Addressing the knowledge gap in the genomic landscape and tailored therapeutic approaches to adolescent and young adult cancers.

BACKGROUND: Adolescents and young adults (AYAs) represent a small proportion of patients with cancer. The genomic profiles of AYA patients with cancer are not well-studied, and outcomes of genome-matched therapies remain largely unknown. PATIENTS AND METHODS: We investigated differences between Japanese AYA and older adult (OA) patients in genomic alterations, therapeutic evidence levels, and genome-matched therapy usage by cancer type. We also assessed treatment outcomes. RESULTS: AYA patients accounted for 8.3% of 876 cases. Microsatellite instability-high and/or tumor mutation burden was less common in AYA patients (1.4% versus 7.7% in OA; P = 0.05). However, BRCA1 alterations were more common in AYA patients with breast cancer (27.3% versus 1.7% in OA; P = 0.01), as were MYC alterations in AYA patients with colorectal cancer (23.5% versus 5.8% in OA; P = 0.02) and sarcoma (31.3% versus 3.4% in OA; P = 0.01). Genome-matched therapy use was similar between groups, with overall survival tending to improve in both. However, in AYA patients, the small number of patients prevented statistical significance. Comprehensive genomic profiling-guided genome-matched therapy yielded encouraging results, with progression-free survival of 9.0 months in AYA versus 3.7 months in OA patients (P = 0.59). CONCLUSION: Our study suggests that tailored therapeutic approaches can benefit cancer patients regardless of age.

Merkel cell carcinoma in Taiwan: A rare tumour with a better prognosis in those harbouring Merkel cell polyomavirus.

Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour affecting mainly elderly patients and is more common in the West than in Asia. It is associated with Merkel cell polyomavirus (MCPyV), immunosuppression, and ultraviolet light. In this study, we retrospectively investigated the first series of MCC from Taiwan and identified 19 cases from three tertiary centres. All patients were males with a median age of 67.5. Twelve (63%) cases occurred in the extremities, with one unique case presenting initially as nodal metastasis of unknown primary. Immunohistochemically, the great majority of tumours expressed CK20 (89%), synaptophysin (89%), and INSM1 (84%), with none positive for TTF1. Eleven (58%) cases were positive for MCPyV by immunohistochemistry (clone CM2B4). All patients were treated with excision, including four with additional radiotherapy and one with radiotherapy and chemotherapy. Nodal status and treatment modalities significantly affected survival. The median survival time of MCPyV-positive cases was much longer than the negative cases (median 40 vs. 10 months). In summary, we presented the first report on the clinicopathological features of MCC in Taiwan, with 58% cases associated with MCPyV. The prognosis of patients with MCPyV-positive tumours was better than those negative for MCPyV.

Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.

OBJECTIVE: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression. DESIGN: High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated through RT-qPCR and western blotting analyses. Additionally, 10-week-old mice were subjected to destabilization of the medial meniscus (DMM) surgery to induce OA and were sacrificed 12 weeks post-surgery for pathological examination. OA was evaluated using the OARSI scoring system. RESULTS: Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered mice with DMM presented significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% confidence interval (CI) of difference: 0.1651-3.035) and significantly lower synovial membrane inflammation scores (adjusted P: 0.0243, mean difference: 0.6, 95% CI of difference: 0.06158-1.138) than mice with DMM. IPA further revealed that components of the Rho signaling pathways are regulated by cytokines and colchicine. IL-1ß and TNF-α activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-γ1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, leading to the induction of MMP13 expression. CONCLUSIONS: Colchicine is a potential DMOAD candidate that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCγ1-Ca2+ signaling pathway.

A multi-centre, retrospective case series of oocyte cryopreservation in unmarried women diagnosed with haematological malignancies.

STUDY QUESTION: Is oocyte cryopreservation an applicable option for fertility preservation in unmarried patients with haematological malignancies? SUMMARY ANSWER: Oocyte cryopreservation via the vitrification method is accessible and may be considered an option for fertility preservation in unmarried patients with haematological malignancies. WHAT IS KNOWN ALREADY: Haematological malignancies are most commonly observed amongst adolescent and young adult women. Although the survival rate and life expectancy of those with haematological malignancies have improved, chemotherapy and radiotherapy may impair their reproductive potential. Oocyte cryopreservation is thus an ideal option to preserve their fertility. STUDY DESIGN SIZE DURATION: This study retrospectively evaluated 193 unmarried patients (age: 26.2 ± 0.4 years) with haematological malignancies, who consulted for oocyte cryopreservation across 20 different fertility centres in Japan between February 2007 and January 2015. The primary outcome measures were the oocyte retrievals and oocyte cryopreservation outcomes. The secondary outcome measures were the outcomes following oocyte warming for IVF. PARTICIPANTS/MATERIALS SETTING METHODS: The patients had commenced ovarian stimulation cycles via antagonist, agonist, natural and minimal methods for oocyte retrievals, defined according to the treatment strategy of each respective fertility centre. A vitrification method using the Cryotop safety kit was used for oocyte cryopreservation. ICSIs were used for insemination of warmed oocytes. The endometrial preparation method for embryo transfer was hormonal replacement therapy, except in the case of a patient who underwent a spontaneous ovulatory cycle. MAIN RESULTS AND THE ROLE OF CHANCE: Among 193 patients, acute myeloid leukaemia (n = 45, 23.3%) was most common, followed by acute lymphoid leukaemia (n = 38, 19.7%) and Hodgkin's lymphoma (n = 30, 15.5%). In total, 162 patients (83.9%) underwent oocyte retrieval, and oocytes were successfully cryopreserved for 155 patients (80.3%). The mean number of oocyte retrieval cycles and cryopreserved oocytes were 1.7 ± 0.2 and 6.3 ± 0.4, respectively. As of December 2019, 14 patients (9.2%) had requested oocyte warming for IVF. The survival rate of oocytes after vitrification-warming was 85.2% (75/88). The rates of fertilisation and embryo development were 80.0% (60/75) and 46.7% (28/60), respectively. Ten patients (71.4%) had successful embryo transfers, and seven live births (50.0%) were achieved. LIMITATIONS REASONS FOR CAUTION: This study was limited by its retrospective nature. Additionally, there remains an insufficient number of cases regarding the warming of vitrified oocytes to reliably conclude whether oocyte cryopreservation is effective for patients with haematological malignancies. Further long-term follow-up study is required. WIDER IMPLICATIONS OF THE FINDINGS: Oocyte retrieval and oocyte cryopreservation were accessible for patients with haematological malignancies; however, the number of oocyte retrievals may have been limited due to the initiation of cancer treatments. Acceptable embryonic and pregnancy outcomes could be achieved following oocyte warming; therefore, our results suggest that oocyte cryopreservation can be considered an option for fertility preservation in patients with haematological malignancies. STUDY FUNDING/COMPETING INTERESTS: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Periodontitis Is Associated with Chronic Obstructive Pulmonary Disease.

Although they are known to share pathophysiological processes, the relationship between periodontitis and chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study was to test the hypothesis that periodontitis is associated with a greater risk of development of COPD, when smoking is taken into account. The analysis in a 5-y follow-up population-based cohort study was based on 900 community-dwelling Japanese adults (age: 68.8 ± 6.3 [mean ± SD], 46.0% male) without COPD aged 60 or older with at least 1 tooth. Participants were classified into 3 categories according to baseline periodontitis severity (no/mild, moderate, and severe). COPD was spirometrically determined by a fixed ratio of <0.7 for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and by FEV1/FVC below the lower limit of normal. Poisson regression was used to calculate the relative risk (RR) of developing COPD according to the severity of periodontitis. The population attributable fraction (PAF) was also calculated. During follow-up, 22 (2.4%) subjects developed COPD. Compared with no/mild periodontitis subjects, a significantly increased risk of COPD occurred among severe periodontitis subjects (RR = 3.55; 95% confidence interval [CI], 1.18 to 10.67), but no significant differences were observed between the no/mild and moderate categories (RR = 1.48; 95% CI, 0.56 to 3.90). After adjustment for potential confounders, including smoking intensity, the relationship between severe periodontitis and risk of COPD remained significant (RR = 3.51; 95% CI, 1.15 to 10.74). Likewise, there was a positive association of periodontitis severity with risk of COPD ( P for trend = 0.043). The PAF for COPD due to periodontitis was 22.6%. These data highlight the potential importance of periodontitis as a risk factor for COPD.

Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.

Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

Low absolute peripheral blood CD4+ T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lymphoma.

The absolute peripheral blood lymphocyte count at diagnosis is known to be a strong prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but it remains unclear as to which peripheral blood lymphocyte population is reflective of DLBCL prognosis. In this cohort, 355 patients with DLBCL treated with R-CHOP from 2006 to 2013 were analyzed. The low absolute CD4+ T-cell count (ACD4C) at diagnosis negatively correlated with the overall response rate and the complete response rate significantly (P<0.00001). An ACD4C<343 × 106/l had a significant negative impact on the 5-year progression-free survival and the overall survival as compared with an ACD4C⩾343 × 106/l (73.7% (95% confidence interval (CI)=66.7-79.5) versus 50.3% (95% CI=39.0-60.6), P<0.00001 and 83.3% (95% CI=77.1-88.0) versus 59.0% (95% CI=47.9-68.5), P<0.00000001, respectively). Multivariate analysis revealed that the ACD4C was an independent prognostic marker (hazard ratio=2.2 (95% CI=1.3-3.7), P<0.01). In conclusion, a low ACD4C at diagnosis served as an independent poor prognostic marker in patients with DLBCL.

Identification of cell-type-specific mutations in nodal T-cell lymphomas.

Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.

A mild hand cleanser, alkyl ether sulphate supplemented with alkyl ether carboxylic acid and alkyl glucoside, improves eczema on the hand and prevents the growth of Staphylococcus aureus on the skin surface.

OBJECTIVE: Washing the hands using cleansers with antiseptic materials is the most popular method for hand hygiene and helps maintain health by preventing food poisoning and bacterial infections. However, repeated hand washing tends to induce eczema of the hand, such as dryness, cracking and erythema. Moreover, eczema on the hand leads to increased levels in Staphylococcus aureus (S. aureus) on the skin surface in contrast to expectations. Thus, mild hand cleansers which induce less eczema even with repeated washings are desired. Here, we evaluated the efficacy of a hand cleanser formulated with alkyl ether sulphate (AES), alkyl ether carboxylic acid (AEC) and alkyl glucoside (AG) that contains isopropyl methylphenol (IPMP) on skin symptoms and S. aureus levels. METHODS: Eczema of the hand and the presence of S. aureus on the skin surface were analysed prior to and following 4 weeks of usage of the hand cleanser. A soap-based hand cleanser with IPMP was used as a reference cleanser. Eczema and cutaneous conditions were evaluated by visual grading, transepidermal water loss (TEWL), stratum corneum moisture-retention ability (MRA) and skin surface pH. RESULTS: The repeated use of the soap-based hand cleanser significantly worsened the hand dryness, scaling and cracks on the tips of the fingers and significantly increased the TEWL and decreased the MRA. In contrast, usage of the test cleanser only induced a significant increase in skin dryness but did not induce skin scaling or cracking and did not increase TEWL or decrease the MRA. Corresponding to these changes in skin symptoms, the presence of S. aureus increased the following use of the reference cleanser but not the test cleanser. There was no significant difference in skin surface pH between the two cleansers. Moreover, the increase in S. aureus was significantly correlated to the worsening of skin dryness and scaling. CONCLUSION: These results suggest that not only antimicrobial activity but also the mildness, which minimizes cutaneous effects, are important for hand cleansers to prevent the growth of S. aureus. The cleanser formulated with AES, AEC and AG containing IPMP is mild and is effective to promote hand hygiene.

Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).

Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1ß, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.

Cinacalcet, a calcimimetic, prevents nonsteroidal antiinflammatory drug-induced small intestinal damage in rats.

The extracellular calcium-sensing receptor (CaSR), a G protein-coupled cell receptor cloned from bovine parathyroid, has been demonstrated to play a regulatory role in various functions of the gastrointestinal tract. In the present study, we examined the effect of cinacalcet, a drug that acts as a calcimimetic through the allosteric activation of CaSR, on the loxoprofen-induced small intestinal lesions and investigated the mechanisms involved in the protective action. Male Sprague-Dawley rats were used without fasting. The animals were administered loxoprofen p.o. and euthanized 24 hours later and the intestinal mucosa was examined for lesions. Cinacalcet was given p.o. twice, 30 min before and 6 h after loxoprofen. Loxoprofen caused hemorrhagic lesions in the small intestine, accompanied by the upregulation of enterobacterial invasion, myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS)/tumor necrosis factor α (TNF-α) expression as well as the downregulation of Muc2 expression. Prior administration of cinacalcet dose-dependently and significantly reduced the severity of these lesions in response to loxoprofen, with concomitant suppression of the changes in bacterial invasion, iNOS/TNF-α as well as Muc2 expression, and myeloperoxidase activity. Cinacalcet also significantly reversed a decrease in mucus secretion and fluid secretion in the small intestine caused by loxoprofen, but had no effect on the intestinal hypermotility or prostaglandin E2 deficiency caused by loxoprofen. These results suggest that cinacalcet protects the small intestine against loxoprofen-induced damage, and this effect may be functionally associated with an increase in fluid secretion and a reversal of downregulation of Muc2 expression caused by loxoprofen, resulting in suppression of bacterial invasion and iNOS/TNF-α expression, the major pathogenic events in nonsteroidal antiinflammatory drugs-induced small intestinal ulceration.

TGF-ß-induced apoptosis of B-cell lymphoma Ramos cells through reduction of MS4A1/CD20.

Transforming growth factor-ß (TGF-ß) exhibits growth inhibitory effects on various types of tumor cells, including B-cell lymphoma cells. In the present study, the role of TGF-ß in the survival of Epstein-Barr virus-negative B-cell lymphoma Ramos cells was investigated. As TGF-ß-induced apoptosis of Ramos cells in vitro and in vivo, we attempted to identify novel target gene(s) responsible for their survival. Oligonucleotide microarray analysis and chromatin immunoprecipitation revealed that Smad proteins directly regulated the transcription of membrane-spanning 4-domains, subfamily A, member 1 (MS4A1), also known as CD20, in Ramos cells upon TGF-ß stimulation. In addition, immunohistochemical analysis using clinical samples from B-cell lymphoma patients showed an inverse correlation between the expression of MS4A1/CD20 and phosphorylation of Smad3. Although knockdown of MS4A1/CD20 in Ramos cells resulted in an increase of apoptotic cells, Ramos cells stably expressing MS4A1/CD20 were resistant to TGF-ß-induced apoptosis. This suggests that MS4A1/CD20 is responsible for TGF-ß-induced apoptosis of B-cell lymphoma cells. Moreover, downregulation of MS4A1/CD20 by TGF-ß attenuated the effects of the monoclonal anti-MS4A1/CD20 antibody, rituximab, on Ramos cells. Our findings suggest that the sensitivity of B-cell lymphoma cells to rituximab may be affected by TGF-ß signaling.

5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells.

BACKGROUND AND PURPOSE: Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5-HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5-HT3 receptor antagonists on 5-FU-induced intestinal mucositis in mice. EXPERIMENTAL APPROACH: Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5-FU (50 mg·kg⁻¹) for 5 days. Effects of 5-HT3 receptor antagonists, ramosetron (0.01-0.1 mg·kg⁻¹) and ondansetron (5 mg·kg⁻¹), on the accompanying histology, cytokine production and apoptosis were assessed. KEY RESULTS: Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose-dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase-3- and caspase-8-activated cells increased 24 h after the first 5-FU administration, and these responses were reduced by ramosetron. The up-regulation of TNF-α, IL-1ß and IL-6 following 5-FU treatment was also attenuated by ramosetron. CONCLUSIONS AND IMPLICATIONS: 5-HT3 receptor antagonists ameliorated 5-FU-induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5-HT3 receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5-FU chemotherapy.

ROS evaluation for a series of CNTs and their derivatives using an ESR method with DMPO.

Carbon nanotubes (CNTs) are important materials in advanced industries. It is a concern that pulmonary exposure to CNTs may induce carcinogenic responses. It has been recently reported that CNTs scavenge ROS though non-carbon fibers generate ROS. A comprehensive evaluation of ROS scavenging using various kinds of CNTs has not been demonstrated well. The present work specifically investigates ROS scavenging capabilities with a series of CNTs and their derivatives that were physically treated, and with the number of commercially available CNTs. CNT concentrations were controlled at 0.2 through 0.6 wt%. The ROS scavenging rate was measured by ESR with DMPO. Interestingly, the ROS scavenging rate was not only influenced by physical treatments, but was also dependent on individual manufacturing methods. Ratio of CNTs to DMPO/ hydrogen peroxide is a key parameter to obtain appropriate ROS quenching results for comparison of CNTs. The present results suggest that dangling bonds are not a sole factor for scavenging, and electron transfer on the CNT surface is not clearly determined to be the sole mechanism to explain ROS scavenging.

A case of primary squamous cell carcinoma of the endometrium associated with extensive "ichthyosis uteri".

BACKGROUND: Ichthyosis uteri is an uncommon entity in which the entire endometrium is replaced by stratified squamous epithelium. Though the condition often is considered as benign, dysplastic changes have been reported. CASE: We describe herein an exceedingly rare case of primary squamous cell carcinoma of the endometrium (PSCCE) associated with extensive ichthyosis uteri with chronic pyometra, who presented with blood-stained vaginal discharge of six-seven months duration. Although repeated endometrial biopsies revealed only strips of stratified squamous epithelium showing moderate to severe dysplastic changes, the tumor markers and magnetic resonance imaging strongly suggested advanced uterine body malignancy. Exploratory laparotomy was performed, and histologic findings of the superficial layer were consistent with ichthyosis uteri; in contrast the lesion of invasive squamous cell carcinoma was located in the deeper layer and lymph nodes. No dysplastic changes of the cervix were noted. CONCLUSIONS: It is suggested that PSCCE could be associated with pre-existing ichthyosis uteri and deeper biopsies should be performed for the accurate preoperative diagnosis of cases with chronic pyometra.

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors.

Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of ß-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.