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The CRISPR/Cas9 technique applied to modify the cattle genome has value in increasing animal health and welfare. Here, we established a simple, fast, and efficient cloning-free CRISPR/Cas9 protocol for large deletions of genomic loci in the frequently used model bovine MDBK cell line. The main advantages of our protocol are as follows: (i) pre-screening of the sgRNA efficiency with a fast and simple cleavage assay, (ii) reliable detection of genomic edits primarily by PCR and confirmed by DNA sequencing, and (iii) single cell sorting with FACS providing specific genetic information from modified cells of interest. Therefore, our method could be successfully applied in different studies, including functional validation of any genetic or regulatory elements. [ABSTRACT FROM AUTHOR]

Goat milk has been consumed by humans since ancient times and is highly nutritious. Its quality is mainly determined by its casein content. Milk protein synthesis is controlled by a complex network with many signal pathways. Therefore, the aim of our study is to clearly depict the signal pathways involved in milk protein synthesis in goat mammary epithelial cells (GMECs) using state-of-the-art microproteomic techniques and to identify the key genes involved in the signal pathway. The microproteomic analysis identified more than 2253 proteins, with 323 pathways annotated from the identified proteins. Knockdown of IRS1 expression significantly influenced goat casein composition (α, β, and κ); therefore, this study also examined the insulin receptor substrate 1 (IRS1) gene more closely. A total of 12 differential expression proteins (DEPs) were characterized as upregulated or downregulated in the IRS1-silenced sample compared to the negative control. The enrichment and signal pathways of these DEPs in GMECs were identified using GO annotation and KEGG, as well as KOG analysis. Our findings expand our understanding of the functional genes involved in milk protein synthesis in goats, paving the way for new approaches for modifying casein content for the dairy goat industry and milk product development. [ABSTRACT FROM AUTHOR]

Background: The HACOR score for predicting treatment failure includes vital signs and acid–base balance factors, whereas the ROX index only considers the respiratory rate, oxygen saturation, and fraction of inspired oxygen (FiO2). We aimed to externally validate the HACOR score and ROX index for predicting treatment failure in patients with coronavirus disease 2019 (COVID-19) on high-flow nasal cannula (HFNC) therapy in Japan. Methods: This retrospective, observational, multicenter study included patients, aged ≥ 18 years, diagnosed with COVID-19 and treated with HFNC therapy between January 16, 2020, and March 31, 2022. The HACOR score and ROX index were calculated at 2, 6, 12, 24, and 48 h after stating HFNC therapy. The primary outcome was treatment failure (requirement for intubation or occurrence of death within 7 days). We calculated the area under the receiver operating characteristic curve (AUROC) and assessed the diagnostic performance of these indicators. The 2-h time-point prediction was considered the primary analysis and that of other time-points as the secondary analysis. We also assessed 2-h time-point sensitivity and specificity using previously reported cutoff values (HACOR score > 5, ROX index < 2.85). Results: We analyzed 300 patients from 9 institutions (median age, 60 years; median SpO2/FiO2 ratio at the start of HFNC therapy, 121). Within 7 days of HFNC therapy, treatment failure occurred in 127 (42%) patients. The HACOR score and ROX index at the 2-h time-point exhibited AUROC discrimination values of 0.63 and 0.57 (P = 0.24), respectively. These values varied with temporal changes—0.58 and 0.62 at 6 h, 0.70 and 0.68 at 12 h, 0.68 and 0.69 at 24 h, and 0.75 and 0.75 at 48 h, respectively. The 2-h time-point sensitivity and specificity were 18% and 91% for the HACOR score, respectively, and 3% and 100% for the ROX index, respectively. Visual calibration assessment revealed well calibrated HACOR score, but not ROX index. Conclusions: In COVID-19 patients receiving HFNC therapy in Japan, the predictive performance of the HACOR score and ROX index at the 2-h time-point may be inadequate. Furthermore, clinicians should be mindful of time-point scores owing to the variation of the models' predictive performance with the time-point. Trial registration UMIN (registration number: UMIN000050024, January 13, 2023) [ABSTRACT FROM AUTHOR]

A coach's nonverbal communication (NC) plays a central role in the construction of the coach–athlete relationship. Moreover, perceived NC and its effect on communication ability and coaching evaluation may differ according to the athletes' demographics. This study explored the impact of perceived NC on coaching evaluation and overall communication among different genders and age groups. The study recruited 233 athletes from five high schools and seven university teams in Japan. The coaches' NC, communication ability, and coaching evaluations were assessed. Negative and positive NC directly influenced coaching evaluation in female athletes. Specifically, negative NC directly impacted coaching evaluation in high school athletes, whereas positive NC directly influenced coaching evaluation in university athletes. Positive NC consistently influenced communication ability regardless of demographics. The findings promote talent development and team management in the coaching context. [ABSTRACT FROM AUTHOR]

C. Carlet [Boolean functions for Cryptography and Coding theory, p. 381] mentions an observation of Dillon, that is, APN functions f on F 2 n with n greater than 2 must satisfy the condition { f (x) + f (y) + f (z) + f (x + y + z) ∣ x , y , z ∈ F 2 n } = F 2 n . We generalize this condition for functions f from F 2 n to F 2 m as { f (x) + f (y) + f (z) + f (x + y + z) ∣ x , y , z ∈ F 2 n } = F 2 m and call it the D-property. We characterize the D-property for APN functions from F 2 n to F 2 m using F 2 -linear surjections π from F 2 m to F 2 m 1 for m1 smaller than m, and investigate this condition with respect to nonlinearity and CCZ-equivalence. Then, we give several families of APN functions f from F 2 n to F 2 n + 1 with n greater than or equal to 5 that satisfy the D-property. [ABSTRACT FROM AUTHOR]

Oligonucleotide therapeutics, drugs consisting of 10–50 nucleotide‐long single‐ or double‐stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These oligonucleotide therapeutics could potentially become the third pillar of drug development. In particular, ASOs and siRNAs are advanced tools that are widely used to silence gene expression. They are used in clinical trials, as they have high specificity for target mRNAs and non‐coding RNAs and limited toxicity. However, their clinical application remains challenging. Although chemotherapy has benefits, it has severe adverse effects in many patients. Therefore, new modalities for targeted molecular therapy against tumors, including oligonucleotide therapeutics, are required, and they should be compatible with diagnosis using next‐generation sequencing. This review provides an overview of the therapeutic uses of ASOs, siRNAs, and miRNAs in clinical studies on malignant tumors. Understanding previous research and development will help in developing novel oligonucleotide therapeutics against malignant tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene containing a 15-base pair (bp) deletion at L485-P490 is the cause of several cancers. We generated siRNA to specifically knock down BRAF mRNA containing the 15-bp deletion. This siRNA suppressed the expression of BRAF, harboring the deletion without affecting wild-type BRAF expression in BxPC-3 pancreatic ductal adenocarcinoma cells in vitro and in vivo. Cell growth and phosphorylation of downstream extracellular-signal-regulated kinase proteins were also repressed. An off-target effect is the most common side effect of siRNA therapy. In this study, we reveal that siRNA with a 2′-O-methyl chemical modification in the seed region of the siRNA guide strand reduced seed-dependent off-target effects. Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second-most common cause of death within the next 10 years. Due to the limited efficacy of available therapies, the survival rate of PDAC patients is very low. Oncogenic BRAF mutations are one of the major causes of PDAC, specifically the missense V600E and L485–P490 15-bp deletion mutations. Drugs targeting the V600E mutation have already been approved by the United States Food and Drug Administration. However, a drug targeting the deletion mutation at L485–P490 of the BRAF gene has not been developed to date. The BxPC-3 cell line is a PDAC-derived cell line harboring wild-type KRAS and L485–P490 deleted BRAF genes. These cells are heterozygous for BRAF, harboring both wild-type BRAF and BRAF with the 15-bp deletion. In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2′-O-methyl modifications at positions 2–5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

PRDM9 is a histone methyltransferase able to trimethylate histone 3 at lysine-4 and lysine-36 residues. Since its discovery in 2005, there has been significant progress in the characterization of the structure and functions of PRDM9. The primary studies all pointed out at its role in meiosis and recombination; however, there are indications that it may be involved in other cellular processes as well. Such an additional role of PRDM9 in other types of cells and tissues apart the germ cells is still an open question. Small cohort of studies compared to the entire literature for PRDM9 hints for possible expression of this gene in other locations and having clinical significance in reproductive and cancer biology fields. In this review, we summarize the current knowledge about the meiotic and non-meiotic functions of PRDM9, effect of stress on the achievements and we list the remaining questions waiting to be answered. [ABSTRACT FROM AUTHOR]

From the beginning of the COVID-19 pandemic, the demand for diagnostic and screening tests has exceeded supply. Although the proportion of vaccinated people has increased in wealthier countries, breakthrough infections have occurred amid the emergence of new variants. Pooled-sample COVID-19 testing using saliva has been proposed as an efficient, inexpensive, and non-invasive method to allow larger-scale testing, especially in a screening setting. In this study, we aimed to evaluate pooled RT-qPCR saliva testing and to compare the results with individual tests. Employees of Philips Japan, Ltd. were recruited to participate in COVID-19 screening from October to December 2020. Asymptomatic individuals (n = 824) submitted self-collected saliva samples. Samples were tested for the presence of SARS-CoV-2 by RT-qPCR in both 10-sample pools and individual tests. We also surveyed participants regarding their thoughts and behaviors after the PCR screening project. Two of the 824 individuals were positive by RT-qPCR. In the pooled testing, one of these two had no measurable Ct value, but showed an amplification trend at the end of the PCR cycle. Both positive individuals developed cold-like symptoms, but neither required hospitalization. Of the 824 participants, 471 responded to our online questionnaire. Overall, while respondents agreed that PCR screening should be performed regularly, the majority were willing to undergo PCR testing only when it was provided for free or at low cost. In conclusion, pooled testing of saliva samples can support frequent large-scale screening that is rapid, efficient, and inexpensive. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 1A (HNF1A) is the master regulator of liver homeostasis and organogenesis and regulates many aspects of hepatocyte functions. It acts as a tumor suppressor in the liver, evidenced by the increased proliferation in HNF1A knockout (KO) hepatocytes. Hence, we postulated that any loss-of-function variation in the gene structure or composition (mutation) could trigger dysfunction, including disrupted transcriptional networks in liver cells. From the International Cancer Genome Consortium (ICGC) database of cancer genomes, we identified several HNF1A mutations located in the functional Pit-Oct-Unc (POU) domain. In our biochemical analysis, we found that the HNF1A POU-domain mutations Y122C, R229Q and V259F suppressed HNF4A promoter activity and disrupted the binding of HNF1A to its target HNF4A promoter without any effect on the nuclear localization. Our results suggest that the decreased transcriptional activity of HNF1A mutants is due to impaired DNA binding. Through structural simulation analysis, we found that a V259F mutation was likely to affect DNA interaction by inducing large conformational changes in the N-terminal region of HNF1A. The results suggest that POU-domain mutations of HNF1A downregulate HNF4A gene expression. Therefore, to mimic the HNF1A mutation phenotype in transcription networks, we performed siRNA-mediated knockdown (KD) of HNF4A. Through RNA-Seq data analysis for the HNF4A KD, we found 748 differentially expressed genes (DEGs), of which 311 genes were downregulated (e.g., HNF1A, ApoB and SOAT2) and 437 genes were upregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping revealed that the DEGs were involved in several signaling pathways (e.g., lipid and cholesterol metabolic pathways). Protein–protein network analysis suggested that the downregulated genes were related to lipid and cholesterol metabolism pathways, which are implicated in hepatocellular carcinoma (HCC) development. Our study demonstrates that mutations of HNF1A in the POU domain result in the downregulation of HNF1A target genes, including HNF4A, and this may trigger HCC development through the disruption of HNF4A–HNF1A transcriptional networks. [ABSTRACT FROM AUTHOR]

Introduction: There are limited reports on the natural history of hen's egg (HE) allergy (HEA) in children <6 years. We aimed to investigate the natural history of HEA in children aged 6–12 years and the factors affecting its tolerance acquisition. Methods: Using the database in our hospital, a total of 137 patients diagnosed with a definitive immediate-type reaction to HE when they turned 6 years were enrolled, and the natural course of HEA was prospectively examined until patients turned 12 years. Tolerance was defined as being able to pass an oral food challenge to consume a half or whole heated HE or consume heated HE freely without symptoms. Thirty patients (21.9%) who were enrolled for oral immunotherapy and 21 (15.3%) who discontinued follow-up were considered dropouts. Kaplan-Meier estimation was used to evaluate the rate of tolerance. Results: Fifty-five of the 137 patients (40.1%) had a previous HE anaphylaxis history; 61 (44.5%) patients had acquired tolerance to HE by age 12 years; and 25 (18.2%) continued total or partial HE elimination. The estimated acquired tolerance rates by ages 7, 9, and 12 years were 14.6%, 40.8%, and 60.5%, respectively. A previous history of HE anaphylaxis before 6 years of age, reacting to small amounts of heated HE by 6 years of age, and higher ovomucoid-specific immunoglobulin E values at the same age were associated with persistent HEA. Conclusion: This study provides important insights into the natural course of HEA beyond early childhood, with the acquisition of HE tolerance continuing throughout the duration of the study. [ABSTRACT FROM AUTHOR]

Liver cancer, specifically hepatocellular carcinoma (HCC), is a major global health concern due to its high prevalence in many countries. Risk factors for liver cancer include viral infections (hepatitis B and C), alcohol consumption, smoking, and non-alcoholic fatty liver disease. Aflatoxin exposure can also lead to liver cancer by inducing mutations in DNA. Genetic factors also play a role in HCC, and early detection and prevention are crucial. This Special Issue titled "Liver Cancer 2.0" presents eight papers that offer significant insights into liver cancer, focusing on HCC. The papers cover various topics such as potential therapeutic targets, genetic factors, diagnostic markers, diagnostic methods, natural compounds for treatment, and the role of chemokines and the tumor microenvironment. These findings contribute to a deeper understanding of liver-related diseases and offer valuable insights for researchers and clinicians in the field. [Extracted from the article]

PRDM14 is highly expressed in several cancers but is not detected in normal tissues. It confers cancer stem cell‐like properties, including chemoresistance and distant metastasis, to cancer cells. Herein, we aimed to develop a highly effective therapy against advanced stage cancer based on intravenously delivered PRDM14‐targeted siRNA. First, we examined PRDM14 expression and gene amplification in breast and pancreatic tumors and cell lines. PRDM14 was expressed in breast cancer, including the triple‐negative subtype, and pancreatic cancer. PRDM14 was amplified in 23.8% of patients with PRDM14+ breast cancer. Next, we investigated the inoculated tumor growth and distant metastasis following PRDM14 depletion by administering mice with PRDM14‐specific chimeric siRNA combined with a novel branched PEGylated poly‐L‐ornithine (PLO)‐based intravenous drug delivery system, designated PRDM14 unit polyion complex (uPIC) (n = 6/group). Inhibition of PRDM14 expression with PRDM14 uPIC by systemic intravenous injection effectively reduced tumor size and metastasis in vivo, thereby improving survival. Finally, pharmacokinetic/toxicokinetic analyses were performed on PRDM14 uPIC, which was intravenously administered to rats (n = 10‐15/group) and cynomolgus monkeys (n = 3‐5/group), twice weekly for 4 weeks. This revealed that PRDM14 uPIC was relatively nontoxic and the siRNA exposure in serum was greater than that predicted by the administered dose ratio when delivered as a uPIC. Taken together, our study indicated that PRDM14 uPIC is highly effective in suppressing malignant features of solid cancers and does not cause severe toxicity, making it a promising therapeutic agent for cancer treatment. What's new? The transcriptional regulator PRDM14 helps embryonic stem cells maintain pluripotency. Cancer cells that express it are more likely to have stem‐cell properties and metastasize. Here, the authors tested a small interfering RNA (siRNA) against PRDM14 as a therapy against advanced‐stage cancer. They used a novel delivery system that enhances accumulation of the siRNA in the tumors rather than the liver and the spleen. In animal models, they found that treatment of triple‐negative breast and pancreatic cancers with this agent reduced tumor size, prevented metastasis, and prolonged survival, and they observed no severe toxicity. [ABSTRACT FROM AUTHOR]

We recently reported that the terahertz (THz)-wave characteristics of pottery bodies varied significantly with firing temperature. This suggested the feasibility of conducting nondestructive inspection of the sinterability and manufacturing-process management of ceramics by THz-wave analysis. However, it is not clear why the THz-wave characteristics of ceramics change with firing temperature. In this study, we evaluated the THz-wave transmission properties of low-temperature-sintered porcelain bodies fired at various temperatures using THz time-domain spectroscopy and investigated the relationship between the crystal phase and microstructure. We found that the THz-wave transmittance increased with the dehydration of kaolinite and decreased with the formation of mullite and glass phases in the body. Also, as the firing temperature increased, the THz-wave transmittance of these bodies was affected by scattering due to the formation of pores. Additionally, the refractive index in the THz range showed a good correlation with the bulk density. We established that the firing-temperature dependence of the refractive index in the THz range was related to the crystal phase and microstructure. [ABSTRACT FROM AUTHOR]

We present a novel zinc oxide (ZnO) optically transparent electrode (OTE) prepared by the spin‐spray technique for spectroelectrochemistry. The spin‐spray technique can deposit ZnO film at a low cost, high rate deposition, and at a low temperature (<100 °C) in a single step. This new technique provides good optical transparency and electrical conductivity for ZnO. The electrochemical and spectroelectrochemical properties of the ZnO electrode were investigated for varying thicknesses of ZnO using methylene blue as a redox indicator. A ZnO OTE chip that includes three electrodes on a glass chip was developed for thin‐layer spectroelectrochemistry. Moreover, the ZnO films were successfully applied in an electrochemical‐localized surface plasmon resonance (LSPR) method for methylene blue detection by using them as a transparent conducting substrate for loading gold nanoparticles. [ABSTRACT FROM AUTHOR]

Purpose: Our previous studies demonstrated that mature adipocyte-derived dedifferentiated fat (DFAT) cells possess similar multipotency as mesenchymal stem cells. Here, we examined the immunoregulatory potential of DFAT cells in vitro and the therapeutic effect of DFAT cell transplantation in a mouse inflammatory bowel disease (IBD) model.Methods: The effect of DFAT cell co-culture on T cell proliferation and expression of immunosuppression-related genes in DFAT cells were evaluated. To create IBD, CD4+CD45RBhigh T cells were intraperitoneally injected into SCID mice. One week later, DFAT cells (1 × 105, DFAT group) or saline (Control group) were intraperitoneally injected. Subsequently bodyweight was measured every week and IBD clinical and histological scores were evaluated at 5 weeks after T cell administration.Results: The T cell proliferation was inhibited by co-cultured DFAT cells in a cell density-dependent manner. Gene expression of TRAIL, IDO1, and NOS2 in DFAT cells was upregulated by TNFα stimulation. DFAT group improved IBD-associated weight loss, IBD clinical and histological scores compared to Control group.Conclusion: DFAT cells possess immunoregulatory potential and the cell transplantation promoted recovery from colon damage and improved clinical symptoms in the IBD model. DFAT cells could play an important role in the treatment of IBD. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer mortality worldwide. Infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is the most predominant cause of HCC. Concerns arise for the presence of additional risk factors, as there is still a large proportion of patients without HBV or HCV infection. Previous studies have reported that higher intake of fruits and vegetables and reduced consumption of red/processed meat might play a protective role in HCC etiology, though the nationwide proof is limited. Hence, we studied multiple risk factors including food habit, lifestyle, and clinical implications of HCC patients in Bangladeshi. Demographic, clinical, and biochemical data, as well as data on food habits, were collected in this study. Our results indicated that a high intake of rice (AOR 4.28, 95% CI 1.48 to 14.07, p = 0.011), low intake of fruits (AOR = 4.41 95% CI 1.48–15.46; p = 0.012), leafy vegetables (AOR = 2.80, 95% CI 1.32–6.08; p = 0.008), and fish (AOR = 4.64 95% CI 2.18–10.23; p<0.001) increased the HCC risk. Moreover, a high intake of eggs (AOR = 2.07 95% CI 0.98–4.43; p = 0.058) also showed an increased risk. Roti, non-leafy vegetables, red meat, and tea were found to have no association with HCC risk. This study revealed that food habit patterns and lifestyle may have a profound effect on HCC development among Bangladeshi patients in addition to well established risk factors. [ABSTRACT FROM AUTHOR]

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia. [ABSTRACT FROM AUTHOR]

The corpus luteum (CL) is an important tissue of the female reproductive process which is established through ovulation of the mature follicle. Pulsatile release of prostaglandin F2α from the uterus leads to the regression of luteal cells and restarts the estrous cycle in most non-primate species. The rapid functional regression of the CL, which coincides with decrease of progesterone production, is followed by its structural regression. Although we now have a better understanding of how the CL is triggered to undergo programmed cell death, the precise mechanisms governing CL protein degradation in a very short period of luteolysis remains unknown. In this context, activation of ubiquitin-proteasome pathway (UPP), unfolded protein response (UPR) and autophagy are potential subcellular mechanisms involved. The ubiquitin-proteasome pathway (UPP) maintains tissue homeostasis in the face of both internal and external stressors. The UPP also controls physiological processes in many gonadal cells. Emerging evidence suggests that UPP dysfunction is involved in male and female reproductive tract dysfunction. Autophagy is activated when cells are exposed to different types of stressors such as hypoxia, starvation, and oxidative stress. While emerging evidence points to an important role for the UPP and autophagy in the CL, the key underlying transcriptional mechanisms have not been well-documented. In this review, we propose how CL regression may be governed by the ubiquitin-proteasome and autophagy pathways. We will further consider potential transcription factors which may regulate these events in the CL. [ABSTRACT FROM AUTHOR]

A construction of APN functions using the bent function B (x , y) = x y is proposed in Carlet (Des Codes Cryptogr 59:89–109, 2011). At this time, two families of APN functions using this construction are known, that is, the family of Carlet (2011) and the family of Zhou and Pott (Adv Math 234:43–60, 2013). In this note, we propose another family of APN functions with this construction, which are not CCZ equivalent to the former two families on F 2 8 . We also propose a family of presemifields and determined the middle, left, right nuclei and the center of the associated semifields. [ABSTRACT FROM AUTHOR]

Two patients with rheumatoid arthritis (RA) developed adult T-cell leukaemia/lymphoma (ATLL) in the course of RA treatment. We previously reported another case of ATLL that developed during RA treatment and summarised all three cases of ATLL. The mean age at onset of ATLL was 63.7 ± 9.6 years and treatment regimens included biological disease-modifying anti-rheumatic drugs (bDMARDs), such as abatacept (ABT) and tocilizumab, and conventional synthetic DMARDs (i.e. iguratimod (IGU) and methotrexate [MTX]) and/or glucocorticoids. Two patients were complicated with bronchiectasis and/or interstitial pneumonia and one patient developed ATLL after MTX-related lymphoproliferative disease. All three patients with ATLL were encountered for 5 years of clinical practice at our centre. The prevalence of ATLL that developed from 78 human T-cell leukaemia virus type 1 (HTLV)-1-seropositive RA patients was 3.85%. In conclusion, we described three cases of ATLL development during the treatment for RA. It is suggested that HTLV-1 seropositive RA patients should be managed and treated carefully. A nationwide survey is necessary to elucidate if the progression to ATLL after immunosuppressive treatment for RA occurs at higher in incidence than that in the natural course of an HTLV-1 infection. [ABSTRACT FROM AUTHOR]

In Discret Math 337:65-75, 2014, we construct a bilinear dual hyperoval called Sc(l,GF(2r)), or simply Sc, for rl≥4 and c∈GF(2r) with Tr(c)=1. In this note, we modify the bilinear mapping of Sc for l≥2 using multiplications of presemifields, and have a dual hyperoval Sc′ from this bilinear mapping. We also investigate on the isomorphism problems of these dual hyperovals under the conditions that c≠1 and the presemifields are not isotopic to commutative presemifields (see Theorem 2 for precise statement), and see that, under these conditions, Sc′ is not isomorphic to the dual hyperovals in Taniguchi (Discret Math 337:65-75, 2014). [ABSTRACT FROM AUTHOR]

Watchful waiting (WW) is among the treatment options indicated for patients with indolent adult T-cell leukemia-lymphoma (ATL). However, we previously showed that the long-term prognosis of patients with smoldering and chronic ATL is often worse than expected, with many undergoing transformation to aggressive ATL. To identify clinical features associated with transformation of smoldering/chronic ATL, we retrospectively analyzed the clinical features of 44 patients (14 smoldering and 30 chronic) who experienced transformation during WW. An elevated lactate dehydrogenase (LDH) value was most often observed (n = 30) at the time of transformation, especially in the chronic type (n = 24). Major organ involvement, lymphadenopathy, and hypercalcemia were shown to be associated with transformation in transformed patients without elevated LDH. The median overall survival time after transformation was only 7.8 months, and the prognosis was poor after transformation in those fulfilling the criteria of acute type, similar to that of de novo aggressive ATL. Laboratory data, such as LDH, and clinical signs including exacerbation of performance status, skin lesions, and lymphadenopathy should all be monitored during WW to ensure appropriate timing of chemotherapy initiation. Identification of optimal predictive markers for transformation and new therapeutic options is warranted to improve outcomes in indolent ATL. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia-lymphoma (ATL) is a distinct T-cell malignancy caused by human T-cell leukemia virus type-1; the prognosis is very poor. Mogamulizumab (Moga), an antibody drug for CC chemokine receptor type 4, has been introduced for the treatment of ATL. However, the prognosis of relapsed or refractory ATL remains poor and the characteristics of patients who derive clinical benefit from treatment with Moga remain poorly understood. We analyzed the associations of clinical factors with the outcome after Moga treatment. Forty-five patients treated with Moga monotherapy were evaluated. The median age of the patients was 69 years, and 40% were female. The median overall survival (OS) time was 17.6 months and the 2-year OS rate was 43.2%. Number of prior therapies and response to prior therapy were predictive clinical features in univariate analysis for OS. Performance status, corrected serum calcium level, serum lactate dehydrogenase level, Japan Clinical Oncology Group-prognostic index (PI), and simplified ATL-PI at Moga treatment were also associated with the prognosis after Moga monotherapy. Improved understanding of the clinical factors predicting the prognosis after Moga may contribute to improved treatment strategies for ATL. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer that is typically diagnosed at a later stage with metastases and is difficult to treat. Therefore, investigating the mechanism of PDAC initiation is important to aid early‐stage cancer detection. PRDM14 is a transcription factor that maintains pluripotency in embryonic stem cells and is overexpressed in several cancers. We previously reported that PRDM14 is overexpressed and regulates cancer stem‐like phenotypes in PDAC, and herein, we assess whether PRDM14 expression increases prior to tumorigenesis. Through immunohistochemistry analyses of clinical tissues, we detected PRDM14‐positive cells in precursor pancreatic intraepithelial neoplasia and chronic pancreatitis, which is a risk factor for PDAC, lesions. PRDM14 staining in chronic pancreatitis was as high as that in PDAC and cancer adjacent tissues. We induced pancreatitis in mouse models by cerulein injection, and observed that PRDM14 expression increased in chronic pancreatitis models but not in control or acute pancreatitis mice. Moreover, cerulein treatment increased PRDM14 expression in PK‐1 and AsPC‐1 pancreatic cancer cell lines. Our results suggest that inflammation increases the expression of PRDM14, which regulates cancer stem‐like phenotypes, and this occurs prior to PDAC initiation and progression. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia-lymphoma (ATL) is an intractable hematopoietic malignancy with a very poor prognosis. Although improved responses have been achieved through intensive chemotherapy in newly diagnosed patients with aggressive ATL, most patients suffer from relapse or disease recurrence, and an effective salvage therapy, especially for candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT), is yet to be established. The efficacy of the EPOCH regimen has been reported for several lymphoid malignancies; however, its efficacy for ATL has not been sufficiently evaluated. Here, we report results of a study of the EPOCH regimen as a salvage therapy for ATL. We retrospectively analyzed patients with relapsed or refractory ATL treated in our institution, with EPOCH as a first salvage therapy. Fourteen patients with a median age of 58 years were analyzed, among whom eight achieved a response, including a complete response in one patient and partial responses in seven. Seven patients underwent allo-HSCT after EPOCH therapy; however, the median overall survival (OS) could not be determined, whereas OS at 2 years after allo-HSCT was estimated to be 85.7%. These results suggest that EPOCH is an option for salvage therapy in patients with ATL, including candidates for allo-HSCT. [ABSTRACT FROM AUTHOR]

The world population is expected to increase from 7.3 to 9.7 billion by 2050. Pest outbreak and increased abiotic stresses due to climate change pose a high risk to tropical crop production. Although conventional breeding techniques have significantly increased crop production and yield, new approaches are required to further improve crop production in order to meet the global growing demand for food. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 (CRISPR-associated protein9) genome editing technology has shown great promise for quickly addressing emerging challenges in agriculture. It can be used to precisely modify genome sequence of any organism including plants to achieve the desired trait. Compared to other genome editing tools such as zinc finger nucleases (ZFNs) and transcriptional activator-like effector nucleases (TALENs), CRISPR/Cas9 is faster, cheaper, precise and highly efficient in editing genomes even at the multiplex level. Application of CRISPR/Cas9 technology in editing the plant genome is emerging rapidly. The CRISPR/Cas9 is becoming a user-friendly tool for development of non-transgenic genome edited crop plants to counteract harmful effects from climate change and ensure future food security of increasing population in tropical countries. This review updates current knowledge and potentials of CRISPR/Cas9 for improvement of crops cultivated in tropical climates to gain resiliency against emerging pests and abiotic stresses. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to examine the influence of single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-δ (PPAR-γ), PPAR- , and α2 isoforms of the catalytic subunit of AMP-activated protein kinase (PRKAA2) on the extent of changes in anthropometric indices and blood measurements through exercise-centered lifestyle intervention in middle-aged men. A total of 109 Japanese middle-aged male subjects (47.0 ± 0.4 years) participated in the baseline health checkup, 6-month exercise-centered lifestyle intervention, and second checkup conducted several months after the subject completed the intervention. The body mass index (BMI), waist circumference, and clinical measurements, including hemoglobin Alc (HbA1c), triglyceride (TG), alanine aminotransferase (ALT), and γ-glutamyl-transpeptidase ( γ-GTP), were measured at the baseline and second checkup. The three SNPs of PPAR-δ A/G (rs2267668), PPAR-γ C/G (rs1801282), and PRKAA2 A/G (rs1418442) were determined. Blunted responses in the reduction in the BMI and waist circumference were observed in A/A carriers of PPAR-δ SNP compared with G allele carriers (all p < 0.05). The A/A carriers also displayed less-marked improvements in HbA1c, TG, ALT, and γ-GTP (all p < 0.05). The current results suggest that A/A carriers of PPAR-δ SNP (rs2267668) may enjoy fewer beneficial effects of exercise-centered lifestyle intervention on anthropometric indices and blood measurements. [ABSTRACT FROM AUTHOR]

PRDM14 is overexpressed in various cancers and can regulate cancer phenotype under certain conditions. Inhibiting PRDM14 expression in breast and pancreatic cancers has been reported to reduce cancer stem‐like phenotypes, which are associated with aggressive tumor properties. Therefore, PRDM14 is considered a promising target for cancer therapy. To develop a pharmaceutical treatment, the mechanism and interacting partners of PRDM14 need to be clarified. Here, we identified the proteins interacting with PRDM14 in triple‐negative breast cancer (TNBC) cells, which do not express the three most common types of receptor (estrogen receptors, progesterone receptors, and HER2). We obtained 13 candidates that were pulled down with PRDM14 in TNBC HCC1937 cells and identified them by mass spectrometry. Two candidates—glucose‐regulated protein 78 (GRP78) and heat shock protein 90‐α (HSP90α)—were confirmed in immunoprecipitation assay in two TNBC cell lines (HCC1937 and MDA‐MB231). Surface plasmon resonance analysis using GST‐PRDM14 showed that these two proteins directly interacted with PRDM14 and that the interactions required the C‐terminal region of PRDM14, which includes zinc finger motifs. We also confirmed the interactions in living cells by NanoLuc luciferase‐based bioluminescence resonance energy transfer (NanoBRET) assay. Moreover, HSP90 inhibitors (17DMAG and HSP990) significantly decreased breast cancer stem‐like CD24− CD44+ and side population (SP) cells in HCC1937 cells, but not in PRDM14 knockdown HCC1937 cells. The combination of the GRP78 inhibitor HA15 and PRDM14 knockdown significantly decreased cell proliferation and SP cell number in HCC1937 cells. These results suggest that HSP90α and GRP78 interact with PRDM14 and participate in cancer regulation. [ABSTRACT FROM AUTHOR]

Cancer stem cells ( CSCs) are thought to be responsible for tumor initiation, drug and radiation resistance, invasive growth, metastasis, and tumor relapse, which are the main causes of cancer-related deaths. Gastrointestinal cancers are the most common malignancies and still the most frequent cause of cancer-related mortality worldwide. Because gastrointestinal CSCs are also thought to be resistant to conventional therapies, an effective and novel cancer treatment is imperative. The first reported CSCs in a gastrointestinal tumor were found in colorectal cancer in 2007. Subsequently, CSCs were reported in other gastrointestinal cancers, such as esophagus, stomach, liver, and pancreas. Specific phenotypes could be used to distinguish CSCs from non- CSCs. For example, gastrointestinal CSCs express unique surface markers, exist in a side-population fraction, show high aldehyde dehydrogenase-1 activity, form tumorspheres when cultured in non-adherent conditions, and demonstrate high tumorigenic potential in immunocompromised mice. The signal transduction pathways in gastrointestinal CSCs are similar to those involved in normal embryonic development. Moreover, CSCs are modified by the aberrant expression of several micro RNAs. Thus, it is very difficult to target gastrointestinal CSCs. This review focuses on the current research on gastrointestinal CSCs and future strategies to abolish the gastrointestinal CSC phenotype. [ABSTRACT FROM AUTHOR]

Background: Composition of atherosclerotic arterial walls is rich in lipids such as cholesterol, unlike normal arterial walls. In this study, we aimed to utilize this difference to diagnose atherosclerosis via multispectral fluorescence imaging, which allows for identification of fluorescence originating from the substance in the arterial wall. Methods: The inner surface of extracted arteries (rabbit abdominal aorta, human coronary artery) was illuminated by 405 nm excitation light and multispectral fluorescence images were obtained. Pathological examination of human coronary artery samples were carried out and thickness of arteries were calculated by measuring combined media and intima thickness. Results: The fluorescence spectra in atherosclerotic sites were different from those in normal sites. Multiple regions of interest (ROI) were selected within each sample and a ratio between two fluorescence intensity differences (where each intensity difference is calculated between an identifier wavelength and a base wavelength) from each ROI was determined, allowing for discrimination of atherosclerotic sites. Fluorescence intensity and thickness of artery were found to be significantly correlated. Conclusions: These results indicate that multispectral fluorescence imaging provides qualitative and quantitative evaluations of atherosclerosis and is therefore a viable method of diagnosing the disease. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia/lymphoma ( ATL) is an aggressive T-cell malignancy caused by human T-cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti-chemokine (C-C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI-8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T-cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI-8000 on ATL-derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI-8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 ( NLRP3) inflammasome pathway in HBI-8000-induced ATL cell death. Further investigations using si RNAs confirmed that Bim contributes to HBI-8000-induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI-8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI-8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway. [ABSTRACT FROM AUTHOR]

Adult T cell leukaemia/lymphoma ( ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense ( NS) and frameshift ( FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type ( WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Oncogenic transformation is characterized by morphological changes resulting from alterations in actin dynamics and adhesive activities. Emerging evidence suggests that the protocadherin FAT4 acts as a tumor suppressor in humans, and reduced FAT4 gene expression has been reported in breast and lung cancers and melanoma. However, the mechanism controlling FAT4 gene expression is poorly understood. In this study, we show that transient activation of the Src oncoprotein represses FAT4 mRNA expression through actin depolymerization in the immortalized normal human mammary epithelial cell line MCF-10A. Src activation causes actin depolymerization via the MEK/Erk/Cofilin cascade. The MEK inhibitor U0126 blocks the inhibitory effect of Src on FAT4 mRNA expression and Src-induced actin depolymerization. To determine whether actin dynamics act on the regulation of FAT4 mRNA expression, we treated MCF-10A cells with the ROCK inhibitor Y-27632. Y-27632 treatment decreased FAT4 mRNA expression. This suppressive effect was blocked by siRNA-mediated knockdown of Cofilin1. Furthermore, simultaneous administration of Latrunculin A (an actin depolymerizing agent), Y-27632, and Cofilin1 siRNA to the cells resulted in a marked reduction of FAT4 mRNA expression. Intriguingly, we also found that FAT4 mRNA expression was reduced under both low cell density and low stiffness conditions, which suggests that mechanotransduction affects FAT4 mRNA expression. Additionally, we show that siRNA-mediated FAT4 knockdown induced the activity of the Hippo effector YAP/TAZ in MCF-10A cells. Taken together, our results reveal a novel inhibitory mechanism of FAT4 gene expression through actin depolymerization during Src-induced carcinogenesis in human breast cells. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia-lymphoma ( ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 ( HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP- AUY922 ( AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus ( PIM) in ATL cells. The PIM family ( PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan- PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1 %, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6 %, respectively. Eleven of 34 patients (32 %) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7 %, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 37-year-old man with systemic lymphadenopathy, circulating abnormal lymphocytes, and an elevated serum lactate dehydrogenase level (411 IU/l) and diagnosed with acute T-cell leukemia/lymphoma in donor cells (ATL). The patient underwent second allogeneic hematopoietic stem cell transplantation (HSCT) using unrelated cord blood. Results suggest the potential of a second allo-HSCT for ATL-DC.

Disruptions in chromatin regulator genes are frequently the cause of neurodevelopmental and neuropsychiatric disorders. Chromatin regulators are widely expressed in the brain, yet symptoms suggest that specific circuits can be preferentially altered when they are mutated. Using Drosophila allows targeted manipulation of chromatin regulators in defined neuronal classes, lineages, or circuits, revealing their roles in neuronal precursor self-renewal, dendrite and axon targeting, neuron diversification, and the tuning of developmental signaling pathways. Phenotypes arising from chromatin regulator disruption are context dependent - defined by interaction networks between the regulators, transcription factors, and chromatin remodeling complex partners. Future challenges are to determine the complexity of partner interactions, and to ascertain the degree to which cognitive deficits are due to loss of chromatin regulator activity in building a circuit or in maintaining homeostasis and activity within it. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development, and this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of the human cancers with the worst prognosis and has two main histologies: squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously, we have reported that detection of the IGF axis may be useful for the prediction of recurrence and poor prognosis of ESCC. We have also shown the successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative IGF-IR (ad-IGF-IR/dn). The aim of this study is to develop potential targeted therapeutics to IGF-IR and to assess the effect of IGF-IR blockade in both of these types of esophageal cancer. We determined immunohistochemical expression of IGF-IR in a tissue microarray. We then assessed the effect of IGF-IR blockade on signal transduction, proliferation, apoptosis, and motility. Ad-IGF-IR/dn, a tyrosine kinase inhibitor, BMS-536924, and adenovirus expressing shRNA for IGF-IR were used. IGF-IR expression was common in both tumor types but not in normal tissues. IGF-IR was detected in metastatic sites at similar levels compared to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both cancers. IGF-IR blockades up-regulated both stress- and chemotherapy-induced apoptosis and reduced migration. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. The IGF axis might play a key role in tumor progression of esophageal carcinomas. The IGF-IR targeting strategies might thus be useful anticancer therapeutics for human esophageal malignancies. [ABSTRACT FROM AUTHOR]

The accumulation of mutations in cancer driver genes, such as tumor suppressors or proto-oncogenes, affects cellular homeostasis. Disturbances in the mechanism controlling proliferation cause significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indicated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (virus-associated hepatocellular carcinoma) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function in liver cancer has never been investigated. Here, using functional analysis and next generation sequencing, we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, and SERPIND1, which are possibly regulated by the BRAF V600E-mediated, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrate that BRAF L537M, D594A, and E648G mutations alone are not pathogenic in liver cancer. The investigation of genome mutations and the determination of their impact on cellular processes and functions is crucial to unraveling the molecular mechanisms of liver cancer development. [ABSTRACT FROM AUTHOR]

To better understand indeterminate HTLV-1 carriers and smoldering (SM) subtype of adult T-cell leukemia (ATL), HTLV-1 proviral integrated status, proviral load (PVL) and ATL-related biomarkers were examined in 57 smoldering cases, including unusual carriers with a percentage of ATL-like cells. We found that according to Southern blot hybridization analytic features, 28 patients with SM ATL could be divided into 3 groups consisting of 16 (57.4%) patients with a monoclonal band, 6 (21.4%) with oligoclonal bands and the remaining 6 with smears. Although no clinical differences were observed among the 3 SM subtypes, HTLV-1-infected CD4 T-cell counts increased in order of poly-, oligo- and monoclonal subtypes. This trend began in the carrier stage and also was observed in PVL, CD25 and CCR4, indicating that a clone consisting of leukemic phenotypic cells was continuously growing. Moreover, the antigen modulation rates of CD26 and CD7 and the increasing rate of CD25 and CCR4 cells were closely correlated to growing clonal size, indicating that these markers had the possibility to predict a monoclonal band. In particular, CD26 or the ratio of CD26/CD25 had a validity differential for leukemic nature and predictive detection of clonal band. Conclusively, the present study shows that smoldering ATL is heterogeneous in the leukemogenic process, and the behavior of CD26 plays a central role in the evolution from early occult to overt smoldering ATL. [ABSTRACT FROM AUTHOR]

Neuronal-class diversification is central during neurogenesis. This requirement is exemplified in the olfactory system, which utilizes a large array of olfactory receptor neuron (ORN) classes. We discovered an epigenetic mechanism in which neuron diversity is maximized via locus-specific chromatin modifications that generate context-dependent responses from a single, generally used intracellular signal. Each ORN in Drosophila acquires one of three basic identities defined by the compound outcome of three iterated Notch signaling events during neurogenesis. Hamlet, the Drosophila Evi1 and Prdm16 proto-oncogene homolog, modifies cellular responses to these iteratively used Notch signals in a context-dependent manner, and controls odorant receptor gene choice and ORN axon targeting specificity. In nascent ORNs, Hamlet erases the Notch state inherited from the parental cell, enabling a modified response in a subsequent round of Notch signaling. Hamlet directs locus-specific modifications of histone methylation and histone density and controls accessibility of the DNA-binding protein Suppressor of Hairless at the Notch target promoter. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility. ( Cancer Sci 2012; 103: 252-261) [ABSTRACT FROM AUTHOR]

Aims: Patients with prior major cardiovascular or cerebrovascular events (MACE) are more likely to have future recurrent events independent of traditional cardiovascular disease risk factors. The purpose of this study was to determine if patients with traditional risk factors and prior MACE had increased cardiovascular magnetic resonance (CMR) plaque burden measures compared to patients with risk factors but no prior events. Methods and Results: Black blood carotid and thoracic aorta images were obtained from 195 patients using a rapid extended coverage turbo spin echo sequence. CMR measures of plaque burden were obtained by tracing lumen and outer vessel wall contours. Patients with prior MACE had significantly higher MR plaque burden (wall thickness, wall area and normalized wall index) in carotids and thoracic aorta compared to those without prior MACE (Wall thickness carotids: 1.03 ± 0.03 vs. 0.93± 0.03, p = 0.001; SD wall thickness carotids: 0.137 ± 0.0008 vs. 0.102 ± 0.0004, p < 0.001; wall thickness aorta: 1.63 ± 0.10 vs. 1.50 ± 0.04, p = 0.009; SD wall thickness aorta: 0.186 ± 0.035 vs. 0.139 ± 0.012, p = 0.009 respectively). Plaque burden (wall thickness) and plaque eccentricity (standard deviation of wall thickness) of carotid arteries were associated with prior MACE after adjustment for age, sex, and traditional risk factors. Area under ROC curve (AUC) for discriminating prior MACE improved by adding plaque eccentricity to models incorporating age, sex, and traditional CVD risk factors as model inputs (AUC = 0.79, p = 0.05). Conclusion: A greater plaque burden and plaque eccentricity is prevalent among patients with prior MACE. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer is one of the deadliest human cancers. High-throughput analysis of cancer cell genomes has established that hotspot mutations in HNF4α and HNF1α occur in a variety of human cancers, including liver cancer. Here, we review recent findings pertaining to role of HNF1α and HNF4α in liver cancer, and their possible targeting for liver cancer treatment. The hepatocyte nuclear factor-4α (HNF4α) and hepatocyte nuclear factor-1α (HNF1α) are transcription factors that influence the development and maintenance of homeostasis in a variety of tissues, including the liver. As such, disruptions in their transcriptional networks can herald a number of pathologies, such as tumorigenesis. Largely considered tumor suppressants in liver cancer, these transcription factors regulate key events of inflammation, epithelial–mesenchymal transition, metabolic reprogramming, and the differentiation status of the cell. High-throughput analysis of cancer cell genomes has identified a number of hotspot mutations in HNF1α and HNF4α in liver cancer. Such results also showcase HNF1α and HNF4α as important therapeutic targets helping us step into the era of personalized medicine. In this review, we update current findings on the roles of HNF1α and HNF4α in liver cancer development and progression. It covers the molecular mechanisms of HNF1α and HNF4α dysregulation and also highlights the potential of HNF4α as a therapeutic target in liver cancer. [ABSTRACT FROM AUTHOR]