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Article: Fusion of bone marrow-derived cells with cancer cells: metastasis as a secondary disease in cancer.

Pawelek, John M

2014 Volume 33, Issue 3, Page(s) 133–139

Abstract: This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human ...

Abstract	This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cell is a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cell with a leukocyte-cancer cell hybrid epigenome.
MeSH term(s)	Animals ; Bone Marrow Cells/cytology ; Bone Marrow Cells/pathology ; Cell Fusion ; Humans ; Hybrid Cells/pathology ; Neoplasm Metastasis ; Neoplasms/pathology ; Neoplastic Stem Cells/pathology
Language	English
Publishing date	2014-03-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1045160-2
ISSN	1944-446X ; 1000-467X
ISSN (online)	1944-446X
ISSN	1000-467X
DOI	10.5732/cjc.013.10243
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Article ; Online: Chimeric antigen receptor T-cell therapy for melanoma.

Razavi, Azadehsadat / Keshavarz-Fathi, Mahsa / Pawelek, John / Rezaei, Nima

Expert review of clinical immunology

2021 Volume 17, Issue 3, Page(s) 209–223

Abstract: Introduction: In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for the treatment of solid tumors including ... ...

Abstract	Introduction: In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for the treatment of solid tumors including melanoma. Areas covered: T cells need to be reprogramed to recognize specific antigens expressed only in tumor cells, a difficult problem since cancer cells are simply transformed normal cells. Tumor antigens, namely, CSPG4, CD70, and GD2 have been targeted by CAR-T cells for melanoma. Moreover, different co-stimulatory signaling domains need to be selected to direct T cell fate. In this review, various approaches for the treatment of melanoma and their effectiveness are comprehensively reviewed and the current status, challenges, and future perspective of CAR-T cell therapy for melanoma are discussed. Literature search was accomplished in three databases (PubMed, Google scholar, and Clinicaltrials.gov). Published papers and clinical trials were screened and relevant documents were included by checking pre-defined eligibility criteria. Expert opinion: Despite obstacles and the risk of adverse events, CAR T cell therapy could be used for patients with treatment-resistant cancer. Clinical trials are underway to determine the efficacy of this approach for the treatment of melanoma.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy, Adoptive ; Melanoma/immunology ; Melanoma/therapy ; Receptors, Chimeric Antigen/immunology
Chemical Substances	Antigens, Neoplasm ; Receptors, Chimeric Antigen
Language	English
Publishing date	2021-01-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2274260-8
ISSN	1744-8409 ; 1744-666X
ISSN (online)	1744-8409
ISSN	1744-666X
DOI	10.1080/1744666X.2021.1880895
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Article ; Online: Clinical evaluation of the lightening effect of cytidine on hyperpigmented skin.

Baswan, Sudhir M / Leverett, Jesse / Pawelek, John

Journal of cosmetic dermatology

2018 Volume 18, Issue 1, Page(s) 278–285

Abstract: Background: Melanocytes, which reside in the basal layer of the epidermis, produce the pigment melanin in cytoplasmic organelles known as melanosomes. Melanosomes are transferred to keratinocytes which provide the color in our skin. Recently, Diwakar et ...

Abstract	Background: Melanocytes, which reside in the basal layer of the epidermis, produce the pigment melanin in cytoplasmic organelles known as melanosomes. Melanosomes are transferred to keratinocytes which provide the color in our skin. Recently, Diwakar et al reported the crucial roles of protein glycosylation in both melanogenesis and melanosome transfer to keratinocytes, and each was inhibited by the nucleotide cytidine. Objective: The main objective of this study was to determine the clinical effects of topical application of cytidine to the hyperpigmented regions of the face in a group of human volunteers. Methods: A randomized, vehicle-controlled study was conducted for 12 weeks on healthy Korean female subjects. Cytidine was formulated into the lotion at concentrations of 2%, 3%, and 4% (w/w) and compared to the vehicle control formulation. The clinical outcomes were evaluated by performing visual assessment grading, measuring melanin index, skin brightness, and skin color parameters. In vitro skin penetration studies were conducted using Franz cell chambers for the 2% cytidine test formulation. Results: The test group showed significant improvements in the visual assessment scores, melanin index, skin brightness, and skin color compared to the control group. Although significant dose-dependent improvements were seen in the clinical study, the in vitro Franz cell studies indicated that the clinical efficacy and potency of cytidine might be further enhanced by formulating a better topical delivery system, which will be the goal of our future studies. Conclusions: This randomized, double-blind, 12-week clinical study successfully demonstrated the efficacy of cytidine on skin depigmentation in a dose-dependent manner.
MeSH term(s)	Administration, Cutaneous ; Adult ; Cytidine/administration & dosage ; Cytidine/pharmacokinetics ; Cytidine/therapeutic use ; Double-Blind Method ; Facial Dermatoses/drug therapy ; Female ; Humans ; Hyperpigmentation/drug therapy ; Middle Aged ; Permeability ; Skin Lightening Preparations/administration & dosage ; Skin Lightening Preparations/pharmacokinetics ; Skin Lightening Preparations/therapeutic use ; Young Adult
Chemical Substances	Skin Lightening Preparations ; Cytidine (5CSZ8459RP)
Language	English
Publishing date	2018-10-05
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	2280551-5
ISSN	1473-2165 ; 1473-2130
ISSN (online)	1473-2165
ISSN	1473-2130
DOI	10.1111/jocd.12784
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Article ; Online: Is spinal height gain associated with rod orientation and the use of cross-links in magnetically controlled growing rods in early-onset scoliosis?

Hosseini, Pooria / Akbarnia, Behrooz A / Pawelek, Jeff B / Tran, Stacie / Zhang, Justin / Johnston, Charles E / Shah, Suken A / Emans, John B / Mundis, Gregory M / Yaszay, Burt / Samdani, Amer F / Sponseller, Paul D / Sturm, Peter F

Journal of pediatric orthopedics. Part B

2023 Volume 32, Issue 6, Page(s) 531–536

Abstract: Optimal orientation for magnetically controlled growing rods (MCGRs) is unclear. The objective of this study was to investigate associations of rod orientation with implant-related complications (IRCs) and spinal height gains. Using an international ... ...

Abstract	Optimal orientation for magnetically controlled growing rods (MCGRs) is unclear. The objective of this study was to investigate associations of rod orientation with implant-related complications (IRCs) and spinal height gains. Using an international early-onset scoliosis (EOS) database, we retrospectively reviewed 57 patients treated with dual MCGRs from May 2013 to July 2015 with minimum 2-year follow-up. Outcomes of interest were IRCs and left/right rod length gains and thoracic (T1-T12) and spinal (T1-S1) heights. We compared patients with two rods lengthened in the cephalad ( standard; n = 18) versus opposite ( offset; n = 39) directions. Groups did not differ in age, sex, BMI, duration of follow-up, EOS cause, ambulatory status, primary curve magnitude, baseline thoracic height, or number of distractions/year. We compared patients whose constructs used ≥1 cross-link (CL group; n = 22) versus no CLs (NCL group; n = 35), analyzing thoracic height gains per distraction ( α = 0.05). Offset and standard groups did not differ in left or right rod length gains overall or per year or in thoracic or spinal height gain. Per distraction, the CL and NCL groups did not differ significantly in left or right rod length or thoracic or spinal height gain. Complications did not differ significantly between rod orientation groups or between CL groups. MCGR orientation and presence of cross-links were not associated with differences in rod length gain, thoracic height, spinal height, or IRCs at 2-year follow-up. Surgeons should feel comfortable using either MCGR orientation. Level of evidence: 3, retrospective.
MeSH term(s)	Humans ; Scoliosis/surgery ; Retrospective Studies ; Follow-Up Studies ; Spine/surgery ; Orthopedic Procedures ; Postoperative Complications ; Treatment Outcome
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Journal Article
ISSN	1473-5865
ISSN (online)	1473-5865
DOI	10.1097/BPB.0000000000001103
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Article ; Online: Fusion of bone marrow-derived cells with cancer cells

John M. Pawelek

Chinese Journal of Cancer, Vol 33, Iss 3, Pp 133-

metastasis as a secondary disease in cancer

2014 Volume 139

Abstract	This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cell is a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cell with a leukocyte-cancer cell hybrid epigenome.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2014-03-01T00:00:00Z
Publisher	Cancer Center,Sun Yat-sen University
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cancer-cell fusion with migratory bone-marrow-derived cells as an explanation for metastasis: new therapeutic paradigms.

Pawelek, John M

Future oncology (London, England)

2008 Volume 4, Issue 4, Page(s) 449–452

MeSH term(s)	Animals ; Autophagy ; Biomarkers ; Cell Fusion ; Cell Movement ; Female ; Glycosylation ; Humans ; Hybrid Cells/pathology ; Hybrid Cells/transplantation ; Leukocytes/cytology ; Macrophages/cytology ; Male ; Melanins/chemistry ; Melanoma/chemistry ; Melanoma/pathology ; Mice ; Models, Biological ; N-Acetylglucosaminyltransferases/metabolism ; Neoplasm Metastasis/pathology ; Neoplasm Metastasis/therapy ; Neoplasm Proteins/metabolism ; Neoplasm Transplantation ; Neoplastic Stem Cells/cytology ; Oligosaccharides/analysis
Chemical Substances	Biomarkers ; Melanins ; Neoplasm Proteins ; Oligosaccharides ; N-Acetylglucosaminyltransferases (EC 2.4.1.-) ; alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase (EC 2.4.1.155)
Language	English
Publishing date	2008-08
Publishing country	England
Document type	Editorial
ZDB-ID	2184533-5
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/14796694.4.4.449
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Article ; Online: Viewing malignant melanoma cells as macrophage-tumor hybrids.

Pawelek, John M

Cell adhesion & migration

2007 Volume 1, Issue 1, Page(s) 2–6

Abstract: Cutaneous malignant melanoma (CMM) begins in the epidermis as the clonal emergence of melanocytes having a deregulated mitotic cycle. In a manner not yet understood, some descendents of these cells loosen their adhesions in situ and migrate into the ... ...

Abstract	Cutaneous malignant melanoma (CMM) begins in the epidermis as the clonal emergence of melanocytes having a deregulated mitotic cycle. In a manner not yet understood, some descendents of these cells loosen their adhesions in situ and migrate into the dermis, thus initiating the processes of invasion and metastasis. These cells look and act much like macrophage-melanoma hybrids created in the lab or arising in mice. But genetic proof for hybrids in human melanoma is still lacking. Nonetheless, should tumor cell hybridization account for the invasive phenotype, this would surely evoke new therapeutic approaches regarding mechanisms of cell fusion and hybrid-specific molecular signatures. Here are described some of the remarkable phenotypic similarities between experimental macrophage-melanoma hybrids and CMM. The results suggest that invasive and metastatic CMM might well arise through fusion and genomic hybridization between melanoma cells and migratory bone marrow-derived cells.
MeSH term(s)	Animals ; Cell Movement ; Humans ; Hybridomas/metabolism ; Hybridomas/pathology ; Macrophages/metabolism ; Macrophages/pathology ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasm Transplantation ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Transplantation, Heterologous
Language	English
Publishing date	2007-01-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2268518-2
ISSN	1933-6926 ; 1933-6918
ISSN (online)	1933-6926
ISSN	1933-6918
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Article ; Online: Cytidine decreases melanin content in a reconstituted three-dimensional human epidermal model.

Baswan, Sudhir M / Yim, Sunghan / Leverett, Jesse / Scholten, Jeff / Pawelek, John

Archives of dermatological research

2019 Volume 311, Issue 3, Page(s) 249–250

Abstract: The process of melanin biosynthesis and its distribution throughout the skin is regulated by complex processes involving several enzymes in melanocytes. Recently, Diwakar et al. demonstrated that cytidine-a sialyltransferase inhibitor, 6'-sialyllactose ( ... ...

Abstract	The process of melanin biosynthesis and its distribution throughout the skin is regulated by complex processes involving several enzymes in melanocytes. Recently, Diwakar et al. demonstrated that cytidine-a sialyltransferase inhibitor, 6'-sialyllactose (6'-SL) and 3'-sialyllactose (3'-SL) inhibited melanogenesis and melanosome transfer process. In this study, we have furthered this research, considering cytidine as a commercially viable and safe option over 6'-SL and 3'-SL. The efficacy of 2% w/v cytidine was studied in MelanoDerm™ skin equivalents in comparison with the positive control 1% w/v kojic acid and the vehicle control. Both the positive control and cytidine demonstrated a significant reduction in melanin content relative to the vehicle control. These experiments conclude that cytidine can effectively reduce melanin content in a skin equivalence assay and suggests that cytidine may be a good candidate for a skin lightening agent for human skin.
MeSH term(s)	Cytidine/pharmacology ; Down-Regulation ; Enzyme Inhibitors/pharmacology ; Humans ; Melanins/metabolism ; Pyrones/pharmacology ; Sialyltransferases/antagonists & inhibitors ; Sialyltransferases/metabolism ; Skin/cytology ; Skin/drug effects ; Skin/enzymology ; Skin Lightening Preparations/pharmacology ; Skin Pigmentation/drug effects ; Tissue Culture Techniques
Chemical Substances	Enzyme Inhibitors ; Melanins ; Pyrones ; Skin Lightening Preparations ; Cytidine (5CSZ8459RP) ; kojic acid (6K23F1TT52) ; Sialyltransferases (EC 2.4.99.-)
Language	English
Publishing date	2019-02-20
Publishing country	Germany
Document type	Comparative Study ; Journal Article
ZDB-ID	130131-7
ISSN	1432-069X ; 0340-3696
ISSN (online)	1432-069X
ISSN	0340-3696
DOI	10.1007/s00403-019-01897-x
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Article ; Online: Risk Factors for Reoperation Following Final Fusion After the Treatment of Early-Onset Scoliosis with Traditional Growing Rods.

Du, Jerry Y / Poe-Kochert, Connie / Thompson, George H / Hardesty, Christina K / Pawelek, Jeff B / Flynn, John M / Emans, John B

The Journal of bone and joint surgery. American volume

2020 Volume 102, Issue 19, Page(s) 1672–1678

Abstract: Background: Although there is a high rate of reoperation after final fusion following the treatment of early-onset scoliosis with use of traditional growing rods, the risk factors for reoperation are unknown. The purpose of the present study was to ... ...

Abstract	Background: Although there is a high rate of reoperation after final fusion following the treatment of early-onset scoliosis with use of traditional growing rods, the risk factors for reoperation are unknown. The purpose of the present study was to identify risk factors associated with the need for reoperation after final fusion for the treatment of early-onset scoliosis. Methods: A multicenter database for patients with early-onset scoliosis was retrospectively analyzed. Patients managed with traditional growing rods and final fusion were identified (n = 248). The inclusion criteria were ≥1 lengthening procedure with traditional growing rods and ≥2 years of follow-up after final fusion or revision surgery within 2 years after final fusion (167 patients; 67%). Patients requiring reoperation following final fusion were compared with patients who did not require reoperation. The data that were analyzed included demographic characteristics, comorbidities, spinal deformity characteristics, radiographic measurements, perioperative details, and complications during all stages of treatment. A multivariate regression model was used to identify independent risk factors. Results: The mean duration of follow-up from the initial visit to the latest visit was 10.7 ± 4.1 years, and the mean duration of follow-up after final fusion was 4.9 ± 3.1 years. Thirty-two (19%) of the 167 patients required reoperation following final fusion. Curve progression requiring revision surgery during lengthening with traditional growing rods (adjusted odds ratio [aOR], 21.137 per event; p = 0.028), the number of levels spanned with traditional growing rods (aOR, 1.378 per level; p = 0.007), and the duration of treatment with traditional growing rods (aOR, 1.220 per year; p = 0.035) were independently associated with revision surgery after final fusion. Conclusions: Independent risk factors for curve progression requiring reoperation during lengthening with traditional growing rods that require operative intervention include increasing number of levels spanned with traditional growing rods and longer duration of treatment with traditional growing rods. These findings may help with patient counseling and potentially guide surgeon decision-making. Level of evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
MeSH term(s)	Case-Control Studies ; Child ; Disease Progression ; Female ; Humans ; Male ; Reoperation ; Retrospective Studies ; Risk Factors ; Scoliosis/surgery ; Spinal Fusion/instrumentation ; Spinal Fusion/methods ; Time Factors
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	220625-0
ISSN	1535-1386 ; 0021-9355
ISSN (online)	1535-1386
ISSN	0021-9355
DOI	10.2106/JBJS.20.00312
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Article ; Online: Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.

Rostamian, Hosein / Khakpoor-Koosheh, Mohammad / Jafarzadeh, Leila / Masoumi, Elham / Fallah-Mehrjardi, Keyvan / Tavassolifar, Mohammad Javad / M Pawelek, John / Mirzaei, Hamid Reza / Hadjati, Jamshid

BMC cancer

2022 Volume 22, Issue 1, Page(s) 39

Abstract: Background: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve ... ...

Abstract	Background: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells. Result: We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis. Conclusion: Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dichloroacetic Acid/pharmacology ; Glycolysis/drug effects ; Humans ; Lactic Acid/metabolism ; Lymphocyte Activation/drug effects ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species ; T-Lymphocytes/drug effects ; Tumor Microenvironment/drug effects
Chemical Substances	Antineoplastic Agents ; Reactive Oxygen Species ; Lactic Acid (33X04XA5AT) ; Dichloroacetic Acid (9LSH52S3LQ)
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-021-09151-2
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