
• Chen, H., Klein, R., Arnold, S., Wang, Y., Chambers, S., & Zheng, W. (2017). Tubal Cytology of the Fallopian Tube as a Promising Tool for Ovarian Cancer Early Detection. Journal of visualized experiments : JoVE.
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  Currently, it is widely accepted that the vast majority of ovarian high-grade serous carcinoma (HGSC) originate from the fallopian tube. However, due to the lack of markers or tools for the ovarian cancer identification, the early detection of HGSC remains challenging. Direct sampling of the fallopian tube can enhance sensitivity for detection of neoplastic cells when the tumor is not grossly visible. We developed a procedure to collect fallopian tube cells directly from freshly received surgical specimens, which has shown excellent correlation with histological findings. This approach lays a foundation for the future utility of minimally invasive laparoscopic screening in high-risk patient populations.
• Vanderbilt, D. B., Ho, Q. A., Goyal, U., Bell, R. C., Klein, R. R., & Yi, S. K. (2017). HPV-related nasopharyngeal and cervical cancer in a married couple in North America. Practical radiation oncology.
• Klein, R. (2016). Association of Antemortem Central Nervous System (CNS) Symptoms and Location of Aortic Dissections; A Retrospective Study from 2001-2014.. Academic Forensic Pathology, 6(3), 517-523.
• Klein, R. (2016). Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI. Molecular Imaging & Biology. doi:10.1007/s11307-016-1029-7
• Klein, R. (2016). Communicating Uncertainty in Surgical Pathology Reports: A Survey of Staff Physicians and Residents at an Academic Medical Center. Academic Pathology, 3. doi:10.1177/2374289516659079
• Klein, R. R. (2015). Cytologic Diagnosis of Coccidioidomycosis: Spectrum of Findings in Southern Arizona Patients Over a 10-Year Period. Diagnostic Cytopathology, 4(6), S14. doi:10.1016/j.jasc.2015.09.032
• Klein, R. R. (2015). Fallopian Tube Cytology in Patients Undergoing Salpingo-Oophorectomy. American Journal of Clinical Pathology, 144(Suppl 2), A075. doi:10.1093/ajcp/144.suppl2.075
• Wang, Y., Mang, M., Wang, Y., Wang, L., Klein, R., Kong, B., & Zheng, W. (2015). Tubal origin of ovarian endometriosis and clear cell and endometrioid carcinoma. American journal of cancer research, 5(3), 869-79.
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  Current research has strongly proposed that contrary to prior beliefs, many ovarian epithelial cancers (OECs) do not, as their name suggests, originate in the ovaries. Recent findings regarding both high-grade and low-grade serous carcinomas has implicated the fallopian tube as a cell source for these OECs, but until now, there has been little insight into the cellular source for clear cell and endometrioid carcinomas. In this commentary review article, we aimed to discuss the new findings that support the possible contribution from the fallopian tube in clear cell and endometrioid carcinomas. Specifically, we have provided results that showcased ovarian surface epithelia (OSE) and ovarian epithelial inclusions (OEIs) as having mesothelial and tubal origins and have strongly recognized the secondary müllerian system and the ability for tubal epithelia to implant upon the ovarian surface as contributing to fallopian tube-derived OEIs (F-OEIs). We have provided initial indications of these F-OEIs and their relationship to endometriosis and then clear cell and endometrioid carcinomas and subsequently offer our new proposal of a probable tubal origin. This new proposal is a paradigm that drastically changes the understanding behind the origin of these OECs and has significant clinical implications in the near future.