Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome.

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Relationship between the number of lymph nodes dissected and prognosis in muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy.

OBJECTIVES: Many studies have shown a good prognostic association with a large number of lymph node dissections. However, most of these studies did not include patients who have received neoadjuvant chemotherapy. The purpose of this study was to verify the relationship between survival outcomes and the number of lymph nodes removed during radical cystectomy in patients with muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy. METHODS: This retrospective study considered patients who were diagnosed with clinical ≥T2N0M0 muscle-invasive bladder cancer and treated with radical cystectomy at the Nagoya University Hospital and affiliated hospitals from January 2004 to December 2019. We excluded patients who had a history of upper tract urothelial cancer or non-urothelial carcinoma. The association between prognosis and the number of lymph nodes removed was investigated. RESULTS: We retrospectively enrolled a total of 477 patients. The mean number of lymph nodes dissected was 14. Two hundred and twenty-six patients (47.4%) received neoadjuvant chemotherapy. More extensive lymphadenectomy (≥15 lymph nodes) correlated with better 5-year overall survival across all patients (68% vs. 57%, p = 0.01). In patients who received neoadjuvant chemotherapy, there was no difference in overall survival according to the number of dissected lymph nodes (66% vs. 71%, p = 0.433). In patients who did not receive neoadjuvant chemotherapy, ≥15 lymph nodes dissected was associated with significantly better overall survival (70.3% vs. 46.9%, p < 0.01). CONCLUSIONS: No association between more aggressive lymph node dissection and prognosis was found in patients who underwent neoadjuvant chemotherapy. Conversely, extended lymph node dissection is desirable for patients who have not received neoadjuvant chemotherapy.

Development of potent antipseudomonal ß-lactams by means of polycarboxylation of aminopenicillins.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that presents a serious risk to immunosuppressed individuals and other extremely vulnerable patients such as those in intensive care units. The emergence of multidrug-resistant Pseudomonas strains has increased the need for new antipseudomonal agents. In this study, a series of amino group-modified aminopenicillin derivatives was synthesized that have different numbers of carboxyl groups and structurally resemble carboxypenicillin-ureidopenicillin hybrids, and their antipseudomonal activities were evaluated. Among the derivatives synthesized, diethylenetriaminepentaacetic acid (DTPA)-modified amoxicillin (DTPA-Amox) showed potent antipseudomonal activity, not only against the laboratory strain PAO1 but also against clinically isolated Pseudomonas strains that were resistant to piperacillin and carbenicillin. DTPA-Amox had no obvious cytotoxic effects on cultured mammalian cells. In addition, in an in vivo model of leukopenia, DTPA-Amox treatment produced a moderate but statistically significant improvement in the survival of mice with P. aeruginosa strain PAO1 infection. These data suggest that polycarboxylation by DTPA conjugation is an effective approach to enhance antipseudomonal activity of aminopenicillins.

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.

Mesh exposure after transvaginal mesh prolapse surgery: Out of permissible range?

OBJECTIVES: To investigate the prevalence of postoperative complications after transvaginal mesh prolapse surgery, and whether modified transvaginal mesh prolapse surgery (without transobturator arms or posterior mesh) has less prevalence of mesh exposure compared with conventional transvaginal mesh prolapse surgery. METHODS: Medical charts were retrospectively examined for 2648 patients who underwent transvaginal mesh prolapse surgery in a general hospital (2006-2017). Conventional transvaginal mesh prolapse surgery (Prolift-type, n = 2258) was used, with a shift from 2015 to modified transvaginal mesh prolapse surgery (Uphold-type, n = 330). Patients were instructed to have >2 years of follow up and to report if they had problems regarding the operation. RESULTS: The prevalence of mesh exposure was 34 out of 2648 (1.28%); 18 vagina (0.68%), 10 bladder (0.38%), two ureter (0.08%) and four rectum (0.15%). The modified transvaginal mesh prolapse surgery group had only one case with vaginal exposure. Vaginal exposure was managed transvaginally or followed by observation. Rectal exposure was managed transvaginally without colostomy. Bladder exposure was managed by transurethral resection with saline. Open ureterocystostomy was carried out to treat ureteral exposure. In the conventional transvaginal mesh prolapse surgery group, three cases of ureteral stenosis and one case with vaginal evisceration of the small intestine were managed transvaginally. The prevalence of postoperative chronic pain was 13 out of 2648 (0.49%; with one patient in the modified transvaginal mesh prolapse surgery group). The patients underwent pharmacotherapy, and one patient underwent additional surgical treatment. CONCLUSIONS: The reoperation rate as a result of complications after transvaginal mesh prolapse surgery seems to be low. The reoperation rate as a result of prolapse recurrence is also low. A shift from conventional transvaginal mesh prolapse surgery to modified transvaginal mesh prolapse surgery might contribute to a further decrease in the risk of complications.

[Molecular mechanisms of myeloid malignancies].

Almost all genetic abnormalities involved in the occurrence and progression of myelodysplastic syndromes (MDS) and acute myeloid leukemia have been reported within the last decade. The molecular mechanisms of these genetic changes involved in causing dysfunctions in hematopoietic cells have also been clarified in recent years. For MDS, gene mutations of RNA splicing factors and cohesin complex have been shown to trigger not only aberrant RNA splicing or decreased chromatin insulation but also DNA damage response and transcriptional dysregulation through inefficient interaction between promoters and enhancers. Consequently, these newly identified disease-causing mechanisms may be considered potential therapeutic targets.

Long-term prognoses of patients with and without re-rupture after arthroscopic rotator cuff repair.

[Purpose] We followed-up patients who underwent arthroscopic rotator cuff repair (ARCR) for 2 years to assess the prognosis of rotator cuff tears and compared the outcomes of the patients with and without re-rupture. We also examined the usefulness of Shoulder36, a self-assessment tool, for assessing the long-term prognosis in patients undergoing ARCR. [Participants and Methods] We included 28 patients who received occupational therapy pre- and post-ARCR between April 2012 and August 2015 and categorized them based on the occurrence of re-rupture. We followed-up on their prognoses for 2 years using physical examination and Shoulder36 assessment. [Results] Re-rupture occurred in five patients within 3 months of treatment. During the 2 year follow-up, the control group showed a significant improvement in pain and bi-directional active range of motion during physical assessment and in five out of six domains during Shoulder36 assessment. In contrast, the re-rupture group showed significant differences for only three domains of the Shoulder36 assessment twelve months after surgery. [Conclusion] We confirmed the long-term functional improvement and maintenance in the re-rupture group, suggesting that continued rehabilitation, compensatory movements, and detailed guidance on daily life activities are required for patients after ARCR. Furthermore, Shoulder36 can be useful for assessing the prognosis of patients with and without re-rupture.

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.

The enigma of monosomy 7.

Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. SAMD9 (sterile α motif domain 9) and SAMD9L (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in SAMD9L-deficient mice over their lifetime, SAMD9/SAMD9L are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. EZH2 (enhancer of zeste homolog 2) and MLL3 (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to SAMD9/SAMD9L, loss of EZH2 or MLL3 likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of TET2 or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).

Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome.

BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (Bcor ΔE4/y ) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (Bcor ΔE9-10/y ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. Bcor ΔE9-10/y mice developed lethal T-ALL in a similar manner to Bcor ΔE4/y mice, whereas Bcor ΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2 Tet2 Δ/Δ Bcor ΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2 Δ/Δ Bcor ΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in Bcor ΔE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.

A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1.

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation.

During prometaphase, dense microtubule nucleation sites at centrosomes form robust spindles that align chromosomes promptly. Failure of centrosome maturation leaves chromosomes scattered, as seen routinely in cancer cells, including myelodysplastic syndrome (MDS). We previously reported that the Miki (LOC253012) gene is frequently deleted in MDS patients, and that low levels of Miki are associated with abnormal mitosis. Here we demonstrate that Miki localizes to the Golgi apparatus and is poly(ADP-ribosyl)ated by tankyrase-1 during late G2 and prophase. PARsylated Miki then translocates to mitotic centrosomes and anchors CG-NAP, a large scaffold protein of the γ-tubulin ring complex. Due to impairment of microtubule aster formation, cells in which tankyrase-1, Miki, or CG-NAP expression is downregulated all show prometaphase disturbances, including scattered and lagging chromosomes. Our data suggest that PARsylation of Miki by tankyrase-1 is a key initial event promoting prometaphase.

Razor-type dermatomes enable quick and thin vaginal dissection with less bleeding in colpocleisis.

INTRODUCTION AND HYPOTHESIS: Although colpocleisis is a low-invasive surgical option to treat pelvic organ prolapse, it sometimes involves a long operative time with substantial bleeding. To streamline the vaginal dissection process in colpoclesis, we introduced the usage of dermatomes. METHODS: All patients were sexually inactive women with post-hysterectomy prolapse. Data of the dermatome group were retrospectively compared with those of the historical control group based on operative features, perioperative complications and pathology of dissected tissue. In the dermatome group, 34 women underwent total colpocleisis with vaginal dissection using dermatomes; 4 were done mainly with electric dermatomes, and 30 were done with razor-type dermatomes. In the control group, 20 women underwent total colpocleisis with vaginal dissection using Metzenbaum scissors. RESULTS: Using dermatomes in vaginal dissection was helpful to shorten total operative time (including perineoplasty) by one third from 76 to 51 min, to shorten the time of colpocleisis by half, from 62 to 32 min, and to reduce intraoperative bleeding by 76%, from 62 to 15 ml. In addition, none in the dermatome group and 2/20 patients in the control group had unintended peritoneal opening. Dissection with scissors removed not only the epithelium and submucosal layer but also the muscle layer. This was minimized with razor-type dermatomes and never occurred with electric dermatomes. Whereas electric dermatomes are difficult to get accustomed to and are expensive, razor-type dermatomes enable thinner dissection compared with scissors, are easy to handle and are inexpensive. CONCLUSIONS: Razor-type dermatomes enable quick and thin vaginal dissection with less bleeding. Therefore, they can be recommended as a practical tool for colpocleisis, a prolapse operation mainly for frail elderly patients.

Usefulness of relative apical longitudinal strain index to predict positive 99m Tc-labeled pyrophosphate scintigraphy findings in advanced-age patients with suspected transthyretin amyloid cardiomyopathy.

BACKGROUND: We previously reported that a high score (2 or 3 points) according to the Kumamoto criteria, a combination of high-sensitivity cardiac troponin T (hs-cTnT) ≥0.308 ng/mL, the length of QRS ≥ 120 ms in electrocardiogram, and left ventricular (LV) posterior wall thickness ≥ 13.6 mm, increases the pretest probability of 99m Tc-labeled pyrophosphate (99m Tc-PYP) scintigraphy in patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM). However, some patients with a low score (0 or 1 point) show positive findings on 99m Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of 99m Tc-PYP scintigraphy for these patients. METHODS AND RESULTS: We examined 109 consecutive patients aged ≥70 years with low scores according to the Kumamoto criteria who underwent 99m Tc-PYP scintigraphy. Nineteen patients (17%) had positive 99m Tc-PYP scintigraphy findings. The relative apical longitudinal strain (LS) index (apical LS/ basal LS + mid LS) (RapLSI) was significantly higher in patients with positive than negative 99m Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P < .01). Multivariable logistic regression analysis revealed that a high RapLSI (≥1.04) was significantly associated with 99m Tc-PYP positivity (odds ratio, 14.14; 95% confidence interval, 3.36-59.47; P < .01). The sensitivity, specificity, and accuracy of the diagnostic model using the RapLSI for identification of 99m Tc-PYP positivity were 53%, 94%, and 87%, respectively. CONCLUSIONS: A high RapLSI can raise the pretest probability of 99m Tc-PYP scintigraphy in patients with a low score according to the Kumamoto criteria. The RapLSI can assist clinicians in determining strategies for these patients.

Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor-ß (TGF-ß) signalling by inducing stabilization of TGF-ß receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-ß stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF-ß signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hemolysis causes a decrease in HbA1c level but not in glycated albumin or 1,5-anhydroglucitol level.

HbA1c has been widely used as a glycemic control indicator or as a diagnostic indicator for diabetes mellitus. However, HbA1c is affected by the erythrocyte life span and, therefore, shows falsely low values in hemolytic patients. Erythrocyte creatine (EC) is a sensitive hemolytic marker that reflects the mean erythrocyte age. In the present study, the relationships of HbA1c, glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with different hemolytic markers, including EC, were investigated in non-diabetic individuals. A total of 43 non-diabetic individuals whose complete blood count and reticulocytes were measured via medical examinations were included in this study (28 individuals with hemolysis and 15 individuals without hemolysis). Those with suspected diabetes mellitus based on medical history, low 1,5-AG values, or had comorbid liver and renal diseases were excluded from this study. HbA1c, GA, 1,5-AG, and various hemolytic markers were measured to examine the correlation of the glycemic control indicators with the various hemolytic markers. A significant correlation was observed between GA and 1,5-AG but not between HbA1c and GA or 1,5-AG. Significant correlations were observed between HbA1c values and various hemolytic markers (reticulocytes, haptoglobin, and EC) but not between GA or 1,5-AG values and those hemolytic markers. HbA1c, but not with GA and 1,5-AG, showed significant correlations with the hemolytic markers. These results suggested that HbA1c does not reflect the glycemic control accurately in hemolytic patients, while GA and 1,5-AG values are not affected by mean erythrocyte age and, therefore, accurately reflect the glycemic control.

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression.

Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, our work provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies.

Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes.

Setdb1, also known as Eset, is a methyltransferase that catalyzes trimethylation of H3K9 (H3K9me3) and plays an essential role in the silencing of endogenous retroviral elements (ERVs) in the developing embryo and embryonic stem cells (ESCs). Its role in somatic stem cells, however, remains unclear because of the early death of Setdb1-deficient embryos. We demonstrate here that Setdb1 is the first H3K9 methyltransferase shown to be essential for the maintenance of hematopoietic stem and progenitor cells (HSPCs) in mice. The deletion of Setdb1 caused the rapid depletion of hematopoietic stem and progenitor cells (HSPCs), as well as leukemic stem cells. In contrast to ESCs, ERVs were largely repressed in Setdb1-deficient HSPCs. A list of nonhematopoietic genes was instead ectopically activated in HSPCs after reductions in H3K9me3 levels, including key gluconeogenic enzyme genes fructose-1,6-bisphosphatase 1 (Fbp1) and Fbp2 The ectopic activation of gluconeogenic enzymes antagonized glycolysis and impaired ATP production, resulting in a compromised repopulating capacity of HSPCs. Our results demonstrate that Setdb1 maintains HSPCs by restricting the ectopic activation of nonhematopoietic genes detrimental to their function and uncover that the gluconeogenic pathway is one of the critical targets of Setdb1 in HSPCs.

Efficacy of docetaxel in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate.

BACKGROUND: This study aimed to investigate the efficacy of docetaxel in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). PATIENTS AND METHODS: We retrospectively identified 79 CRPC patients with distant metastasis at initial diagnosis from June 2002 to January 2014. All patients received initial androgen deprivation therapy and 46 received docetaxel chemotherapy after progressing to CRPC. The primary outcome of interest was cancer-specific survival (CSS) from the time of CRPC diagnosis. The Cox regression model was used to confirm whether IDC-P and docetaxel would act as independent factors for prognosis. RESULTS: IDC-P was found in 62 of 79 patients. The median CSS in the IDC-P-present group was 18.2 versus 45.6 months in the IDC-P-absent group (HR 2.67; 95% CI 1.18 to 6.06; P = 0.019). Docetaxel was administered to 36 patients with IDC-P and 10 patients without IDC-P, with a median CSS of 20.5 versus 53.2 months, respectively (HR 2.98; 95% CI 1.02 to 8.64; P = 0.044). Multivariate analysis demonstrated that the presence of IDC-P and docetaxel were independent prognostic factors for CSS (P = 0.026 and 0.005, respectively) and overall survival (OS) (P = 0.029 and 0.001, respectively). CONCLUSION: The presence of IDC-P is an independent prognostic factor in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. Docetaxel may prolong CSS and OS in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis.

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2.

We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 5'-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation.