Faculty Bibliography

PURPOSE/OBJECTIVE:Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules. METHODS:In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth. RESULTS:The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells. CONCLUSIONS:These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo. Graphical Abstract The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFβ, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).

BACKGROUND:Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma with elevated serum immunoglobulin M and multi-organ involvement. Primary systemic amyloidosis usually develops due to immunoglobulin light chains depositions in different organs due to an underlying gammopathy. CASE PRESENTATION/METHODS:Our patient was an 86-year-old man with macroglossia, ecchymotic patches and bullous lesions associated with a skin laxity on the periorbital, palmar, and glans penis areas. Skin biopsy confirmed dermal amyloid depositions. In serum immunofixation electrophoresis, prominent monoclonal immunoglobulin-M lambda light chains were detected associated with prominent lymphoplasmacytic infiltration in bone marrow biopsy which was diagnosed as Waldenstrom macroglobulinemia. CONCLUSION/CONCLUSIONS:Skin involvement presenting as cutaneous amyloidosis could be the first manifestation of Waldenstrom macroglobulinemia. We should think about an underlying gammopathy in an old patient with skin laxity and ecchymosis.

Large granular lymphocyte leukemia (LGL) is a clonal, lymphoproliferative disorder with an indolent disease course. T-cell LGL (T-LGL) is the most common type of LGL driven from T-cell lineage (85%). The coexistence of T-LGL with several types of autoimmune disorders, mostly rheumatoid arthritis (RA), has been reported. Felty's syndrome (FS) is defined by splenomegaly, low neutrophil count, and destructive arthritis and is usually seen in <1% of patients with RA. About 30% to 40% of patients with FS have been reported to have an expansion of large granulated lymphocytes in the circulation. FS and T-LGL are similar in terms of clinical manifestations, response to immunosuppressive therapy, their smoldering course, and immunogenetic findings, proposing FS and T-LGL with RA might be different aspects of a single disease spectrum. In this article, we present a case with long-standing RA who had never been on DMARD (Disease Modifying Anti-Rheumatic Drugs) treatment found to have constitutional symptoms, neutropenia, and splenomegaly, and the patient was diagnosed with T-LGL.

Ultraviolet (UV) radiation could disintegrate folate molecule, so phototherapy may reduce folate levels in the patients. The effect of phototherapy on serum folate in human body is questionable. We investigated the effect of bath PUVA therapy on serum folate level. This study was designed as a before-after study. Thirty-two patients completed study during 2 years. Our variables were demographic data, folate levels before and 8 weeks after treatment and cumulative dosage of UVA during 8 weeks of treatment. Serum folate was evaluated with chemiluminescence immunoassay technique. All data were analyzed using SPSS 18 software. Folate level changes were statistically significant before and after bath PUVA therapy. There was no significant difference in folate levels in psoriasis patients compared with nonpsoriasis patients. In psoriasis patients, folate levels had no significant correlation with psoriasis activity index before treatment. Decrease in folate levels was more significant in fair-skinned patients. There was no association between folate status and cumulative dosage of UVA. Bath PUVA therapy reduced serum folate level in our patients although none of them were folate deficient. Folate deficiency should be evaluated and corrected especially in fair-skinned cases, as it may be aggravated by phototherapy.

BACKGROUND:Wegener granulomatosis or granulomatosis with polyangiitis is a pauci-immune small vessel vasculitis which is usually associated with anti-neutrophil cytoplasmic antibodies (ANCA) mainly in old men. This small vessel vasculitis is usually characterized by necrotizing granulomatous inflammation with multiorgan involvement. Kidneys could be involved as the main and life-threatening condition in Wegener granulomatosis. Oral or ocular lesions may occur as the first and uncommon presentations before internal organ involvement in these patients and could be misdiagnosed with other diseases. CASE PRESENTATION/METHODS:We present a 24-year-old man with erosions and ulcerations on palatal mucosa and a strawberry-like gingival hypertrophy associated with nasal congestion and epistaxis which two stated months ago. Also he had an episode of unilateral blepharitis and upper eyelid edema five months ago. Mucosal biopsy showed perivascular infiltrations of mainly neutrophils, some eosinophils and rare giant cells. He had elevated level of proteinase 3-ANCA or C-ANCA with microscopic hematuria without significant kidney involvement in kidney biopsy. Mucosal lesions and hematuria improved after two months of treatment with oral prednisolone. CONCLUSION/CONCLUSIONS:Unilateral eyelid edema and mucosal erosions in a young man could be the uncommon presentations of Wegener granulomatosis.

Bullous pemphigoid is an acquired autoimmune subepidermal blistering disease which is associated with mucocutaneous lesions. The type and amount of autoantibody deposition may have a role in mucosal lesions. We studied the association between mucosal involvement and direct immunofluorescence pattern in cutaneous lesions of patients with bullous pemphigoid. In this retrospective analytical cross-sectional study, we studied the demographic data, clinical presentations, and immunopathological findings of 69 patients with bullous pemphigoid admitted to our hospital 2008-2016. Patients were allocated into two groups on the basis of the mucosal involvement, and direct immunofluorescence patterns were evaluated. The data were analyzed using SPSS version18. The mean age of patients was 70.9±14.97 (mean ± Standard Deviation) years old. In our study, 56.5% of patients were women. All patients showed deposition of IgG and C3 in the dermoepidermal junction, with different severity. Patients with mucosal involvement (40.6% of cases) had a more prominent deposition of IgG, IgA, and C3 at the dermoepidermal junction compared with patients without mucosal involvement, which represented a statistically significant difference (P<0.05). Logistic regression analysis showed that lower age, IgA, and C3 deposition (P<0.05) were associated with mucosal involvement. Deposition of IgA and C3 (in addition to IgG) at the dermoepidermal junction seems to be a marker of mucosal involvement in patients with bullous pemphigoid. Attention to direct immunofluorescence pattern in patients with bullous pemphigoid may be helpful in prediction of mucosal involvement in these patients.