FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling.

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the antitumor activity of FPFT-2216-a novel low molecular weight compound-in lymphoid tumors and elucidated its molecular mechanism of action. In addition, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic antiproliferative activity and induced rapid tumor regression in immunodeficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after 10 days; this was continuously observed in 5 of 7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the antitumor activity of rituximab and showed antitumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NFκB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NFκB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma. SIGNIFICANCE: We found potential vulnerability to CK1α degradation in certain lymphoma cells refractory to IKZF1/3 degraders. Targeting CK1α with FPFT-2216 could inhibit the growth of these cells by activating p53 signaling. Our study demonstrates the potential therapeutic application of CK1α degraders, such as FPFT-2216, for treating lymphoma.

C-MYC and Its Main Ubiquitin Ligase, FBXW7, Influence Cell Proliferation and Prognosis in Adult T-cell Leukemia/Lymphoma.

Smoldering-type and chronic-type adult T-cell leukemia/lymphomas (ATLL) patients have relatively indolent clinical courses, but often progress into aggressive lymphoma-type and acute-type disease. We examined the roles of transcription factor C-MYC and its ubiquitin ligase FBXW7 in tumor tissues from 137 patients with ATLL. Immunohistochemical tests showed ≥50% of lymphoma cells in 78.7% (48/61) of lymphoma-type, and 64.9% (24/37) of acute-type samples expressed C-MYC, significantly higher than was seen in smoldering-type (3.6%) and chronic-type (9.1%) samples (P<0.01). Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01). C-MYC expression was highly correlated with its mRNA levels (ρ=0.65, P<0.0001), chromosomal amplification and duplication (ρ=0.3, P=0.045) and MIB1 labeling index (ρ=0.69, P<0.0001). Expression of FBXW7 protein and mRNA in lymphoma-type samples were significantly lower than those of smoldering-type (P<0.01 for each), and both were inversely correlated with C-MYC (protein: ρ=-0.4, P=0.0002; mRNA: ρ=-0.31, P=0.015). Seven patients with smoldering-type or chronic-type ATLL converted to acute-type, in 4 of whom C-MYC expression increased from <50% to ≥50%. Patients with ≥50% C-MYC or MIB1 had significantly worse prognosis than those with <50% C-MYC (P=0.0004) or MIB1 (P<0.0001), as did those with ≥7.5 C-MYC mRNA scores (P=0.033); whereas significantly better prognosis was associated with ≥50% FBXW7 protein (P=0.0006) or ≥0.17 FBXW7 mRNA (P=0.016). C-MYC and FBXW7 affect ATLL proliferation and progression, and low FBXW7 may increase C-MYC expression. C-MYC was a critical prognostic factor in ATLL patients.

Dermatitis caused by metal allergy after coil embolization for unruptured cerebral aneurysm.

We report a rare case of metal-induced dermatitis after coil embolization for cerebral aneurysm. A 51-year-old woman experienced a rash around the lips and neck 3 weeks after coil embolization. Judging from the clinical course and results of several patch tests, platinum coils were considered to have induced the dermatitis. Symptoms were relieved with administration of oral steroids. This represents the first report of metal-induced dermatitis after neuroendovascular treatment. The possibility of metal allergy was difficult to suspect preoperatively. However, early evaluation and referral are important when skin symptoms are observed postoperatively.

Dermatitis caused by metal allergy after coil embolization for unruptured cerebral aneurysm.

We report a rare case of metal-induced dermatitis after coil embolization for cerebral aneurysm. A 51-year-old woman experienced a rash around the lips and neck 3 weeks after coil embolization. Judging from the clinical course and results of several patch tests, platinum coils were considered to have induced the dermatitis. Symptoms were relieved with administration of oral steroids. This represents the first report of metal-induced dermatitis after neuroendovascular treatment. The possibility of metal allergy was difficult to suspect preoperatively. However, early evaluation and referral are important when skin symptoms are observed postoperatively.

Bilateral nevus comedonicus syndrome.

Nevus comedonicus is an uncommon skin abnormality characterized by an aggregation of dilated follicular orifices filled with keratinous material. Nevus comedonicus is occasionally complicated with other conditions including cataracts, skeletal defects, central nervous system abnormalities or other extra-cutaneous diseases (nevus comedonicus syndrome). Although most cases of nevus comedonicus occur unilaterally on the face, neck and chest, the lesions occasionally show a bilateral distribution (bilateral nevus comedonicus). We report here an unusual case of bilaterally disseminated nevus comedonicus with various systemic complications. A 62-year-old Japanese man presented with a 50-year history of numerous keratotic papules and comedo-like lesions, which gradually worsened with time. Physical examination revealed that the papules were skin-colored and 1-4 mm in diameter. Some papules had dark-black keratinous materials on their surface, giving them a comedo-like appearance. The lesions were located predominantly on the face, head, neck and trunk with symmetric distribution, following Blaschko's lines. The patient's past medical history was noteworthy; he had undergone surgical treatments for thyroid cancer, pneumothorax and schwannoma in the cauda equina. He also suffered from scoliosis, cervical spondylosis and atrial fibrillation. Histopathologic examination revealed dilated and invaginated follicular structures filled with lamellar keratin, compatible with nevus comedonicus. Our patient's case did not fit with any previously reported diseases, and we thought a diagnosis of "bilateral nevus comedonicus syndrome" was the most appropriate for our patient's condition. He was treated with topical retinoic acid and activated vitamin D3 ointment for 3 months each, but the lesions remained unchanged.

The effect of low-dose corticosteroids on short- and long-term renal outcome in patients with cholesterol crystal embolism.

BACKGROUND: The effect of corticosteroids on renal cholesterol crystal embolism (CCE) remains uncertain. The aim of the present study was to elucidate the effect of steroid therapy on short- and long-term renal outcome in CCE patients. METHODS: Fifty-one patients diagnosed with renal CCE were included in this retrospective study. The patients were divided into two groups according to whether or not they had received steroid therapy (steroid therapy (+), n = 32; (-), n = 19). Corticosteroids were administered at an initial dose of 10-20 mg/day after CCE diagnosis. The values of the estimated glomerular filtration rate (eGFR) in the two groups were examined at CCE diagnosis, 4 weeks after diagnosis and the last follow-up. Additionally, the % change in eGFR at 4 weeks after diagnosis and % change per year in eGFR at the last follow-up were calculated for each patient. RESULTS: The median values of eGFR at diagnosis in patients with and without steroid therapy were 16.4 and 17.9 mL/min/1.73 m(2), respectively. The median % change in eGFR between diagnosis and 4 weeks after diagnosis was 24% in patients with steroid therapy and 5% in those without, and this difference was statistically significant. On the other hand, there was no significant difference between the two groups in the % change in eGFR per year between diagnosis and the last follow-up. CONCLUSIONS: During the short period after CCE diagnosis, steroid therapy showed a good renal outcome in CCE patients. However, this treatment did not have a favorable effect on long-term renal outcome.

Differential expression of phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated p38 mitogen-activated protein kinase and nuclear factor-kappaB p105/p50 in chronic inflammatory skin diseases.

The keratinocytes actively participate in the cutaneous immune responses. Dysregulation and abnormal expression of inflammatory mediators or their receptors in keratinocytes are relevant to the pathogenesis of chronic inflammatory skin diseases. The mechanism of long-lasting inflammatory processes is related with the activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK), which play a crucial role in the immune responses. There are potential interaction points between these two pathways. The aim of this study is to investigate the differences in expression levels and distributions of phosphorylated extracellular signal-regulated kinase (ERK)1/2, phosphorylated p38 MAPK and NF-kappaB p105/p50 in chronic inflammatory skin diseases. An immunohistochemical staining technique was employed to measure the expression of these molecules in 25 cases of lichen planus, 22 cases of psoriasis, 26 cases of chronic eczema, seven cases of prurigo and seven cases of normal skin. We observed that the expression of phosphorylated ERK1/2, phosphorylated p38 MAPK and NF-kappaB p105/p50 was significantly more augmented in the lesional epidermis of all the inflammatory skin diseases than those in normal skin (P < 0.05), and the number of positive keratinocytes was significantly more in lichen planus than that in other inflammatory diseases (P < 0.001). Moreover, the positive keratinocytes of these three molecules were more widely distributed in the entire layer of the epidermis in lichen planus than those in other diseases. We concluded that ERK1/2, p38 MAPK and NF-kappaB p105/p50 might play important roles in the pathophysiology of chronic inflammatory skin diseases.

Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

Concordant overexpression of phosphorylated ATF2 and STAT3 in extramammary Paget's disease.

BACKGROUND: Activating transcription factor 2 (ATF2) and signal transducer and activator of transcription 3 (STAT3) play important roles in the pathogenesis of various tumors, but ATF2 expression/activation and the relationship with STAT3 activation have not yet been investigated in extramammary Paget's disease (EMPD). OBJECTIVE: To investigate potential contributions of ATF2 and STAT3 pathways to the pathogenesis of EMPD. METHOD: Paraffin-embedded 45 EMPD specimens (43 primary EMPD and 2 nodal metastases) were subjected to immunohistochemical staining for ATF2, phosphorylated (p)-ATF2 and p-STAT3. RESULTS: P-ATF2 expression in advanced EMPD, non-invasive EMPD and normal skin (NS) controls were 97.9 +/- 1.8%, 82.0 +/- 23.4% and 45.8 +/- 3.2%, respectively, and p-STAT3 expression in advanced EMPD, non-invasive EMPD and NS were 97.0 +/- 2.9%, 83.2 +/- 23.3% and 50.1 +/- 6.7%, respectively. P-ATF2 and p-STAT3 expressions in EMPD were significantly higher than those in NS, indicating a possible contribution of these pathways to the tumor development. P-ATF2 and p-STAT3 expressions in advanced EMPD were significantly higher than those in non-invasive EMPD, possibly indicating that these pathways might also contribute to the tumor invasion and/or metastasis. We also found an exceptionally high positive correlation between p-ATF2 and p-STAT3 expressions in EMPD. CONCLUSIONS: P-ATF2 and p-STAT3 are concordantly overexpressed in EMPD and their expressions may possibly be associated with the tumor stage.

Bullous pemphigoid followed by pustular psoriasis showing Th1, Th2, Treg and Th17 immunological changes.

Psoriasis vulgaris is occasionally accompanied by autoimmune bullous diseases, but the opposite is very rare. We document here the first reported case of generalized pustular psoriasis that appeared during steroid therapy for bullous pemphigoid. The serum cytokine levels and the results of an immunohistochemical study over the disease course suggest that the immunological state was consistent with a shift from Th2-dominance to Th1-dominance. IL-17-producing cells appeared in the skin lesions when each disease was most exacerbated and disappeared after remission. Thus, the present case demonstrated a dynamic immunological state in which the appearances of Th1 and Th2 as well as Th17 varied during the course of the disease.

A case of Crohn's disease associated with Takayasu's arteritis and Henoch-Schönlein purpura.

A 14-year-old Japanese man was diagnosed with Crohn's disease in October 2001. Four years later, the patient was referred to our institution because of neck pain, fever and asymmetrical blood pressure. Magnetic resonance angiography, computed tomography and ultrasonography revealed findings compatible with Takayasu's arteritis. In March 2006, the patient developed purpura over bilateral hands and lower extremities, arthralgia, lower abdominal pain and microhematuria. The patient was diagnosed with Henoch-Schönlein purpura. This is the first reported case of Crohn's disease associated with two types of vascular complications.

Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma.

BACKGROUND: Activating transcription factor-2/Activator protein-1 (AP-1), Signal transducer and activator of transcription-3 and p53 are important regulators of cellular proliferation, apoptosis, differentiation in the pathogenesis of many human tumors, but the expression of phosphorylated (p)-activating transcription factor-2 (p-ATF2), phosphorylated (p)-signal transducer and activator of transcription-3 (p-STAT3) and p53 family (p63 and p73) has not been investigated in cutaneous angiosarcoma (CAS) and pyogenic granuloma (PG) so far. OBJECTIVES: To investigate the expression of p-ATF2, p-STAT3 and p53 and its family in cutaneous vascular tumors (CAS and PG). METHODS: Paraffin-embedded specimens of 14 CAS and 19 PG were subjected to immunohistochemical staining for p-ATF2, p-STAT3, p53, p63 and p73. RESULTS: P-ATF2 was expressed in 13 out of 14 CAS and in all of 19 PG. P-STAT3 was expressed in all of 14 CAS and 19 PG. P53 was expressed in all of 14 CAS and 19 PG, while both p63 and p73 were negative in CAS and PG. The p-ATF2-, p-STAT3- and p53 expression (% positive cells) in CAS and PG were significantly higher than in normal dermal vessels, but none of these transcription factors distinguished malignant (CAS)- from benign (PG) vascular tumor. CONCLUSIONS: The present study suggests that overexpression of p-ATF2, p-STAT3 and possibly p53, but not p63 or p73, may contribute to the tumorigenesis of cutaneous vascular tumors.