Synchronous colorectal carcinoma: predisposing factors and characteristics.

AIM: Whether some diseases are related to the occurrence of synchronous colorectal carcinoma (sCRC) is unknown. Investigating the risk factors and presentation of sCRC could aid in the treatment of patients with colorectal cancer (CRC). The prognosis of sCRC compared with that of solitary CRC remains unclear. METHODS: A total of 17 093 CRC patients were recruited between 1st January 1995 and 31th December 2016. The risk factors of sCRC development were assessed using univariate and multivariate logistic regression. The effect of sCRC on survival was analysed using the multivariate Cox regression model. RESULTS: The prevalence of sCRC was 5.6% in this study. The independent risk factors of sCRC development were advanced age (P < 0.001), male sex (P < 0.001), hereditary cancer (P < 0.001), hypertension (P < 0.001) and liver cirrhosis (P = 0.024). Compared with solitary CRC, a higher number of patients with sCRC presented with an abnormal carcinoembryonic antigen (CEA) level (P = 0.011), anaemia (P < 0.001) and hypoalbuminemia (P < 0.001). Multivariate analysis revealed that sCRC was a significant factor for poor survival in patients at TNM Stage I [hazard ratio (HR) = 1.86; P < 0.001], Stage II (HR = 1.65; P < 0.001) and Stage III (HR = 1.40; P < 0.001). CONCLUSIONS: In addition to hypertension and liver cirrhosis, other risk factors for sCRC were identified in this study. The prognosis of patients with sCRC was significantly worse than that of those with solitary CRC through TNM Stages I to III. Anaemia, abnormal CEA and hypoalbuminemia were more commonly seen in patients with sCRC.

Role of hepatitis C virus substitutions and interleukin-28B polymorphism on response to peginterferon plus ribavirin in a prospective study of response-guided therapy.

Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity-determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin-28B (IL-28B) locus affect the outcome of interferon (IFN)-based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response-guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV-1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non-EVR patients. Logistic regression analysis showed that ISDR mutation (≥2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts≥15×10(4) /µL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (≥2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy.

Stress preconditioning of boar spermatozoa: a new approach to enhance semen quality.

Semen preparation and cryopreservation require finely adjusted procedures. Gametes are sensitive to environmental stresses, so in vitro procedures aim to minimize the inevitable harmful conditions. Applying stress to precondition cells has only been investigated recently. Studies demonstrated that by utilizing a well defined and properly applied hydrostatic pressure (HP) stress treatment to spermatozoa before in vitro storage, cryopreservation or insemination, cell survival and fertility improved compared with untreated controls. The birth of healthy piglets from treated fresh or frozen-thawed semen demonstrates the in vivo safety of the procedure. Although the biological mechanism is still unclear, several processes incorporating cellular stress response might explain the observations. This paper summarizes results, background, aspects and considerations of HP treatment for porcine semen. The new principle, i.e. to improve the stress tolerance by a defined sublethal stress may outline a new strategy in assisted reproductive technologies with unique theoretical and practical consequences.

Epitaxially-grown Ge/Si avalanche photodiodes for 1.3 microm light detection.

We designed and fabricated Ge/Si avalanche photodiodes grown on silicon substrates. The mesa-type photodiodes exhibit a responsivity at 1310 nm of 0.54 A/W, a breakdown voltage thermal coefficient of 0.05%/ degrees C, a 3 dB-bandwidth of 10 GHz. The gain-bandwidth product was measured as 153 GHz. The effective k value extracted from the excess noise factor was 0.1.

Linear accelerator radiosurgery for treatment of vestibular schwannomas in neurofibromatosis 2.

Management of vestibular schwannomas in patients with neurofibromatosis 2 (NF2) balances growth control against preservation of hearing with the primary aim of maintaining patient quality of life. Surgical resection of these lesions carries greater risk of functional deterioration than in sporadic cases. Stereotactic radiosurgery is a less invasive option that provides comparable, if not superior outcomes to resection. Previous studies on the efficacy of stereotactic radiosurgery for vestibular schwannomas in NF2 have reported results from delivery by Gamma Knife systems. The efficacy of linear accelerator (LINAC) delivered treatment has not been specifically addressed. Modelling studies suggest that lesional conformality is superior with Gamma Knife, but clinical studies on sporadic vestibular schwannomas show equivalent results between the two systems. Our experience with LINAC radiosurgery in NF2 reported here shows good long-term growth control in four patients with vestibular schwannomas.

Modelling acute myeloid leukaemia in a continuum of differentiation states.

Here we present a mathematical model of movement in an abstract space representing states of cellular differentiation. We motivate this work with recent examples that demonstrate a continuum of cellular differentiation using single cell RNA sequencing data to characterize cellular states in a high-dimensional space, which is then mapped into ℝ 2 or ℝ 2 with dimension reduction techniques. We represent trajectories in the differentiation space as a graph, and model directed and random movement on the graph with partial differential equations. We hypothesize that flow in this space can be used to model normal and abnormal differentiation processes. We present a mathematical model of hematopoeisis parameterized with publicly available single cell RNA-Seq data and use it to simulate the pathogenesis of acute myeloid leukemia (AML). The model predicts the emergence of cells in novel intermediate states of differentiation consistent with immunophenotypic characterizations of a mouse model of AML.

Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion.

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.

Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) has long been used as a traditional Chinese medicine for dysfunctions of the endocrine system and inflammation conditions. However, the effect of adlay seed on the endocrine system has not yet been reported. In the present study, the effects and the mechanisms of methanolic extract of adlay bran (ABM) on progesterone synthesis in rat granulosa cell were studied. ABM was further partitioned with different solvents including water, 1-butanol, ethyl acetate and n-hexane. Four subfractions named ABM-Wa (water fraction), ABM-Bu (1-butanol fraction), ABM-EA (ethyl acetate fraction) and ABM-Hex (n-hexane fraction) were obtained. ABM-Bu was further fractionated using Diaion HP-20 resin column chromatography with gradient elution. Granulosa cells were prepared from pregnant mare serum gonadotropin-primed immature female rats and challenged with different reagents including human chorionic gonadotropin (hCG 0.5 IU/ml), forskolin (10 microM), 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP, 1 mM), A23187 (10 microM), phorbol 12-myristate 13-acetate (PMA, 0.01 microM), 25-OH-cholesterol (0.1-10 microM) and pregnenolone (0.1-10 microM) in the presence or absence of ABM-Bu (100 microg/ml). The functions of steroidogenic enzyme including protein expression of the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (P450scc) protein were investigated. Expressions of both P450scc and StAR mRNA have also been explored. We found that ABM decreased progesterone production via an inhibition on (1) the cAMP-PKA and PKC signal transduction pathway, (2) P450scc and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) enzyme activity, (3) P450scc and StAR protein and mRNA expressions and (4) the phosphorylation of ERK1/2 in rat granulosa cells.

Antioxidant properties of demethyldiisoeugenol.

The antioxidant properties of demethyldiisoeugenol were investigated in this study using various models. Demethyldiisoeugenol inhibited Fe(2+)-induced lipid peroxidation in rat brain homogenate in a concentration-dependent manner with an IC50 1.8 +/- 0.1 microM. Demethyldiisoeugenol was more effective than alpha-tocopherol and BHT in reducing the stable free radical diphenyl-2-picrylhydrazyl (DPPH). It also scavenged superoxide anion generated by xanthine/xanthine oxidase and peroxyl radical (ROO.) derived from 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH) in aqueous system with a stoichiometric factor of 1.3 +/- 0.2. Furthermore, it prevented conjugated-diene formation and apolipoprotein B (apo B) oxidation of LDL. However, demethyldiisoeugenol did not scavenge 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN)-derived peroxyl radical in hexane. It also did not chelate Fe2+, did not inhibit xanthine oxidase activity or possessed hydroxyl radical (.OH) scavenging activity. Experimental results indicate that demethyldiisoeugenol is a potentially effective antioxidant and can protect rat brain homogenate and LDL against oxidation.

Risk associated with traumatic intracranial bleed and outcome in patients following a fall from a standing position.

BACKGROUND: A fall from a standing position (FFS) is a low impact injury; however, in certain patient populations it can result in serious, complex injuries associated with significant morbidity and mortality. OBJECTIVES: The purpose of the study was to identify the patient population, risk factors and outcomes of intracranial bleed (ICB) after a fall from a standing position. METHODS: Data of all patients from the trauma database at State designated Trauma Center were analyzed who FFS. Patient's demography, clinical information was obtained. An ICB seen on computed tomography (CT) scan was considered positive. RESULTS: From January 2001 through December 2008, 163 patients admitted to the trauma center after FFS. Ninety-one out of 163 patients (56 %) had positive CT scan. There was no significant difference between the groups with a positive or negative CT regarding age (P = 0.07), gender (P = 0.58), race (P = 0.15), Glasgow Coma Scale (P = 0.27), aspirin use (P = 0.06), Plavix (P = 0.92), combination of aspirin and Plavix (P = 0.86) or use of Coumadin (P = 0.82). Patients with ICB had significantly higher injury severity score (ISS) than patients without ICB (P < 0.0001). However, the overall mortality between the groups was not significant (P = 0.66). From a multiple logistic regression model, age ≥70 years was the only predictor for the ICB. CONCLUSION: A high proportion of our patients had positive ICB due to falls from a standing position. No significant differences were seen between the groups in terms of mortality. Age ≥70 years was the only factor for positive ICB. LEVEL OF EVIDENCE: Prognostic study investigating the effect of a patient characteristic on the outcome of the disease, level III.

Regulation of alpha-amylase-encoding gene expression in germinating seeds and cultured cells of rice.

Four alpha-amylase-encoding cDNA (alpha Amy-C) clones were isolated from a cDNA library derived from poly(A)+RNA of gibberellic acid (GA3)-treated rice aleurone layers. Nucleotide sequence analysis indicates that the four cDNAs were derived from different alpha Amy genes. Expression of the individual alpha Amy gene in germinating seeds and cultured suspension cells of rice was studied using gene-specific probes. In germinating seeds, expression of the alpha Amy genes is positively regulated by GA3 in a temporally coordinated but quantitatively distinct manner. In cultured suspension cells, in contrast, expression of the alpha Amy genes is negatively and differentially regulated by sugars present in the medium. In addition, one strong and one weak carbohydrate-starvation-responsive alpha Amy genes have been identified. Interactions between the promoter region (HS501) of a rice alpha Amy gene and GA3-inducible DNA binding proteins in rice aleurone cells were also studied. A DNA mobility-shift assay showed that the aleurone proteins interact with two specific DNA fragments within HS501. One fragment is located between nt -131 to -170 and contains two imperfect directly repeated pyrimidine elements and a putative GA3-response element. The other fragment is located between nt -92 to -130 that contains a putative enhancer sequence. The interactions between aleurone proteins and these two fragments are sequence-specific and GA-responsive.

Protection of oxidative hemolysis by demethyldiisoeugenol in normal and beta-thalassemic red blood cells.

The purpose of this study was to evaluate the ability of demethyldiisoeugenol to protect normal and beta-thalassemic human red blood cells (RBCs) against oxidative damage in vitro. Oxidative hemolysis and lipid peroxidation of normal and beta-thalassemic human RBCs induced by aqueous peroxyl radical were suppressed by demethyldiisoeugenol in a concentration-dependent manner. The formation of proteins with high molecular weight and concomitant decrease of the low-molecular-weight proteins of RBCs challenge with aqueous peroxyl radical were inhibited by demethyldiisoeugenol. It also prevented the shortening of the Russell's viper venom (RVV)-clotting time mediated by prelytic radical-treated RBCs. In contrast, demethyldiisoeugenol inhibited oxidative hemolysis but not those metHb and ferrylHb formations caused by hydrogen peroxide (H2O2) in normal RBCs. Furthermore, demethyldiisoeugenol did not prevent the consumption of the cytosolic antioxidant, glutathione (GSH), in radical-treated RBCs. It also did not cause of a loss of sulfhydryl group during incubation with GSH. However, the diphenyl-2-picrylhydrazyl (DPPH) scavenging activity of demethyldiisoeugenol was dramatically increased in the presence of GSH. These results imply that demethyldiisoeugenol can regenerate from its oxidized form to its active reduced form in the presence of GSH. It may be useful in diminishing oxidative damage to pathological RBCs.

Antitumor agents. 113. New 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II.

A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA topoisomerase II, a basic unsubstituted 4 beta-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.

Antitumor agents. 111. New 4-hydroxylated and 4-halogenated anilino derivatives of 4'-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II.

A series of C-4 hydroxylated and halogenated anilino derivatives of epipodophyllotoxin or 4'-demethylepipodophyllotoxin have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 11-17 and 22 are more potent than etoposide in causing DNA breakage, while compounds 11-13, 15, 16, and 20 are as active or more active than etoposide in their inhibition of the human DNA topoisomerase II. The cytotoxicity in KB cells appears to have no direct correlation with their ability to inhibit DNA topoisomerase II and to cause protein-linked DNA breaks in cells.

Identification of a protein kinase C (PKC) activator, daphnoretin, that suppresses hepatitis B virus gene expression in human hepatoma cells.

We examined the antiviral activity of a crude extract prepared from a Chinese medicinal herb Wikstroemia indica C.A. Mey. One active component, daphnoretin (7-hydroxyl-6-methoxy-3,7'-dicoumarylether), was identified, which showed strong suppressive effects on the expression of the hepatitis B surface antigen (HBsAg) in human hepatoma Hep3B cells. To examine the signaling pathway of daphnoretin on the Hep3B cells, we pretreated Hep3B cells with 12-O-tetradecanoylphorbol-13-O-acetate (200 nM) for 24 hr to down-regulate intracellular protein kinase C (PKC) levels and found that the PKC-down-regulated Hep3B cells did not respond at all to daphnoretin. Furthermore, daphnoretin induced translocation of PKC from the cytosol to the membrane and down-regulated intracellular PKC levels in the Hep3B cells, indicating that it may directly activate PKC. This hypothesis was supported by the observation that daphnoretin directly competed with [3H]phorbol dibutyrate for the binding of PKC in the whole cell and activated purified PKC activity in vitro. Our results demonstrated that daphnoretin, with a structure distinct from phorbol ester, is a PKC activator and has suppressive effects on HBsAg gene expression in human hepatoma cells.

Stage III colon cancers: why adjuvant chemotherapy is not offered to elderly patients.

HYPOTHESIS: Adjuvant chemotherapy is not offered to elderly patients with stage III colon cancer. DESIGN: A retrospective review of hospital and office records. SETTING: A suburban community hospital. PATIENTS: The medical records of 69 patients with stage III colon cancer were reviewed. All identified from the Tumor Registry at Jersey Shore Medical Center, Neptune, NJ, were included in this study. RESULTS: Thirty-five patients (51%) did not receive adjuvant chemotherapy. After adjusting for age, women were 5.8 times less likely to receive chemotherapy (P = .002). Patients not receiving chemotherapy were significantly older (78.7 vs 70.4 years; P = .003) than those who received adjuvant chemotherapy. There was no relation found between the year of diagnosis and the administration of chemotherapy. There were 4 major reasons for not receiving chemotherapy: (1) not offered (n = 12, 34%), (2) refused (n = 11, 31%), (3) too old (n = 7, 20%), and (4) significant concomitant disease (n = 5, 14%). CONCLUSIONS: A large group of elderly patients who had been surgically treated for colon cancer and who were eligible for adjuvant chemotherapy either were not referred for treatment or refused treatment. This suggests a bias on the part of surgeons, primary care physicians, and patients against the use of chemotherapy in elderly patients.

Decreasing occupational risk related to blood-borne viruses in cardiovascular surgery in Paris, France.

BACKGROUND: Surgeons face the risk of patient-to-physician transmission of blood-borne viruses. This risk is related to the seroprevalence of the viruses in the patient population. METHODS: The seroprevalence of the human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were determined in cardiovascular patients at Hôpital Broussais in Paris, France, over a 5-year period (1994 to 1998). RESULTS: Hepatitis C virus is the most prevalent virus in the patient population, whereas human immunodeficiency virus is the least frequent. The seroprevalence of hepatitis C virus and human immunodeficiency virus has decreased over time, whereas hepatitis B virus has remained constant. We apply the seroprevalence data to a mathematical model to estimate the occupational risk of seroconversion faced by surgeons over the length of their career. Our results show that the principal risk faced by the surgeon arises from hepatitis B virus and hepatitis C virus. The decreasing seroprevalence of the hepatitis C virus has resulted in a decrease in the occupational risk. CONCLUSIONS: The probability of becoming infected with a blood-borne virus over the career of the surgeon is notable. The greatest occupational risk to the surgeon is from the hepatitis viruses and not HIV.