bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Scenario of Postcholecystectomy Bile Leak and Bile Duct Injury at a Tertiary Care Referral Centre of Nepal
Authors: Pandit Narendra , Yadav Tek Narayan , Awale Laligen , Deo Kunal Bikram , Dhakal Yogesh , Adhikary Shailesh
Published: April 2020

Objective. With the adoption of safe cholecystectomy principles at an academic institute, the risk of major bile duct injury has decreased. This study aims at evaluating the present status of bile duct injury, compared to the study published in 2013 by index centre. Methods. This is a retrospective review of a prospectively maintained database of bile leak and bile duct injury from 2014 to 2019. Patients who completed postcholecystectomy bile leak or bile duct injury treatment and were on regular follow-up were included. Results. Eighteen patients (0.78%) among 2,300 consecutive cholecystectomies presented with bile duct injury, including 8 (0.35%) major bile duct injuries and 10 (0.43%) bile leaks compared to major bile duct injury rate of 0.68% (92/11,345 cholecystectomies) between 2001 and 2010. Injuries were classified as Strasberg’s type A (52.9%), type D (5.9%), and type E (41.1%). Eight patients (47%) of bile leak were managed conservatively with drains, while two required laparotomy and lavage. The mean time for spontaneous closure of bile leak was 11 days. Intraoperative repair was done in three cases: Roux en Y hepaticojejunostomy in 2 and end-to-end repair over T-tube in 1 for sharp transection of the duct. Delayed repair (Roux-en-Y hepaticojejunostomy) was done in five patients. The median postcholecystectomy hospital stay was 8 days, with no mortality. There was no restricture at a median follow-up of 13 months. Conclusion. With the adoption of a safe culture of cholecystectomy, the major bile duct injury rate has decreased currently. Repair of bile duct injury by experienced hepatobiliary surgeon results in excellent outcome.
Role of Mitochondrial Stress Protein HSP60 in Diabetes-Induced Neuroinflammation
Authors: Liyanagamage Donisha Shani Niharika Keembiya , Martinus Ryan D.
Published: April 2020

Diabetes mellitus is the most common metabolic disorder characterized by hyperglycemia and associated malfunctions of the metabolism of carbohydrates, proteins, and lipids. There is increasing evidence of a relationship between diabetes and vascular dementia. Interestingly, hyperglycemia-linked neuroinflammation in the central nervous system is considered to play a key role during vascular dementia in diabetic patients. However, the mechanisms responsible for the relationship between hyperglycemia and neuroinflammation is not clearly understood. Diabetes-induced alternations in the blood-brain barrier permit high glucose influx into the brain cells via glucose transporters and promote oxidative stress through overproduction of reactive oxygen species. Despite many studies demonstrating a link between oxidative stress and mitochondrial dysfunction, the relationship between mitochondrial dysfunction and neuron inflammation during hyperglycemia remains to be established. In this review, we will focus on diabetes-induced changes in the central nervous system and the role of mitochondrial heat shock protein 60 (HSP60) as an initiator of oxidative stress and potential modulator of neuroinflammation. We suggest that oxidative stress-mediated mitochondrial dysfunction stimulates the upregulation of mitochondrial heat shock protein 60 (HSP60) and ultimately initiates inflammatory pathways by activating pattern recognition receptors. HSP60 also could be a focal point in the development of a biomarker of neuroinflammation as HSP60 is known to be significantly elevated in diabetic patients. Interestingly, extracellular secretion of HSP60 via exosomes suggests that inflammation could spread to neighboring astrocytes by activating pattern recognition receptors of astrocytes via neuronal exosomes containing HSP60. A mechanism for linking neuron and astrocyte inflammation will provide new therapeutic approaches to modulate neuroinflammation and therefore potentially ameliorate the cognitive impairment in diabetic brains associated with vascular dementia.
Density of Langerhans Cells in Nonmelanoma Skin Cancers: A Systematic Review
Authors: Pogorzelska-Dyrbuś Joanna , Szepietowski Jacek C.
Published: April 2020

Langerhans cells (LCs) are bone marrow-derived dendritic cells (DCs) that represent 2-3% of the entire cell population of the human skin, known to have an ability to present antigens to T lymphocytes. Moreover, there is evidence that LCs are probably capable of inducing the local cytotoxic type T-cell-mediated response against the tumour-associated antigens. In the past two decades, a dramatic increase has been noted in the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The purpose of this study was to critically assess the results of available studies quantitatively assessing the LCs in nonmelanoma skin cancers and try to establish a conclusion of its possible impact on their future treatment. The PubMed, EMBASE, and the Web of Science databases were searched, which returned 948 citations. After a thorough analysis of full article texts, 30 studies have been chosen, including 11 of the BCC, 12 of the SCC specimens, and 7 analysing both tumour types. There was an overall trend towards slightly higher numbers of LCs in BCC than in SCC; however, these tendencies were discrepant between the studies. We presume that such differences could be caused by various staining techniques with a broad spectrum of specificity, including anti-S100, anti-CD1a, and ATPase activity staining used for LCs identification. We hypothesise that as there is a high inconsistency between the results of the studies, as far as the densities of LCs observed in the specimens are concerned, it seems that the mechanism of the influence of LCs on the antitumoural immune response is complicated. Finally, as at present, there is a paucity of available risk scores for the recurrence or progression of BCC or SCC, the creation of classification stratifying that risk including the density of LCs could bring additional information both for the physician and the patient.
Genomic Chaos Begets Psychiatric Disorder
Authors: Dwyer Donard S.
Published: April 2020

The processes that created the primordial genome are inextricably linked to current day vulnerability to developing a psychiatric disorder as summarized in this review article. Chaos and dynamic forces including duplication, transposition, and recombination generated the protogenome. To survive early stages of genome evolution, self-organization emerged to curb chaos. Eventually, the human genome evolved through a delicate balance of chaos/instability and organization/stability. However, recombination coldspots, silencing of transposable elements, and other measures to limit chaos also led to retention of variants that increase risk for disease. Moreover, ongoing dynamics in the genome creates various new mutations that determine liability for psychiatric disorders. Homologous recombination, long-range gene regulation, and gene interactions were all guided by spooky action-at-a-distance, which increased variability in the system. A probabilistic system of life was required to deal with a changing environment. This ensured the generation of outliers in the population, which enhanced the probability that some members would survive unfavorable environmental impacts. Some of the outliers produced through this process in man are ill suited to cope with the complex demands of modern life. Genomic chaos and mental distress from the psychological challenges of modern living will inevitably converge to produce psychiatric disorders in man.
Environmental and Socioeconomic Factors Influence the Live‐Born Incidence of Congenital Heart Disease: A Population‐Based Study in California
Authors: Peyvandi Shabnam , Baer Rebecca J. , Chambers Christina D. , Norton Mary E. , Rajagopal Satish , Ryckman Kelli K. , Moon‐Grady Anita , Jelliffe‐Pawlowski Laura L. , Steurer Martina A.
Published: April 2020

BACKGROUND

The development of congenital heart disease (
CHD
) is multifactorial with genetic and environmental influences. We sought to determine the relationship between socioeconomic and environmental factors with the incidence of
CHD
among live‐born infants in California and to determine whether maternal comorbidities are in the causal pathway.

METHODS AND RESULTS

This was a population‐based cohort study in California (2007–2012). The primary outcome was having significant
CHD
. Predictors included socioeconomic status and environmental exposure to pollutants determined by U.S. Census data. A social deprivation index and environmental exposure index was assigned based on neighborhood socioeconomic variables, categorized into 4 quartiles. Quartile 1 was the best with the least exposure to pollutants and social deprivation, and quartile 4 was the worst. Multivariate logistic regression and mediation analyses were performed. Among 2 419 651 live‐born infants, the incidence of
CHD
was 3.2 per 1000 live births. The incidence of
CHD
was significantly higher among those in quartile 4 compared with quartile 1 (social deprivation index: 0.35% versus 0.29%; odds ratio [OR], 1.31; 95% CI, 1.21–1.41; environmental exposure index: 0.35% versus 0.29%; OR, 1.23; 95% CI, 1.15–1.31) after adjusting for maternal race/ethnicity and age and accounting for the relationship between the 2 primary predictors. Maternal comorbidities explained 13% (95% CI, 10%–20%) of the relationship between social deprivation index and environmental exposure index with the incidence of
CHD
.

CONCLUSIONS

Increased social deprivation and exposure to environmental pollutants are associated with the incidence of live‐born
CHD
in California. Maternal comorbidities explain some, but not all, of this relationship. These findings identify targets for social policy initiatives to minimize health disparities.
A new long-legged terrestrial freshwater crab, Calcipotamon puglabrum gen. nov. et sp. nov. (Crustacea: Decapoda: Potamidae), from Hainan Island, China
Authors: HUANG CHAO , HUANG SHENG-ZHUO , SHEN ZHI-XIN
Published: April 2020

A new genus and new species of terrestrial freshwater crab, Calcipotamon puglabrum gen. nov. et sp. nov., is described from the limestone forests of Changjiang, Hainan Island, China, based on morphology and mitochondrial 16S rDNA sequences. The new genus is closest to Neotiwaripotamon Dai & Naiyanetr, 1994, and Tiwaripotamon Bott, 1970, but differs in a combination of carapace, third maxilliped, ambulatory leg and male gonopod characters. Molecular analysis shows that the new genus is closely related with but not clustered within other Hainan potamid genera. Notes on the general biology of this new species are also provided.
The Combination of Aerobic and Resistance Exercise Induces Weight Loss via the PGC-1α/Irisin/UCP-1 Pathway
Authors: Deng Hong , Zhang Wei , Ruan Dingguo , Chen Dezhi , Xu Xiaoyang , He Xuan , Chen Cuicui , Li Laiqing
Published: April 2020

Obesity is a modern disease and the cause is quite complicated. This study explores the effects of aerobic and resistance exercise on weight loss and their relationship with the PGC-1α/Irisin/UCP-1
signaling pathway. First, we selected 52 obese students for aerobic and resistance exercise. Second, we established an obesity rat model, and then subjected them to 12 weeks of aerobic and resistance
exercise. The body weights and blood lipid contents of all the subjects were measured, and mRNA and protein expressions were determined via real-time PCR and western blot. In obese students, aerobic
exercise and the combination of aerobic and resistance exercise significantly reduced body weight and blood lipid levels. In obese model rats, aerobic and resistance exercise significantly reduced the
body weight, blood lipid levels, and increased the PGC-1, Irisin, and UCP-1 levels. Furthermore, the combined effects of aerobic and resistance exercise were similar to those of prolonged aerobic
exercise in both human subjects and model rats. The mechanism of weight loss via aerobic and resistance exercise may be related to the PGC-1α/Irisin/UCP-1 pathway, and the combination of aerobic and
resistance exercise may be a more suitable weight loss option for obese patients.
miR-150 Affects Wnt/β-Catenin Pathway Activity and Regulates MSC Osteogenic Differentiation
Authors: Wang Junsheng , Hu Xiaowu , Ji Qing , Zheng Bai , Huang Lixin
Published: April 2020

The Wnt/β-catenin pathway promotes osteoblast differentiation. Bioinformatics analysis showed a targeting relationship between miR-150 and β-catenin 3′-UTR. This study investigated miR-150's role in β-catenin expression and osteoblast differentiation
of Adipose-Derived Mesenchymal Stem Cells (ADMSCs). Differentiation of ADMSCs into osteoblasts was induced and the expression of miR-150, β-catenin, RUNX2 and OPN on the 0th, 9th and 18th day during differentiation was detected. The dual luciferase gene reporter assay validated
the relationship between miR-150 and β-catenin. ADMSCs were divided into angomir-NC group and angomir-150 group, and then induced for differentiation for 18 days followed by measuring the level of miR-150, β-catenin, RUNX2 and OPN and the degree of osteoblast differentiation
by alizarin red staining. Compared with Day 0, miR-150 expression was gradually decreased on 9th and 18th day of osteoblast differentiation, and the expression of β-catenin, RUNX2 and OPN was gradually increased. There was a targeted regulation relationship between miR-150 and
β-catenin. Compared with angomir-NC group, miR-150 expression was significantly increased in angomir-150 transfection group with decreased expression of β-catenin, RUNX2 and OPN protein and reduced degree of alizarin red staining. miR-150 expression is decreased and
β-catenin expression is increased during osteoblast differentiation of ADMSCs. Up-regulation of miR-150 expression attenuates the ability of ADMSCs to differentiate into osteoblasts by inhibiting β-catenin expression and Wnt/β-catenin pathway.
The Application Value of ApoE Gene Polymorphism in Alzheimer's Disease
Authors: Chen Cong , Zhang Yuhui , Chen Bin , Zeng Chaosheng , Chen Min , Chen Lin , Su Qingjie
Published: April 2020

To explore the association of apolipoprotein E polymorphism with Alzheimer's disease (AD), so as to provide possible research value for potential targeted therapy. 120 AD patients and 50 healthy volunteers were enrolled to extract fasting blood samples. ApoE gene polymorphism and blood
lipids were tested in blood. ApoE gene and genotype frequency between AD group and control group were compared by PCR and sequencing methods. MMSE, CDR, and BPSD were used to determine the intelligence. ApoE genotype was detected by DNA microarray. ɛ4 carrier accounted for 45%
in AD group, which was significantly elevated compared with control group (12%) (P < 0.05). TG, TC, and LDL-C levels were increased, while HDL-C was reduced in ɛ4 allele carriers (allP < 0.05). The MMSE scores of ApoEɛ4 genotype carriers in AD
group were markedly lower than those of nonApoEɛ4 genotype carriers (P < 0.05) and control (P < 0.01). The proportion of dementia in ApoEɛ4 genotype carriers from AD group was apparently higher than the ɛ4 gene non-carriers (P <
0.05). The ApoEɛ4 gene is an AD risk factor. The changes of genotype and frequency of ApoEɛ4 gene are the main factors leading to abnormal lipid metabolism in AD patients, suggesting that ApoEɛ4 gene detection might be helpful for the early diagnosis
and treatment of AD.
Performance Evaluation of H-Type Darrieus Vertical Axis Wind Turbine with Different Turbine Solidity
Authors: Ramlee Muhamad Fadhli , Fazlizan Ahmad , Mat Sohif
Published: April 2020

Among renewable energy resources, wind energy is one of the best alternative for power generation. Recently, vertical axis wind turbine (VAWT) received renewed interest as small-scale wind energy converter due to its suitability for urban application, where the wind condition is known
to be unsteady and turbulence. Amongst various type of VAWTs, H-type Darrieus rotor has become more popular, thanks to its simple construction features, resulting to low manufacturing and installation cost. The aim of this paper is to evaluate numerically the power performance of straight-bladed
Darrieus VAWT with different turbine solidity using computational fluid dynamic (CFD) technology. A series of two-dimensional CFD simulations of a three-bladed H-type Darrieus rotor were performed with 3 different solidities, σ (0.3, 0.5 and 0.7) to evaluate their power performance.
Unsteady Reynolds-Averaged Navier-Stokes (URANS) equations were used to calculate the instantaneous moment coefficient, Cm and power coefficient, Cp over a range of tip speed ratio, λ (0.5–4.5) with a free stream velocity of 8.0 m/s.
The simulation results show that high solidity turbine performed well at low values of λ while turbine with low solidity has a wider operating range of λ and performed better at λ > 3.0 due to less blade-wake interactions between upstream and downstream
halves of the turbine and lower blockage effect. The findings lend substantially to our understanding of physics flow around blades and turbine in order to optimize the power performance of small scale straight-bladed Darrieus VAWT operating in unsteady and turbulence wind condition.
Optimization of Surface Roughness by Using Different Cutting Tools for Aluminum Alloy 6063
Authors: Abdullah Allina , Azman Afiqah , Khirulrizwan B. M.
Published: April 2020

This research outlines an experimental study to determine the optimum parameter of cutting tool for the best surface roughness (Ra) of Aluminum Alloy (AA) 6063. For the experiment in this research, cutting parameters such as cutting speed, depth of cut and feed rate are used to identify
the effect of both cutting tools which are tungsten carbide and cermet towards the surface roughness (Ra) of material AA6063. The machining operation involved to cut the material is turning process by using Computer Numerical Control (CNC) Lathe machine. The experimental design was designed
by Full Factorial. The experiment that had been conducted by the researcher is 33 with 2 replications. The total number of the experiments that had been run is 54 runs for each cutting tool. Thus, the total number of experiments for both cutting tools is 108 runs. ANOVA analysis had been analyzed
to identify the significant factor that affect the Ra result. The significant factors that affect the Ra result of AA6063 are feed rate and cutting speed. The researcher used main effect plot to determine the factor that most influenced the surface roughness of AA6063, the optimum condition
of surface roughness and the optimum parameter of cutting tool. The factor that most influenced the surface roughness of AA6063 is feed rate. The optimum condition of surface roughness is at the feed rate of 0.05 mm/rev, cutting speed of 600 rpm and depth of cut of 0.10 mm. While the optimum
parameter of cutting tool is cermet insert with the lowest value of surface roughness (Ra) result which is 0.650 μm.
The Effect of Eggshell Powder as an Accelerator for Blended Cement Concrete
Authors: Rasid Nur Nadhira Abdul , Sam Abdul Rahman Mohd. , Mohamed Azman , Shukor Lim Nor Hasanah Abdul , Majid Zaiton Abdul , Khalid Nur Hafizah A.
Published: April 2020

Blended concrete has later strength development with long maturity strength development. An accelerator is thus needed to enhance the early strength development of concrete. This paper shows the combination of ground palm oil fuel ash and eggshell powder that was designed for later
and early strength development, respectively. Two types of eggshell powder were utilised in concrete: uncarbonised eggshell powder and decarbonised eggshell powder. The study was initiated with compression test for concrete curing at age 1, 3, 7, and 28 days followed by rapid evaluation test
of setting time to investigate the preliminary performance between materials. The results revealed decarbonised eggshell powder as a high accelerator that can improve the early age of concrete strength development. Meanwhile, despite showing the best performance, uncarbonised eggshell powder
is a very low accelerator thus not fit the purpose. In conclusion, the combination of ground palm oil fuel ash (rich with silica oxide) and decarbonised eggshell powder (rich with calcium oxide) provided dual function, where ground palm oil fuel ash and decarbonised eggshell powder took later
and early strength development, respectively. The combination between silica oxide and calcium oxide in cementitious materials has potential to be utilised to enhance the early age of a blended concrete strength development.
The Development of Microhydro Power Plant in the River Village of Wioy Province of North Sulawesi
Authors: Sojow Luckie , Sangi Nontje M. , Wajong Altje
Published: April 2020

This study aims to reveal that analysing the energy source of river water at village of Wioy province of North Sulawesi. Prototype of generator of microhydro. Expansion models of this research by using approach of ADDIE that covering phase of analysis, design, develop, implement) and
evaluate. Result of research Development of paddle wheel of conventional turbine of size of its diameter side with capacities of debit that with turbine of cross of flow is more producing the speed of higher rotary. Is produced electricity 26.34 kWs, where this also is very affected by discharge,
head of water and volume of deep-water accumulating basin.
Graphic Technology in Computer Games at Internet Shop Pay for Teenage Impications
Authors: Musa Azlina
Published: April 2020

This paper discusses about graphic technology in computer games or gaming pc at internet stores with pay implications for adolescents. This paper will examine the existence of a paid internet store that has been offering fast broadband services accessible at the fingertips to surrounding
communities. However, there are adolescents who misuse the services provided by accessing computer games with no restrictions, monitoring and escort. This paper will examine whether the adolescent driving factor that is still in school is willing to spend time, energy and invest money solely
for enjoying the fun of computer games at a paid internet shop. In addition, paid internet shop dealers who offer dvd and vcd computer games with unlimited payment rates have attracted teenagers. Research on teenager’s attitude towards the influence of computer games. Examine how computer
games affect youth health. Besides examining teenage obsessors on computer graphics technology to reality realms and teenage satisfaction exploring computer games at paid internet shops regardless of the surrounding community. Besides examining the negative implications of computer games on
the quality of teenage education. Hence the lack of parent’s awareness of child supervision led to the spreading outbreak of school dropouts for being trapped by computer games during school days of fun with computer games at paid internet shops. This paper is obtained through field
research such as observation, interviews and questionnaire with one hundred respondents involved in the study area. Through the documentation of the findings of this study can add further references to other researchers in the future.
Analysing Step Patterns on the Malaysian Folk Dance Zapin Lenga
Authors: Mustaffa Norsimaa , Idris Muhammad Zaffwan
Published: April 2020

Zapin Lenga is a Malaysian folk dance within Zapin Melayu and specifically known as Zapin Johor. Zapin Lenga was originated in Muar, one of the district in Johor state and the oldest Zapin Melayu repertoire that had been found in Johor. Zapin Lenga which usually performed for religious
significance comprises of six-step patterns, known as ‘langkah’ that were performed only by the males during the olden days. In the meaning of preservation, we have used Motion Capture (MoCap) technology in recording and digitising human motions. In this paper, we present a primary
work in preserving the dance movements of Zapin Lenga through Laban Movement Analysis (LMA) including Body, Effort, Shape and Space in order to identify qualities on dance movements. The dance movements were analysed by considering musical rhythm using segmentation method and the distances
between markers were measured to define speed.
Research on piezoelectric vibration energy harvester with variable section circular beam
Authors: Ma Tianbing , Ding Yongjing , Wu Xiaodong , Chen Nannan , Yin Menghan
Published: April 2020

In order to reduce the natural frequency of the piezoelectric vibration energy harvester, improve performance of the piezoelectric vibration energy harvester, and meet the requirements of energy acquisition in the low-frequency vibration environment, a variable-section circular piezoelectric vibration energy harvester is presented. The dynamic model and electromechanical coupling model of variable-section circular piezoelectric vibration energy harvester are established. The main factors affecting the output performance of piezoelectric vibration energy harvester are analyzed. The structure parameters of piezoelectric vibration energy harvester are optimized by orthogonal experiment. An experimental platform is built to test output voltage and output power of piezoelectric vibration energy harvester. The experimental results show that when the number of energy harvester is 4 and the external load is 180KΩ, the parallel output power can reach 0.213mW, which can meet the requirements of micro-power device power supply.
Extreme disruption of heterochromatin is required for accelerated hematopoietic aging
Authors: Keenan Christine R. , Iannarella Nadia , Naselli Gaetano , Bediaga Naiara G. , Johanson Timothy M. , Harrison Leonard C. , Allan Rhys S.
Published: April 2020

Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell types. However, a comprehensive analysis of hematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in hematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on hematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced hematopoietic stem cell function, thymic involution and decreased lymphoid output with a skewing toward myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied by molecular changes consistent with aging, including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the hematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire hematopoietic system from changes associated with premature aging.
SHP-1 regulates Fcγ receptor–mediated phagocytosis and the activation of RAC
Authors: Kant Anita M. , De Pradip , Peng Xiaodong , Yi Taolin , Rawlings David J. , Kim Jong Suk , Durden Donald L.
Published: April 2020

Fcγ receptor–mediated phagocytosis is a complex process involving the activation of protein tyrosine kinases, events that are potentially down-regulated by protein tyrosine phosphatases. We used the J774A.1 macrophage cell line to examine the roles played by the protein tyrosine phosphatase SHP-1 in the negative regulation of Fcγ receptor–mediated phagocytosis. Stimulation with sensitized sheep red blood cells (sRBCs) induced tyrosine phosphorylation of CBL and association of CBL with CRKL. These events were completely or partially abrogated by PP1 or the heterologous expression of dominant-negative SYK, respectively. Heterologous expression of wild-type but not catalytically inactive SHP-1 also completely abrogated the phagocytosis of IgG-sensitized sRBCs. Most notably, overexpressed SHP-1 associates with CBL and this association led to CBL dephosphorylation, loss of the CBL-CRKL interaction, and the suppression of Rac activation. These data represent the first direct evidence that SHP-1 is involved in the regulation of Fcγ receptor–mediated phagocytosis and suggest that activating signals mediated by SRC family kinases SYK, CBL, phosphatidyl inositol-3 (PI-3) kinase, and Rac are directly opposed by inhibitory signals through SHP-1.
The CXCR4 Score: A New Prognostic Marker in Acute Myelogenous Leukemia.
Authors: Spoo Anke C. , Wierda William G. , Burger Jan A.
Published: April 2020

Despite major improvements in the understanding and treatment of certain leukemias during the past years, the overall survival of patients with acute myelogenous leukemia (AML) remains poor and new prognostic markers and therapeutic strategies are urgently needed. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play key roles in retention of hematopoietic cells in the marrow microenvironment and release into the circulation. Rambouts and colleagues recently reported that CXCR4 expression on AML cells correlates with Flt3 mutations and prognosis (Blood 104: 550-57, July 2004). The aim of our study is to evaluate the prognostic significance of CXCR4 surface expression by AML blasts. Ninty newly diagnosed patients with AML were were divided into three groups based on expression of CXCR4 by AML blasts (CXCR4 score A–C). Group A contains patients with a mean fluorescence intensity ratio (MFIR) for CXCR4 <5 (n=32), group B: MFIR 5–10 (n=26), and group C: MFIR >10 (n=32). MFIR was calculated by divding the mean flourescence intensity for CXCR4 by that for the non-specific isotype control of the respective sample and indicates the level of CXCR4 expression. The characteristics for each group are summarized in Table 1.

Previously, we demonstrated that CXCR4 receptors on AML cells mediate adesion and induce migration beneath marrow stromal cells (Burger JA,et al., Br J Haematol. 122: 579–89, August 2003). Because adhesion to stromal elements can affect survival and induce adhesion-mediated drug resistance, antagonists of the CXCR4/SDF-1 axis may increase the efficacy of current treatments. We conclude that CXCR4 expression at time of diagnosis correlates with leukocytosis, LDH, blast persistence after first therapy, relapse rate, and survival. Therfore, CXCR4 expression in AML may be an important progostic factor for complete remission and survival. As such, CXCR4/SDF-1 interaction may provide the basis for a novel therapeutic approach in AML.

Characteristic Score A (N=32) Score B (N=26) Score C (N=32) Median CXCR4 MFIR (range) 2.8 (1.0–4.9) 6.9 (5.1–9.4) 17.2 (10.3–73.4) Median Age (range) 62.0 (21–89) 59.5 (18–80) 65.0 (32–93) Median WBC (range) 2.3 (1.0–14.0) 10.2 (10.2–17) 30.0 (2.7–240) Median PLT (range) 56.0 (8–211) 86.0 (13.6–265) 82.5 (4–218) Median LDH (range) 251.5 (140–2637) 368.0 (187–1489) 357.0 (144–2760) Unfavorable Cytogenetics 4/28 10/24 7/27 blast persistence after first therapy N=6, 22.2% N=13, 65% N=14, 73.7% Relapse Rate 13.8% 52.4% 40% Total Deaths N=7, 21.9% N=13, 50% N=17, 53.1% Mean overall survival (months) 12.4±11.9 10.3±9.8 8.3±7.4 Mean follow-up (months) 12.0±19.7 Median Overall Survival (months) 9.0 (2–52) 6.5 (0–42) 7.0 (0–25) Median follow-up (months) 7.0 (0–52)

Table
Favorable Outcome of High-Risk Mediastinal Diffuse Large B-Cell Lymphoma (DLBCL) after Dose-Intensive Chemotherapy, Rituximab and Autologous Transplant (ASCT).
Authors: Pytlik R. , Kubackova K. , Kozak T. , Belada D. , Pirnos J. , Jankovska M. , Pukyova J. , Papajik T. , Siffnerova H. , Zak P. , Vasova I. , Hamouzova M. , Trneny M.
Published: April 2020

Background. According to the gene expression profiling studies, mediastinal variant of DLBCL is closely related to classical Hodgkins lymphoma (HL). As dose-intensive chemotherapy markedly improves survival in advanced HL, we investigated whether the same is true for high-risk mediastinal DLBCL.

Methods. Since 1998, three studies utilising dose-intensive chemotherapy with ASCT for high-risk DLBCL (aaIPI 2–3) were conducted by Czech Lymphoma Study Group. From 1998–1999, patients were induced with 3–4 cycles of MegaCHOP every 3 weeks (Cyclophosphamide, 3 g/m2 d 1, Vincristin 2 mg d 1, Doxorubicin 75 mg/m2 d 1, Prednison 60 mg/m2 d 1–5, G-CSF 5 ug/kg from day 6) and consolidated with BEAM and ASCT (Protocol 1). From 2000–2002, patients received 3 cycles of MegaCHOP, followed by 3 cycles of ESHAP and BEAM with ASCT (Protocol 2). From 2002, 4–6 doses of Rituximab 375 mg/m2 were added to the previous regimen (Protocol 3). Outcome of patients with mediastinal DLBCL was compared with outcome of other DLBCL patients treated by the same protocols with log-rank test.

Results. 24 patients with mediastinal DLBCL with at least 12 months follow-up were identified. Their median age was 26 years (range, 21–59) and 15 of them were women (62%). 88% of patients had stage IV disease based on extensive pulmonary, pleural or pericardial involvement and 25% of patients had subfrenic disease. LDH was elevated in 88% of cases. Nine patients were aaIPI 2 (38%) and 14 patients aaIPI 3 (58%). Five patients were treated with Protocol 1 (21%), 9 with Protocol 2 (37%) and 10 with Protocol 3 (42%). 22 patients (92%) were successfully mobilized after one of the induction cycles with median 8.03x106 CD34+ cells/kg collected and 21 of them were transplanted as a part of primary treatment (88%). After chemotherapy and ASCT, there were 18 CR (75%) and 4 PR (17%). Twenty patients (84%) were further consolidated by mediastinal radiotherapy because not being in CR or because of bulky disease at diagnosis. Overall, 21 patients achieved CR and one achieved PR at the end of the treatment (ORR, 92%). Two patients progressed on treatment and two other relapsed; three of these were salvaged by additional therapy. After median follow-up of 31 months (12–70), the 3-year FFS is 87% and OS is 95%. Compared with other DLBCL patients, patients with mediastinal DLBCL had significantly better 3-year survival (95% v. 64%, p = 0.007).

Conclusion. Dose-intensive chemotherapy in high-risk mediastinal DLBCL patients leads to equally good results as in advanced Hodgkins lymphoma patients. Further studies are needed with aim to reduce the treatment burden while maintaining the efficacy of the therapy.
Phase 1 Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Concomitant Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine (HDAra-C) Consolidation in Newly Diagnosed Patients with AML.
Authors: Giles Francis , Schiffer C. , Kantarjian H. , Fischer T. , Paquette R. , Pelov D. M. , Resta D. J. , Cohen P. S. , Wang Y. F. , Stone R.
Published: April 2020

The Fms-like tyrosine kinase 3 (FLT3), a receptor expressed in 80% of AML patients, is constitutively activated in 25–35% of adult AML patients due to mutations, in the form of either ITDs or activating loop point mutations, most commonly at D835Y. PKC412 is an oral multi-targeted tyrosine kinase inhibitor known to potently inhibit both activated wild type (WT) and mutated (mut) FLT3 kinase. PKC412 (100 mg po bid) was tested in a phase IB study in newly diagnosed AML patients between 18 and 60 years of age (both WT and mut FLT3) in combinations with DA for induction therapy (up to 2 cycles) and HDAra-C for consolidation (up to 3 cycles).

Study design: PKC412 was given daily beginning on Day 8 (Arm 1) or Day 1 (Arm 2) of induction chemoRX in cycle 1. Primary endpoints were PK, tolerability, and safety as defined by fewer than 2 drug-related deaths in the initial cohort of 6 pts per arm (stage 1) and fewer than 4 drug-related deaths among the total 20 pts per arm (stage 2) during induction.

Results: 15 pts were enrolled (median age 50; 1 FLT3 ITD+, 14 WT; ): 7 in Arm 1 and 8 in Arm 2. Cytogenetic prognostic categories of the 15 patients were: 0 (good), 9 (intermediate) and 6 (bad). Of the 15 pts, 14 were evaluable for toxicity; 1 pt did not receive PKC412; no drug-related deaths were observed during induction therapy. The most common G3 drug-related toxicities included: nausea (46%), vomiting (32%), transaminitis (18%), and hyperbilirubinemia (18%), all were transient and/or reversible. 13/15 patients were evaluable for response: 2 pts were not evaluated: one pt never received PKC412 and one pt did not complete the full-course of induction chemoRx; 3/7 (43%) achieved a CR in Arm 1 and 3/6 (50%) achieved a CR in Arm 2. 3 pts have completed the study (Days 143, 141, 132) and one pt is ongoing (Day 127). Because of the high rate of G3 nausea and vomiting, the study was amended, (5 patients are ongoing) such that PKC412 is given with each cycle of chemoRx on either Days 1–7 and 15–21 (Arm 1), or on Days 8–21 (Arm 2).

Conclusions: PKC412 can be given safely in newly diagnosed AML patients in combinations with DA and HDAra-C chemoRx. An update of this study, along with PK data of PKC412, daunorubicin, and Ara-C levels will be presented.
Possible Relation of Crohn’s Disease and Hereditary Thrombophilia: Detection of ASCA Seropositivity. (Preliminary Results).
Authors: Lazaraki Georgia , Girtovitis Fotios , Dokas Stefanos , Pithara Eleftheria , Tsaousidou Maria , Spartali Aikaterini , Makris Pantelis
Published: April 2020

Introduction: Hereditary thrombophilia (Factor V Leiden mutation -FV G1691A, FVL, FII G20210A -prothrombin mutation), has been reported to be correlated to Crohn’s disease (CD) by some studies. The determination of anti- Saccharomyces Cerevisiae IgA and IgG Antibodies (ASCA) have been described as important serological marker for the differential diagnosis of CD. The aim of the study was to evaluate ASCA seropositivity in a high-risk population (i.e. thrombophilic patients, pts) for CD.

Material-Methods: From April to July 2004, 37 patients (16 men, 21 women, mean age 52,5± 9.6 years old) with hereditary thrombophilia and 28 healthy control subjects (16 men, 12 women, mean age 51,3 ± 8.5 years) were included in the study. Fasting blood samples were drawn from patients and control subjects were examined for serum p-ANCA, ASCA IgA and IgG titers. Pts and control subjects were matched for age, sex and smoking and had to fill a questionnaire concerning history of rectal bleeding, diarrhea lasting longer than 4 weeks, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).Colonoscopy or flexible sigmoidoscopy was proposed to all patients and controls when reported an alarm symptom. ASCA IgA and IgG titers were measured with quantitative enzyme immunoassay method (Medizym ASCA IgG, Medizym ASCA IgA, and MEDIPAN, GERMANY).

Results: In the patient group 8 pts reported IBS symptoms, 2 had history of rectal bleeding while none IBD or chronic diarrhea. In the control group 6 patients reported IBS symptoms while none IBD, rectal bleeding or chronic diarrhea (p>0,05). Ten and 15 pts were found to be positive for ASCA IgG and IgA respectively. In the control group, 6 and 10 subjects were found to be positive for ASCA IgG and IgA respectively (p<0,05 and p<0,1 respectively).

Conclusions: Thrombophilic pts, a high-risk population for CD, present an important rate of ASCA IgG and IgA seropositivity. Although these are preliminary results, thrombophilic pts should be screened for ASCA and some of them with colonoscopy. ASCA seropositivity in the control group was found to be greater than in the literature but this may be explained by the small sample.
A Detailed Phenotypic Analysis Using Six Color Flow Cytometry of Lymphocyte Subsets Mobilized with AMD3100 Compared to G-CSF.
Authors: Takahashi Yoshiyuki , Chakrabarti S. , Sriniivasan R. , Lundqvist A. , Read E.J. , Khuu H. , Leitman S. , Bolan C. , Barrett A.J. , Calandra G. , Childs Richard
Published: April 2020

AMD3100 (AMD) is a bicyclam compound that rapidly mobilizes hematopoietic progenitor cells into circulation by inhibiting stromal cell derived factor-1 binding to its cognate receptor CXCR4 present on CD34+ cells. Preliminary data in healthy donors and cancer patients show large numbers of CD34+ cells are mobilized following a single injection of AMD3100. To determine whether AMD3100 mobilized cells would be suitable for allografting, we performed a detailed phenotypic analysis using 6 color flow cytometry (CYAN Cytometer MLE) of lymphocyte subsets mobilized following the administration of AMD3100, given as a single 240mcg/kg injection either alone (n=4) or in combination with G-CSF (n=2: G-CSF 10 mcg/kg/day x 5: AMD3100 given on day 4). Baseline peripheral blood (PB) was obtained immediately prior to mobilization; in recipients who received both agents, blood was analyzed 4 days following G-CSF administration as well as 12 hours following administration of AMD3100 and a 5th dose of G-CSF. AMD3100 alone significantly increased from baseline the PB WBC count (2.8 fold), Absolute lymphocyte count (ALC: 2.5 fold), absolute monocyte count (AMC: 3.4 fold), and absolute neutrophil count (ANC: 2.8 fold). Subset analysis showed AMD3100 preferentially increased from baseline PB CD34+ progenitor counts (5.8 fold), followed by CD19+ B-cells (3.7 fold), CD14+ monocytes (3.4 fold), CD8+ T-cells (2.5 fold), CD4+ T-cells (1.8 fold), with a smaller increase in CD3−/CD16+ or CD56+ NK cell counts (1.6 fold). There was no change from baseline in the % of CD4+ or CD8+ T-cell expressing CD45RA, CD45RO, or CD56, CD57, CD27, CD71 or HLA-DR. In contrast, there was a decline compared to baseline in the mean percentage of CD3+/CD4+ T-cells expressing CD25 (5.5% vs 14.8%), CD62L (12.1% vs 41.1%), CCR7 (2.1% vs 10.5%) and CXCR4 (0.5% vs 40.9%) after AMD3100 administration; similar declines in expression of the same 4 surface markers were also observed in CD3+/CD8+ T-cells. A synergistic effect on the mobilization of CD34+ progenitors, CD19+ B cells, CD3+ T-cells and CD14+ monocytes occurred when AMD3100 was combined with G-CSF (Figure). In those receiving both AMD3100 and G-CSF, a fall in the % of T-cells expressing CCR7 and CXCR4 occurred 12 hours after the administration of AMD3100 compared to PB collected after 4 days of G-CSF; no other differences in the expression of a variety activation and/or adhesion molecules on T-cell subsets were observed. Whether differences in lymphocyte subsets mobilized with AMD3100 alone or in combination with G-CSF will impact immune reconstitution or other either immune sequela (i.e. GVHD, graft-vs-tumor) associated with allogeneic HCT is currently being assessed in an animal model of allogeneic transplantation.
Are There Potential Predictors for Response to Enoxaparin in the Neonatal Population?.
Authors: McCusker Patricia J. , Punter Fiona A. , Israels Sara J. , Seshia Mary M.K. , Seifert Blair W.
Published: April 2020

The recognition of thromboembolic events (TE) in the pediatric population is increasing. Recently, effort has been directed at determining the correct dosing of low molecular weight heparins necessary to achieve the therapeutic heparin concentration. It has been noted by our group and others that a higher dose of enoxaparin is required for the neonatal population than was originally proposed in the literature. Currently, the reason for this is not understood. Retrospectively, we examined our population of neonates for possible factors that may affect the dose requirements: the presence of sepsis (sepsis is felt to increase the need of heparin by an as yet unknown mechanism), level of antithrombin (AT; it is the protein whose action is accelerated by the presence of heparin and is normally low in the neonate), FVIII (elevated levels >200% have been associated with increased risk of TE) and fibrinogen (an acute phase reactant).

Results: Twenty-five neonates were treated with subcutaneous enoxaparin for venous and arterial TE over a two year period. A total of 84% (21/25), had antithrombin (AT), Factor VIII and fibrinogen levels measured. All AT levels were drawn at the time of diagnosis, prior to initiating enoxaparin. The majority of, but not all, FVIII and fibrinogen levels were drawn at diagnosis. A starting dose of at least 1.6 mg/kg/dose of enoxaparin was received by 18/25 (72%). Therapeutic heparin levels (0.5 –1.0 aXa units/mL) at first measure were achieved in 12/18 (67%) patients. The range of enoxaparin dosages needed to achieve therapeutic heparin levels was 1.42–2.2 mg/kg/dose. The above factors were each compared to the dosage (mg/kg) required to attain a therapeutic heparin concentration. None of these factors appeared to clearly predict for a higher enoxaparin dosage in our population. It is interesting to note that those patients with sepsis seem to need a higher than usual dosage of enoxaparin to achieve a therapeutic heparin level. However, the number of patients in this group is too few to verify this observation.

Conclusions: Higher doses of enoxaparin are needed to treat neonates with TE. We recommend an initial dosage of enoxaparin of 1.65–1.75 mg/kg/dose based on actual body weight for neonates with TE. AT levels at the beginning of therapy, as well as FVIII and fibrinogen levels, are not predictive of the need for higher dosage requirements of low molecular weight heparin in the newborn. A greater number of patients are necessary to substantiate the observation that sepsis may be an important predictor of initial enoxaparin dosage in the neonatal population.
Resolution of Catastrophic Anti Phospholipid Antibody Syndrome with Acute Renal Failure after Treatment with Rituximab.
Authors: Shurafa Muhammad S. , Babbar Nidhika , Khairullah Quresh
Published: April 2020

Antiphospholipid antibody syndrome (APS) is a thrombophilic disorder defined by the presence of recurrent thrombosis associated with anticardiolipin antibodies (ACA). To date, there is no effdective therapy for this condition. Rituximab, a chimeric monoclonal antibody B Cells has been shown to be effective in autoimmune disorders. Sporadic abstracts have reported the disappearance of ACA after Rituximab treatment. We have successfully treated a patient with primary catastrophic APS and renal failure with Rituximab. Case Report: A thirty seven year old male with history of DVT, ischemic cardiomyopathy and cerebrovascular accident was admitted to the Hospital for the treatment of acute renal failure and thrombocytopenia. Physical examination was significant for cognitive deficits, mild hepatomegaly, generalized livido reticulairs, and acrocyanosis. Laboratory data revealed platelet count of 97000, creatinine 3.4 mg/dl, IgG ACA titer of 43.8 and negative IgM ACA and ANA. He had proteinuria with benign urinary sediment. Kidney biopsy showed thrombotic microangiopathy. Plasmaphersis was initiated and hemodialysis for the rapidly progressing renal failure. He continued his treatment in an outpatient hemodialysis unit while on Coumadin. Four weekly cycles of Rituximab were given as an outpatient. Serial laboratory investigations showed gradual normalization of the platelet count and disappearance of the IgG ACA. Gradually renal function recovered and hemodialysis was discontinued after three months. He remains in remission with no further thrombotic events.Conclusion: Rituximab is promising in the treatment of APS and must be considered in the first;line treatment of catastrophic APS. A clinical trial is necessary to test the feasibility of discontinuing anticoagulation in these patients.

PERTINENT LABORATORY DATA

DATE HEMOGLOBIN PLATELETS CREATININE ACA TITER 03/21/02 1.4 11/15/03 14.4 97 3.4 11/21/03 12.5 100 6.2 43.8 12/01/03 12.2 222 ON DIALYSIS 16.1 01/01/04 14.1 276 ON DIALYSIS 20.9 03/17/04 14.1 276 ON DIALYSIS 05/05/04 11.3 330 3.3 NEGATIVE