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.

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.

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.

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.

Undular bore theory for the Gardner equation.

We develop modulation theory for undular bores (dispersive shock waves) in the framework of the Gardner, or extended Korteweg-de Vries (KdV), equation, which is a generic mathematical model for weakly nonlinear and weakly dispersive wave propagation, when effects of higher order nonlinearity become important. Using a reduced version of the finite-gap integration method we derive the Gardner-Whitham modulation system in a Riemann invariant form and show that it can be mapped onto the well-known modulation system for the Korteweg-de Vries equation. The transformation between the two counterpart modulation systems is, however, not invertible. As a result, the study of the resolution of an initial discontinuity for the Gardner equation reveals a rich phenomenology of solutions which, along with the KdV-type simple undular bores, include nonlinear trigonometric bores, solibores, rarefaction waves, and composite solutions representing various combinations of the above structures. We construct full parametric maps of such solutions for both signs of the cubic nonlinear term in the Gardner equation. Our classification is supported by numerical simulations.

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.

Paediatric retinal detachment: comparison of high myopia and extreme myopia.

AIMS: To compare the clinical features and surgical outcomes of paediatric retinal detachment (RD) in high myopia and extreme myopia. METHODS: The clinical charts of 107 children who experienced RD and had a spherical equivalent (SE) of at least 6.00 dioptres (D) were reviewed. The patients were separated into a high myopia group (SE -6.0 to -10.0 D) and extreme myopia group (SE >-10.0 D). RD characteristics and outcomes were compared between these two groups. RESULTS: There were significant differences between the two groups in total RD (p<0.001), the presence of posterior staphyloma (p<0.001) and some types of breaks. More eyes in the extreme myopia group required vitrectomy after the initial RD repair. In the high myopia group, retinal reattachment was achieved in 79 eyes (97.5%) at the end of the intervention, whereas in the extreme myopia group, retinal reattachment was achieved in 22 eyes (73.3%). Multiple logistic regression showed that a higher refractive error was the only negative predictor of surgical outcome (p = 0.026). CONCLUSION: Due to differences in aetiologies, clinical characteristics, required surgical procedure after initial repair, surgical and functional outcomes, paediatric RD with extreme myopia should be addressed differently from paediatric RD with high myopia.

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.

Two new naphthoquinones from the stem of Diospyros maritima.

Two new naphthoquinones, 2-ethoxy-8'-hydroxyisodiospyrin (1) and 3-ethoxy-8'-hydroxyisodiospyrin (2), together with two known naphthoquinones, 6-hydroxy-5-methoxy-2-methyl-1,4-naphthoquinone and bisisodiospyrin were isolated from the stems of Diospyros maritima. The structures of 1 and 2 were established on the basis of spectroscopic data.

Oleanane-type triterpenes from Ludwigia octovalvis.

Two new oleanane-type triterpenes, (23Z)-feruloylhederagenin (1) and (23E)-feruloylhederagenin (2), together with two known oleanane-type triterpenes, beta-amyrin acetate and beta-amyrin palmitate, have been isolated from the whole plant of Ludwigia octovalvis. The structures of 1 and 2 were characterised on the basis of spectral evidence.

Water-soluble constituents from aerial roots of Ficus microcarpa.

Three new water-soluble constituents [ficuscarpanoside B (1), (7E,9Z)-dihydrophaseic acid 3-O-beta-D-glucopyranoside (4) and ficuscarpanic acid (6)] and the natural product 2,2'-dihydroxyl ether (7) have been isolated, together with three known compounds [(7S,8R)-syringoylglycerol (2), (7S,8R)-syringoylglycerol-7-O-beta-D-glucopyranoside (3) and icariside D2 (5)] from the aerial roots of Ficus microcarpa. Identification of their structures was achieved by 1D and 2D NMR experiments, including 1H-1H COSY, NOESY, HMQC and HMBC methods and FAB mass spectral data.

Differential expression of glucocorticoid receptor in human breast tissues and related neoplasms.

Glucocorticoid receptor (GR) is a steroid hormone receptor that has been shown to play important roles in mammary development and differentiation, and has been implicated in breast tumourigenesis, but its precise biological significance in mammary pathophysiology remains unclear. In order to generate a comprehensive expression profile for GR in normal versus neoplastic breast tissues, GR expression was investigated in situ in 400 human breast tissue samples, comprising normal tissue and a range of benign, pre-invasive, and invasive lesions, using immunohistochemical assays. The novel expression of GR in myoepithelium, not observed in luminal epithelium, not only demonstrates expression patterns exclusive to the alpha form of oestrogen receptor and progesterone receptor and suggests distinctive functions between GR and these two important steroid hormone receptors in the breast, but may also indicate unique physiological and perhaps pathological roles for the myoepithelium in mediating the effects of glucocorticoid hormones in the breast. The strong expression of GR in metaplastic carcinomas (94.4%) and malignant phyllodes tumours (92.3%) suggests a pathogenetic role for GR, and implies that targeting GR in these tumours may have potential therapeutic application. However, studies on the roles of GR in mammary carcinogenesis should be interpreted with great caution, based on the lack of GR expression in cancer cells in the great majority (98.2%) of non-metaplastic carcinomas, which has gone unnoticed in previous studies. This marked discrepancy warrants a re-examination of the biological roles of GR in the pathophysiology of breast malignancy. The lack of methylation in the promoter region of the GR gene in all 118 non-metaplastic carcinomas, as demonstrated by methylation-specific PCR and bisulphite DNA sequencing analysis, indicates that methylation is less likely to play a role in the reduction of GR expression in non-metaplastic carcinoma of the breast.

Ras modulation of superoxide activates ERK-dependent fibronectin expression in diabetes-induced renal injuries.

Although previous studies have demonstrated that diabetic nephropathy is attributable to early extracellular matrix accumulation in glomerular mesangial cells, the molecular mechanism by which high glucose induces matrix protein deposition remains not fully elucidated. Rat mesangial cells pretreated with or without inhibitors were cultured in high-glucose or advanced glycation end product (AGE) conditions. Streptozotocin-induced diabetic rats were given superoxide dismutase (SOD)-conjugated propylene glycol to scavenge superoxide. Transforming growth factor (TGF)-beta1, fibronectin expression, Ras, ERK, p38, and c-Jun activation of glomerular mesangial cells or urinary albumin secretion were assessed. Superoxide, not nitric oxide or hydrogen peroxide, mediated high glucose- and AGE-induced TGF-beta1 and fibronectin expression. Pretreatment with diphenyliodonium, not allopurinol or rotenone, reduced high-glucose and AGE augmentation of superoxide synthesis and fibronection expression. High glucose and AGEs rapidly enhanced Ras activation and progressively increased cytosolic ERK and nuclear c-Jun activation. Inhibiting Ras by manumycin A reduced the stimulatory effects of high glucose and AGEs on superoxide and fibronectin expression. SOD or PD98059 pretreatment reduced high-glucose and AGE promotion of ERK and c-Jun activation. Exogenous SOD treatment in diabetic rats significantly attenuated diabetes induction of superoxide, urinary albumin excretion, 8-hydroxy-2'-deoxyguanosine, TGF-beta1, and fibronectin immunoreactivities in renal glomerular mesangial cells. Ras induction of superoxide activated ERK-dependent fibrosis-stimulatory factor and extracellular matrix gene transcription of mesangial cells. Reduction of oxidative stress by scavenging superoxide may provide an alternative strategy for controlling diabetes-induced early renal injury.