ABSTRACT
BACKGROUND: Treatment for most patients with head and neck cancers includes ionizing radiation with or without chemotherapy. This treatment causes irreversible damage to salivary glands in the irradiation field accompanied by a loss of fluid-secreting acinar cells and a considerable decrease of saliva secretion. There is currently no adequate conventional treatment for this condition. In recent years, we developed an effective culture method to enhance the anti-inflammatory and vasculogenic phenotypes of peripheral blood mononuclear cells (PBMNCs), and such effectively conditioned PBMNC (E-MNC) therapy has shown promising improvements to the function of radiation-injured salivary glands in preclinical studies. However, the safety and effect of E-NMC therapy have yet assessed in human. The objective of this ongoing first-in-man study is to assess the safety, tolerability, and in part the efficacy of E-MNC therapy for treating radiation-induced xerostomia. METHODS/DESIGN: This phase 1 first-in-man study is an open-label, single-center, two-step dose escalation study. A total of 6 patients, who had no recurrence of head and neck cancer over 5 years following radiation therapy and suffered from radiation-induced xerostomia, will receive a transplantation of E-NMCs derived from autologous PBMNCs to a submandibular gland. The duration of the intervention will be 1 year. To analyze the recovery of salivary secretion, a gum test will be performed. To analyze the recovery of atrophic salivary glands, computed tomography (CT), and magnetic resonance imaging (MRI) of salivary glands will be conducted. The primary endpoint is the safety of the protocol. The secondary endpoints are the changes from baseline in whole saliva secretion and salivary gland atrophy. DISCUSSION: This will be the first clinical study of regenerative therapy using E-MNCs for patients with severe radiation-induced xerostomia. The results of this study are expected to contribute to developing the low-invasive cell-based therapy for radiation-induced xerostomia. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials (http://jrct.niph.go.jp) as jRCTb070190057.
Subject(s)
Cell- and Tissue-Based Therapy/methods , Leukocytes, Mononuclear/transplantation , Radiation Injuries , Salivary Glands , Xerostomia , Head and Neck Neoplasms/radiotherapy , Humans , Magnetic Resonance Imaging/methods , Radiation Injuries/diagnosis , Radiation Injuries/etiology , Radiation Injuries/physiopathology , Radiation Injuries/therapy , Research Design , Salivary Glands/diagnostic imaging , Salivary Glands/pathology , Salivary Glands/physiopathology , Salivary Glands/radiation effects , Tomography, X-Ray Computed/methods , Transplantation, Autologous/methods , Treatment Outcome , Xerostomia/diagnosis , Xerostomia/etiology , Xerostomia/physiopathology , Xerostomia/therapySubject(s)
Adipose Tissue/transplantation , Carcinoma, Squamous Cell/surgery , Cheek/surgery , Gingival Neoplasms/surgery , Mandible/surgery , Mouth Mucosa/surgery , Plastic Surgery Procedures/methods , Aged , Female , Follow-Up Studies , Humans , Leukemia-Lymphoma, Adult T-Cell/complications , Minimally Invasive Surgical Procedures , Operative TimeABSTRACT
Two amyloidogenic Bence Jones proteins (Am37 VkappaIV and NIG1 VkappaI) and one non-amyloidogenic protein (NIG26 VkappaIII) were characterized. The protein Am37 had four deletions when compared with the translated germ-line gene sequence: two Ser residues following position 27 (27e, 27f) in CDR1 and two amino acids Pro-44, and Tyr-49 in FR2 were deleted. A strictly conserved salt-bridge-forming amino acid, Asp-82, was replaced by the hydrophobic residue Leu. In a comparative study of amyloidogenic and non-amyloidogenic proteins, five amino acids (Ser-10, Ala-13, Ser-65, Gln-90, and Ile-106) were found to be unique to NIG1 and several other amyloidogenic proteins. Additional substitutions also occur within these proteins. These substitutions might be significant in altering protein folding as well as in contributing to their aggregation as amyloid fibrils.
Subject(s)
Amyloidosis/genetics , Bence Jones Protein/chemistry , Immunoglobulin kappa-Chains/chemistry , Amino Acid Sequence , Amino Acid Substitution/genetics , Amino Acids/analysis , Amyloidosis/urine , Bence Jones Protein/genetics , Bence Jones Protein/urine , Chromatography, High Pressure Liquid , Electrophoresis, Polyacrylamide Gel , Germ-Line Mutation , Humans , Immunoblotting , Immunoglobulin kappa-Chains/genetics , Immunoglobulin kappa-Chains/urine , Molecular Sequence Data , Pilot Projects , Sequence Analysis , Sequence Deletion/genetics , Sequence Homology, Amino Acid , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Three human amyloidogenic Bence Jones proteins, NIG76 VlambdaII, NIG204 VlambdaI, and NIG250 VlambdaV, were characterized. In a comparative study, three amino acids, Ser-25a, Thr-68, and Val-95, were found to be common to amyloidogenic proteins of the VlambdaII subgroup. NIG204 had an insertion of Pro residue following position 30 (30a). Proteins having an insertion at this position are invariantly amyloidogenic. NIG250 had a characteristic VlambdaV VL domain, with Mcg+ and KERN+ CL domain isotypes. Following the protein DEL, this is the second example of this subgroup. No common residue is found in the other subgroup proteins but unique substitutions do occur. It would seem that any substitution that causes an alteration in the protein conformation may lead to its being more prone to association with the amyloid processes.
