bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression
Authors: Bowen Cai , Ostrowski Michael C. , Leone Gustavo , Gelmann Edward P.
Published: June 2019

NKX3.1 is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme–substrate interaction. An effect of PTEN on Nkx3.1 gene transcription was seen in vitro, but not in vivo. In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation in vivo. In these mice, Nkx3.1 mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression.

Significance:

PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy
Authors: Kumar Rakesh , de Vijver Marc Van , Tortora Giampaolo , Ciardiello Fortunato , Goldkorn Tzipora , Miller Wilson H. , Norton Larry
Published: June 2019

Cancer scientists and clinicians are mourning the death of one of the most accomplished members of their community: Dr. John Mendelsohn. He was a pioneer in targeted cancer therapy and was instrumental for the discovery and deployment of the first antagonist epidermal growth factor receptor (EGFR) therapeutic antibodies, broadening the concept of targeted EGFR therapy to encompass other receptor tyrosine kinases, such as HER2, and developing blocking antibody-combination therapy with chemotherapies or radiotherapy. Dr. Mendelsohn, who died on January 7, 2019, always led by the strength of his accomplishments and the humility of his character. Above all, he was a well-revered mentor and clinician, who extended compassion and the gift of his time to patients, colleagues, and mentees alike. In tribute to Dr. Mendelsohn, Cancer Research has invited his former mentees and colleagues who were associated with Dr. Mendelsohn for over three decades to reflect on the broad impact of his work. Here, we discuss Dr. Mendelsohn's illustrious career at three elite academic cancer institutions and hospitals in the United States, his acumen to build, grow, and uplift institutions, and train a generation of medical oncologists, physician scientists, and cancer biologists. His profound legacy on targeted therapy and cancer research and treatment continue to prolong and save the lives of cancer patients globally.
Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation
Authors: Jaeger Alex M. , Stopfer Lauren , Lee Sunmin , Gaglia Giorgio , Sandel Demi , Santagata Sandro , Lin Nancy U. , Trepel Jane B. , White Forest , Jacks Tyler , Lindquist Susan , Whitesell Luke
Published: June 2019

Purpose:

Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as “foreign” and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.

Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.

Results:

We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock–inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.

Conclusions:

These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.

See related commentary by Srivastava and Callahan, p. 6277
Association of Human Papillomavirus Genotype 16 Viral Variant and Viral Load with Cervical High-grade Intraepithelial Lesions
Authors: Álvarez-Paredes Ledicia , Santibañez Miguel , Galiana Antonio , Rodríguez Díaz Juan Carlos , Parás-Bravo Paula , Andrada-Becerra Mª Encarnación , Ruiz García María Montserrat , Rodríguez-Ingelmo José María , Portilla-Sogorb Joaquín , Paz-Zulueta María
Published: June 2019

Human papillomavirus genotype 16 (HPV16) is by far the genotype most strongly associated with cervical cancer; viral variant and/or viral load of HPV16 could modulate this association. The objective was to determine the association between the viral variant and viral load of HPV16 and the presence of cervical high-grade lesions. This cross-sectional study included all women in whom HPV infection was found by cervical smear during routine gynecologic health checks. Women with single or multiple HPV16 infections (n = 176) were selected for viral variant and viral load analysis. Smear results were classified using the Bethesda system. HPV types were classified according to the International Agency for Research on Cancer. Odds ratios (OR) with their 95% confidence intervals (CI) were estimated by logistic regression, adjusted for age, immigrant status, and coinfection with other high-risk genotypes. No statistically significant associations were found regarding the detected viral variants. A viral load above the median (>1,367.79 copies/cell) was associated with a significant risk of high-grade epithelial lesion or carcinoma, after adjusting for age, immigrant status, coinfections, and viral variant: (adjusted OR 7.89; 95% CI: 2.75–22.68). This relationship showed a statistically significant dose–response pattern after categorizing by viral load tertiles: adjusted OR for a viral load greater than the third tertile was 17.23 (95% CI: 4.20–70.65), with adjusted linear Ptrend = 0.001. In patients infected with HPV16, viral load is associated with high-grade intraepithelial lesions or cervical carcinoma. This could be useful as prognostic biomarker of neoplastic progression and as screening for cervical cancer.
Prostate Stem Cell Antigen Gene Polymorphism Is Associated with H. pylori–related Promoter DNA Methylation in Nonneoplastic Gastric Epithelium
Authors: Tahara Tomomitsu , Tahara Sayumi , Horiguchi Noriyuki , Kato Takema , Shinkai Yasuko , Okubo Masaaki , Terada Tsuyoshi , Yoshida Dai , Funasaka Kohei , Nagasaka Mitsuo , Nakagawa Yoshihito , Kurahashi Hiroki , Shibata Tomoyuki , Tsukamoto Tetsuya , Ohmiya Naoki
Published: June 2019

Genome-wide association study identified two functional SNPs associated with gastric cancer especially the diffuse type. The first was a polymorphism (rs2294008) in prostate stem cell antigen (PSCA), and the other was a polymorphism (rs4072037) in mucin 1 (MUC1). DNA methylation is associated with gastric cancer and Helicobacter pylori (H. pylori)-induced gastritis, while hypermethylation of promoter CpG island (CGI) is a common characteristic of enlarged-fold gastritis induced by H. pylori, a risk factor of diffuse-type gastric cancer. We evaluated the association between PSCA and MUC1 polymorphisms with H. pylori--related promoter CGI methylation in the nonneoplastic gastric mucosa. PSCA rs2294008 C/T and MUC1 rs4072037 A/G polymorphisms were genotyped in 410 cancer-free subjects in relation to promoter CGI methylation status of three candidate genes, of which the methylation status is associated with H. pylori infection (IGF2, MYOD1, and SLC16A12). Methylation levels of all three genes were significantly higher in subjects with PSCA rs2294008 T/T compared with the PSCA rs2294008 C/C (all P < 0.05). Such associations were more enhanced in H. pylori–positive subjects (all P < 0.01). The multivariate analysis demonstrated that PSCA C/T [OR, 2.37; 95% CI (confidence interval), 1.06–5.29; P = 0.035] and T/T genotypes (OR, 3.2; 95% CI, 1.41–7.25; P = 0.005) were significantly associated with methylation-high gastric mucosa as independent factors. MUC1 rs4072037 A/G polymorphism was not associated with methylation status of all three genes. PSCA C/T and T/T genotypes are associated with H. pylori–related promoter DNA methylation in the gastric mucosa.

Impact: Our observations provided the evidence that PSCA polymorphism influence the susceptibility to gastric cancer through DNA methylation induction.
Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses
Authors: Abd Hamid Megat , Wang Ruo-Zheng , Yao Xuan , Fan Peiwen , Li Xi , Chang Xue-Mei , Feng Yaning , Jones Stephanie , Maldonado-Perez David , Waugh Craig , Verrill Clare , Simmons Alison , Cerundolo Vincenzo , McMichael Andrew , Conlon Christopher , Wang Xiyan , Peng Yanchun , Dong Tao
Published: June 2019

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo. Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.
Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development
Authors: Gui Xun , Deng Mi , Song Hao , Chen Yuanzhi , Xie Jingjing , Li Zunling , He Licai , Huang Fangfang , Xu Yixiang , Anami Yasuaki , Yu Hai , Yu Chenyi , Li Leike , Yuan Zihao , Xu Xiaoying , Wang Qihui , Chai Yan , Huang Tao , Shi Yi , Tsuchikama Kyoji , Liao X. Charlene , Xia Ningshao , Gao George F. , Zhang Ningyan , Zhang Cheng Cheng , An Zhiqiang
Published: June 2019

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.
Ectopic Origin of the Left Anterior Descending Artery from the Proximal Right Coronary Artery: An Imaging Report
Authors: Tripolino Cesare , Tassone Eliezer Joseph , Morabito Gaetano , Grillo Placido , Montesanti Gabriella , Missiroli Bindo
Published: June 2019

Anomalies of the coronary arteries represent rare congenital disorders, which are characterized by a wide spectrum of clinical manifestations. Usually, they are asymptomatic, but sometimes they cause myocardial ischemia or sudden cardiac death. Here, we describe the case of a patient who suffered from angina. Coronary angiography revealed an ectopic origin of the left anterior descending coronary artery from the proximal trait of the right coronary artery and the left circumflex artery, originating from the left sinus; the whole coronary tree was free of atherosclerosis. To better define the coronary anatomy, we performed computed tomography angiography with a three-dimensional reconstruction. The patient was discharged from the clinic after 48 h under optimal medical treatment.
Longer 6-mm Diameter Stent Retrievers Are Effective for Achieving Higher First Pass Success with Fibrin-Rich Clots
Authors: Girdhar Gaurav , Epstein Evan , Nguyen Kevin , Gregg Chelsea , Kumar Tejashri , Wainwright John , Liu Amon Y. , Linfante Italo
Published: June 2019

First pass success (FPS) can be defined as in vitro retrieval of clot in a single pass during mechanical thrombectomy (MT) for acute large vessel occlusion (LVO). Despite advancements in MT technology, retrieval of fibrin-rich clots remains a challenge. Therefore, the effect of stent retriever length on FPS for fibrin-rich clots was investigated by using SolitaireTM 6 × 40 versus 6 × 30 mm devices with a balloon guide catheter (BGC) or distal access catheter (DAC) and sheath, in an in vitro model of anterior circulation neurovascular anatomy. Additionally, vascular safety of the SolitaireTM 6 × 40 versus 6 × 30 mm devices was evaluated in a porcine model for differences in: luminal thrombus, inflammation, endothelial coverage, fibrin deposits, smooth muscle cell loss, elastic lamina and adventitia disruption, intimal hyperplasia, and lumen reduction, at 0, 30, and 90 days post-treatment. In vitro overall FPS was measured as: SolitaireTM 6 × 40 (95%) and SolitaireTM 6 × 30 (67%). FPS for clot location in middle cerebral artery was: (a) BGC (6 × 40 mm: 100%; 6 × 30 mm: 100%; n = 8); (b) DAC with 088 sheath (6 × 40 mm: 83%; 6 × 30 mm: 33%; n = 12). FPS for clot location in internal carotid artery was: (a) BGC (6 × 40 mm: 100%; 6 × 30 mm: 80%; n = 11); (b) DAC with 088 sheath (6 × 40 mm: 100%; 6 × 30 mm: 67%; n = 10). Stent length had a significant effect (Fisher’s exact test; p < 0.05) on FPS. In vivo evaluation in the porcine model showed no difference in vascular safety parameters between the SolitaireTM 6 × 40 and 6 × 30 mm devices (p > 0.05) at all time points in the study. Longer stent retrievers may be safe and effective in improving FPS for fibrin-rich clots in in vitro and in vivo models of LVO.
The Supraoptic Nucleus of the Hypothalamus Modulates Autonomic, Neuroendocrine, and Behavioral Responses to Acute Restraint Stress in Rats
Authors: Lopes-Azevedo Silvana , Fortaleza Eduardo Albino Trindade , Busnardo Cristiane , Scopinho América Augusto , Matthiesen Melina , Antunes-Rodrigues José , Corrêa Fernando Morgan Aguiar
Published: June 2019

Aims: Acute restraint stress (RS) has been reported to cause neuronal activation in the supraoptic nucleus of the hypothalamus (SON). The aim of the study was to evaluate the role of SON on autonomic (mean arterial pressure [MAP], heart rate [HR], and tail temperature), neuroendocrine (corticosterone, oxytocin, and vasopressin plasma levels), and behavioral responses to RS. Methods: Guide cannulas were implanted bilaterally in the SON of male Wistar rats for microinjection of the unspecific synaptic blocker cobalt chloride (CoCl2, 1 mM) or vehicle (artificial cerebrospinal fluid, 100 nL). A catheter was introduced into the femoral artery for MAP and HR recording. Rats were subjected to RS, and it was studied the effect of microinjection of CoCl2 or vehicle into the SON on pressor and tachycardic responses, drop in tail temperature, plasma oxytocin, vasopressin, and corticosterone levels, and anxiogenic-like effect induced by RS. Results: SON pretreatment with CoCl2 reduced the RS-induced MAP and HR increase, without affecting the RS-evoked tail temperature decrease. Microinjection of CoCl2 into areas surrounding the SON did not affect RS-induced increase in MAP and HR, reinforcing the idea that SON influences RS-evoked cardiovascular responses. Also, SON pretreatment with CoCl2 reduced RS-induced increase in corticosterone and oxytocin, without affecting vasopressin plasma levels, suggesting its involvement in RS-induced neuroendocrine responses. Finally, the CoCl2 microinjection into SON inhibited the RS-caused delayed anxiogenic-like effect. Conclusion: The results indicate that SON is an important component of the neural pathway that controls autonomic, neuroendocrine, and behavioral responses induced by RS.
Novel and Recurring NOTCH3 Mutations in Two Chinese Patients with CADASIL
Authors: Chen Xiangyu , Deng Sheng , Xu Hongbo , Hou Deren , Hu Pengzhi , Yang Yan , Wen Jie , Deng Hao , Yuan Lamei
Published: June 2019

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant, inherited, systemic, vascular disorder primarily involving the small arteries. It is characterized by migraine, recurrent ischemic strokes, cognitive decline, and dementia. Mutations in the Notch receptor 3 gene (NOTCH3) and the HtrA serine peptidase 1 gene (HTRA1) are 2 genetic causes for CADASIL. The NOTCH3 gene, located on chromosome 19p13.12, is the most common disease-causing gene in CADASIL. Objective: To investigate genetic causes in 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL. Methods: Exome sequencing was performed on both patients and potential pathogenic mutations were validated by Sanger sequencing. Results: This study reports on 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL, identifying that NOTCH3 mutations were the genetic cause. A common mutation, c.268C>T (p.Arg90Cys), and a novel mutation, c.331G>T (p.Gly111Cys) in the NOTCH3 gene, were detected and confirmed in the patients, respectively, and were predicted to be deleterious based on bioinformation analyses. Conclusions: We identified 2 NOTCH3 mutations as likely genetic causes for CADASIL in these 2 patients. Our findings broaden the mutational spectrum of the NOTCH3 gene accountable for CADASIL. Clinical manifestations supplemented with molecular genetic analyses are critical for accurate diagnosis, the provision of genetic counseling, and the development of therapies for CADASIL.
Clinical Considerations in Physician-Assisted Death for Probable Alzheimer’s Disease: Decision-Making Capacity, Anosognosia, and Suffering
Authors: Mondragón Jaime D. , Salame Latife , Kraus Arnoldo , De Deyn Peter Paul
Published: June 2019

Background: Requests for physician-assisted death (PAD) in patients with cognitive impairment are complex and require careful consideration. Of particular difficulty is determination of whether the request is voluntary and well considered. Results: Euthanasia and physician-assisted suicide (PAS) are both legal in The Netherlands, Luxemburg, Colombia, and Canada. Euthanasia is legal in Belgium, while PAS is legal in Switzerland and Oregon, Washington, Montana, Vermont, and California (USA). Upon a PAD request, evaluation of the capacity to consent medical treatment is relevant for the decision-making process, while evaluation of testamentary capacity is appropriate before an advance euthanasia directive is written. Anosognosia assessment throughout the Alzheimer’s disease continuum provides essential and relevant information regarding the voluntary and well-considered nature of the PAD request; meanwhile, early assessment of hypernosognosia or subjective cognitive decline assists in formulation of a clinical prognosis. Furthermore, the assessment of physical and psychological suffering should incorporate verbal and nonverbal cues as well as consideration of the psychosocial factors that might affect due care criteria. Conclusion: The clinical approach to a PAD request should consider the legal framework and the decision-making capacity, assess memory deficit awareness and the perception of suffering, and evaluate mental competency when considered pertinent.
Histopathologic Patterns of Recurrent Choroidal Melanoma Following I-125 Plaque Brachytherapy
Authors: Echegaray Jose J. , Plesec Thomas , Bellerive Claudine , Singh Arun D.
Published: June 2019

Purpose: Histologic correlation of clinical patterns of recurrent choroidal melanoma following I-125 plaque brachytherapy was performed to identify pathologic mechanisms of recurrence. Methods: We reviewed 7 cases of recurrent choroidal melanoma following I-125 plaque brachytherapy managed with enucleation. Clinical characteristics included tumor dimensions, radiation dose, time to local recurrence, and clinical pattern of recurrence. Histopathology (hematoxylin and eosin and periodic acid – Schiff) and immunohistochemistry (Ki-67, CD-163, HMB45, and SOX10) were performed. Results: Mean follow-up time and time to local recurrence were 42 and 21 months after brachytherapy, respectively. Tumor recurrences were described clinically as marginal in 43%, diffuse in 29%, and extraocular extension (EOE) in 29%. Eighty-six percent were classified as mixed cell type and 14% were epithelioid type. Tumor zonation (histologic demarcation between zones of recurrent and nonrecurrent tumor cells by immunohistochemistry) was present in marginal and EOE cases (n = 6) and absent in the diffuse cases (n = 2). Ki-67 proliferative index was higher in marginal and EOE recurrences, while diffuse cases showed uniform ­Ki-67 staining. CD-163 staining was found to be greater in nonrecurrent tumor. HMB45 correlated with SOX10 with a greater staining in recurrent tumor. Conclusion: Our observations provide a correlation between histopathologic and clinical patterns of local recurrence of choroidal melanoma after brachytherapy.
Evaluation and Disposition of Fetal Myelomeningocele Repair Candidates: A Large Referral Center Experience
Authors: Pan Evelyn T. , Pallapati Joana , Krueger Angel , Yepez Mayel , VanLoh Sarah , Nassr Ahmed A. , Espinoza Jimmy , Shamshirsaz Alireza A. , Olutoye Oluyinka O. , Mehollin-Ray Amy , de Jong Hester , Castillo Heidi , Castillo Jonathan , Whitehead William E. , Olutoye Olutoyin A. , Ayres Nancy , Belfort Michael A. , Sanz Cortes Magdalena
Published: June 2019

Background: Fetal myelomeningocele (fMMC) repair yields superior outcomes to postnatal repair and is increasingly offered at select fetal centers. Objectives: To report the fMMC referral process from initial referral to evaluation and surgical intervention in a large fetal referral center. Methods: We conducted a retrospective cohort study of patients referred to Texas Children’s Fetal Center for fMMC between September 2013 and January 2018, reviewing the process from referral to final disposition. The stepwise evaluation included a phone interview followed by multidisciplinary consultation at our fetal center. We modified the Management of Myelomeningocele Study inclusion and exclusion criteria to allow a maternal body mass index of 35–40 on an individual basis. Results: A total of 204 referrals were contacted for a phone interview; 175 (86%) pursued outpatient evaluation, and 80 (46%) of them qualified for repair. Among the eligible patients, 37 (46%) underwent fetoscopic repair, 20 (25%) underwent open repair, and 17 (21%) declined prenatal surgery. Of the 89 noneligible patients (53%) excluded upon outpatient evaluation, 64 (72%) were excluded for fetal and 17 (19%) for maternal reasons. No hindbrain herniation (16%) and maternal BMI and/or hypertension (5%) were the most common reasons for fetal and maternal exclusion, respectively. A total of 31% of our referral population underwent fetal surgery. Conclusions: A small percentage of fMMC referrals ultimately undergo prenatal surgery. Stepwise evaluation and multidisciplinary teams are key to the success of large referral programs.
The Association of Circulating T Follicular Helper Cells and Regulatory Cells with Acute Myeloid Leukemia Patients
Authors: Guo Zhenxing , Chen Zhenping , Xu Yaru , Zhang Yu , Hu Liangding , Yu Fan , Chai Junyue , Liu Li , Ren Xiuhong
Published: June 2019

Objective: This study aims to investigate the association of circulating T follicular helper (cTfh) cells and T follicular regulatory (cTfr) cells with acute myeloid leukemia (AML) patients. Methods: A total of 22 newly diagnosed, untreated AML patients as well as 26 healthy controls were enrolled. Percentages of cTfh and cTfr cells were detected using flow cytometry. Results: Compared to healthy controls, a significantly higher percentage of cTfr cells was observed in AML patients (4.10 ± 11.18 vs. 0.63 ± 0.38%) (p < 0.05). In addition, a significantly lower cTfh/cTfr ratio was found in the AML patients’ group when compared to the control group (9.04 ± 9.19 vs. 11.66 ± 5.68) (p < 0.05). A lower level of plasma IL-2 and TGF-β1 was found in AML patients. Based on the complete remission (CR) response after one cycle of inductive chemotherapy, patients were divided into two groups at sample collection: AML with and without CR. Significantly lower percentages of cTfr cells and a higher cTfh/cTfr ratio were found in the group of AML patients with CR than in the AML patients without CR. Conclusion: There was a significantly higher percentage of cTfr cells in AML patients. cTfr cells may have a potential association with the pathogenesis of AML patients.
Advance Care Planning for People with Dementia: The Role of General Practitioners
Authors: Bally Klaus W. , Krones Tanja , Jox Ralf J.
Published: June 2019

General practitioners (GPs) play a key role in the timely diagnosis of dementia and also in advance care planning (ACP). They often have known patients and their families for decades and are familiar with their values and treatment preferences; they are, therefore, in a position to initiate the ACP process even before the appearance of the first symptoms of dementia and certainly following disclosure of the diagnosis. To do so, they should recognise whether patients are receptive to an ACP consultation or whether they might reject it for personal, social or cultural reasons. Under no circumstances should the patient or their family be coerced into making these provisions. In most countries, the current framework does not provide enough time and money for GPs to carry out actual ACP consultations completely on their own. There is evidence that specially trained health professionals are able to more effectively discuss treatment goals and limits of life-prolonging measures than GPs who are well acquainted with their patients. Consequently, we suggest that it will be the GPs’ task to seize the right moment for starting an ACP process, to raise awareness of patients and their relatives about ACP, to test the patient’s decision-making capacity and, finally, to involve appropriately trained healthcare professionals in the actual ACP consultation process. Care should be taken that these professionals delivering time-intensive ACP consultations are not only able to reflect on the patient’s values but are also familiar with the course of the disease, the expected complications and the decisions that can be anticipated. The GP will ensure an active exchange with the ACP professional and should have access to the documentation drawn up in the ACP consultation process (treatment plan and advance directive including instructions for medical emergencies) as soon as possible. GPs as coordinators of healthcare provision should document appropriately all specialists involved in the care and ensure that treatment decisions are implemented in accordance with the patient’s preferences for future care or the presumed will of the patient.
Outcomes after Thrombectomy in Belfast: Mothership and Drip-and-Ship in the Real World
Authors: Adams Karen M. , Burns Paul A. , Hunter Annemarie , Rennie Ian , Flynn Peter A. , Smyth Graham , Gordon Patricia L. , Patterson Cathy E. , Fearon Patricia , Kerr Enda L.F. , Wiggam M. Ivan
Published: June 2019

Background: Mechanical thrombectomy has revolutionised the treatment of acute ischaemic stroke due to large vessel occlusion. It is well recognised that patients are more likely to benefit when reperfusion happens quickly, however, there is uncertainty as to how best to deliver this service. Objectives: To compare outcomes of patients in Northern ­Ireland who underwent thrombectomy via direct admission to the single endovascular centre (mothership [MS]) with those transferred from primary stroke centres (drip-and-ship [DS]). Methods: Analysis was conducted on the records of all patients who underwent thrombectomy from January 2014 to December 2017 inclusive. The primary outcome measure was 3 months functional independence (modified Rankin Score [mRS] 0–2). Secondary outcome measures were full recovery (mRS 0) at 3 months, symptomatic intracranial haemorrhage (sICH) rates and mortality rates. Results: Two hundred fourteen patients underwent thrombectomy (MS 124, DS 90). Patients in the MS group were older (median 73 vs. 70 years, p = 0.026), but there was no significant difference in baseline National Institutes of Health Stroke Scale (median 15 MS vs. 16.5 DS, p = 0.162) or thrombolysis rates (41.9% MS vs. 54.4% DS, p = 0.070) between the groups. Time from stroke onset to arrival at thrombectomy centre was shorter in the MS group (median 71 vs. 218 min, p < 0.001) but door to groin puncture time was shorter in the DS group (median 30 vs. 60 min, p < 0.001). There was no significant difference in 3 months functional independence (51.6% MS vs. 62.2% DS, p = 0.123), or in the secondary outcome measures of full recovery (21.8% MS vs. 12.2% DS, p = 0.071), sICH (MS 0.8%, DS 4.4%, p = 0.082) and mortality (MS 24.2%, DS 20.0%, p = 0.468). Conclusions: Our analysis showed similar outcomes after thrombectomy in the MS and DS groups. For patients potentially eligible for thrombectomy, rapid access to the endovascular centre is essential to optimise both the number of patients treated and the outcomes achieved.
The Predictive Value of Ischemia-Modified Albumin in Renal Ischemia-Reperfusion Injury
Authors: Aytac Ates Huseyin , Yücetaş Uğur , Erkan Erkan , Yucetas Esma , Ulusoy Soner , Kadihasanoglu Mustafa , Behzatoglu Kemal , Culha Mehmet Gokhan , Toktas Mahmut Gokhan
Published: June 2019

Objectives: The aim of the study is to investigate the predictive value of ischemia-modified albumin (IMA) as an oxidative stress indicator in renal ischemia-reperfusion (I/R) injury. Methods: Forty female Wistar Albino rats were divided into 5 groups: Group-1, sham; group-2, 20 min I/R, group-3, 30 min I/R; group-4, 40 min I/R; and group-5, 60 min I/R. Blood samples were taken, and nephrectomy was performed in the sham group before ischemia was induced. At the end of the defined periods for each group, reperfusion was achieved and a blood sample was taken and nephrectomy was performed. At the end of the 6-hour reperfusion period, the blood sample was taken again and the other kidney is removed. IMA in serum and total anti-oxidant status (TAS), total oxidant status (TOS), and oxidative stress index in both serum and tissue were examined. Results: Serum IMA values were significantly different between the groups (p = 0.009), and there was a significantly difference in TOS values between ischemic serum (p = 0.024) and tissue samples (p = 0.02). However, there was no significant difference in serum and tissue TAS values after ischemia (p = 0.9). Serum IMA, TOS and TAS and tissue TOS and TAS values after reperfusion were not significantly different. There was a significant correlation between tubular damage and ischemia duration in histopathological examination of renal tissue after I/R (p < 0.0001). Conclusion: Serum IMA values increased in parallel with the duration of ischemia, and this increase was supported by histopathological damage findings.
Objective Monitoring of Driving Behavior in Parkinson’s Disease: The Utility of the Chula Parkinson Car®
Authors: Phokaewvarangkul Onanong , Krootjohn Soradech , Yanthitirat Panamet , Anan Chanawat , Bhidayasiri Roongroj
Published: June 2019

Introduction: Driving competency is important to evaluate among individuals with Parkinson’s disease (PD). Driving in natural situations is the preferred assessment method; thus, we used a naturalistic driving environment to identify driving competency among individuals with PD in comparison to healthy age-matched controls. Methods: Based on a power analysis, we recruited 20 participants (10 with PD and 10 healthy age-matched controls). Each participant completed 3 tasks while driving the ChulaPD car, a 4-door sedan installed with computerized monitoring systems. The tasks were forward and backward vehicle movement, reversing into a parking space, and parking parallel to a sidewalk. Trip start and end times, vehicle speed, and acceleration and deceleration times were logged using steering wheel motion, location parking sensors, and dashboard cameras and compared between groups. Results: Age, gender, possession of a driver’s license, present driving conditions, Thai Mini-Mental State Examination score, and driving experience did not significantly differ between groups. However, the PD group took longer to complete the driving tests (p = 0.002), had slower vehicle speeds (p = 0.002), longer brake times (p = 0.007), and decreased brake pressure ability (p = 0.009). Under normalized conditions, the ratio of failed driver’s license tests was also higher among the PD group than in the control group (70 vs. 10%, p = 0.006). Conclusions: Individuals with PD had less-than-adequate driving ability based on our naturalistic setting. Our assessment method may be useful in other populations with chronic illnesses or for older adults. We discuss how naturalistic assessments could become the standard for evaluating driving ability in Thailand and elsewhere.
Cirrhosis Is a Predictor of Adverse Events in Endoscopic Ultrasound Fine-Needle Aspiration: A Propensity-Score Analysis
Authors: Facciorusso Antonio , Buccino Vincenzo Rosario , Del Prete Valentina , Antonino Matteo , Muscatiello Nicola
Published: June 2019

Background: Cirrhotic patients are at increased risk of adverse events (AEs) after invasive procedures. However, the safety profile of endoscopic ultrasound (EUS) fine-needle aspiration in cirrhotic patients is still unknown. Objectives: To examine the AEs rate after EUS fine-needle aspiration in cirrhotic patients as compared to a control group of noncirrhotic patients. Methods: Out of 735 patients with suspected abdominal lesions referred to our center between 2006 and 2018, after propensity-score matching, 2 groups were compared: 95 cirrhotics and 95 controls. Primary variables included rate of overall and serious AEs. Secondary endpoint was incidence of acute-on-chronic liver failure. Results: Median age was 64 years, and pancreatic lesions represented the sampled tissue in 57 patients (60%) in each group (p = 1.0) with mean size of 22 mm in both cohorts (p = 0.3). Overall, 20 AEs (21%) of which 9 serious (9.4%) were observed in cirrhotic patients and 3 (3.1%) mild events were experienced by noncirrhotic subjects. Only liver cirrhosis was confirmed as a significant predictor of AEs in multivariate analysis (OR 8.11, 2.34–28; p = 0.001). Overall rate of infections was 6/95 (6.3%), of which 4 were serious (4.2%) in cirrhotics and 1/95 (1%) in the control group (p = 0.05). All serious infections led to the occurrence of acute-on-chronic liver failure. Minor bleeding events were more frequent in cirrhotic patients (4.2 vs. 0%; p = 0.04). Conclusions: The rate of AEs after EUS fine-needle aspiration is higher in cirrhotic patients, and acute-on-chronic liver failure may represent a serious complication of this procedure.
Effect of substrate placement in schott vial to hematite properties
Authors: Wan Ahmad Wan Rosmaria , Mamat M. H. , Zoolfakar A. S. , Khusaimi Z. , Ismail A. S. , Yaakub T. N. T. , Rusop M.
Published: June 2019

In the present study, hematite (α-Fe2O3) nanostructures were deposited on fluorine doped tin oxide (FTO) coated glass substrate using sonicated immersion synthesis method. The effect of FTO glass substrate placement in Schott vial during immersion process was studied on the growth of the hematite nanostructure and its properties. XRD pattern has revealed seven diffraction peaks of α-Fe2O3 for both hematite nanostructures samples attributed to polycrystalline with rhombohedral lattice structure. The surface morphologies from FESEM have shown that the hematite nanostructures were grown uniformly in both samples with FTO conductive layer facing up and down. Hematite sample with FTO facing down exhibits a smaller size of nanorod, 26.7 nm average diameter, compared to the hematite sample that FTO face up with 53.8nm average diameter. Optical properties revealed higher transmittance in the sample with FTO facing down, probably due to smaller size of nanostructure. The optical band gap energy plotted and extrapolated at 2.50eV and 2.55eV for FTO face up and FTO face down hematite samples respectively, presenting the sample with FTO face up has a lower optical bandgap energy.
Performance comparison of automatic peak detection for signal analyser
Authors: Jun Teh Yi , Jambek Asral Bahari , Hashim Uda
Published: June 2019

The aim of this paper is to propose a new peak detection method for a portable device, which know as modified automatic threshold peak detection (M-ATPD). M-ATPD evolves out of ATPD with a focus on reducing computational time. The proposed method replaces the clustering threshold calculation in ATPD with a standard deviation threshold calculation. M-ATPD reduces computational time by 2 times faster compared to ATPD for control signal and 8.65 times faster compared to ATPD for raw biosignals. Modified ATPD also shows a slight improvement in terms of detection error, with a decrease of about 6.66% to 13.33% in peak detection of noise signals. Modified ATPD successfully fixes the error of peak detection on pulse control signals associated with ATPD.  For raw biosignals, in total M-ATPD achieved 19.41% lower detection error compare to ATPD.
High-gain PDMS-magnetite zero refractive index metamaterial antenna for Vehicle-to-Vehicle communications
Authors: Md. Jizat Noorlindawaty , Ahmad Nazihah , Yusoff Zubaida , Jamlos Mohd Faizal
Published: June 2019

This paper presents the simulation design of a high-gain antenna using zero refractive index fishnet metamaterial (MTM) perforated on PDMS-Magnetite substrate for Vehicle-to-Vehicle (V2V) communications. In order to design the MTM, magnetite nanoparticles, 10-nm iron oxide (Fe3O4) are dispersed into polydimethylsiloxane (PDMS) matrix. Subsequently, the unit cell is designed by removing the circular hole with radius of 3.69 mm on the PDMS-Magnetite substrate layer and arranged in 5×5 array fishnet configuration. This optimized MTM is inserted between the antenna design and pure PDMS substrate to improve the gain. The characteristic of the respective unit-cell is investigated to operate at 5.9 GHz and the effectiveness of MTM is performed by comparing the antenna performance with and without MTM. The unique characteristics of zero refractive index transform the diverging wave into plane wave for perfectly parallel wave impact on the design to improve the directivity and gain of the antenna. The proposed MTM into design improves the antenna gain to 7.36 dB without having to compromise other antenna parameters of return loss, Voltage Standing Wave Ratio (VSWR), gain, directivity, efficiency, current distribution, radiation pattern and bandwidth. These advantages has made proposed antenna as a suitable candidate for V2V in Dedicated Short Range Communication (DSRC) application since high-gain directional antenna is required to increase the sensitivity towards signals coming from certain direction.
Motor imagery classification in Brain computer interface (BCI) based on EEG signal by using machine learning technique
Authors: Md Isa N. E. , Amir A. , Ilyas M. Z. , Razalli M. S.
Published: June 2019

This paper focuses on classification of motor imagery in Brain Computer Interface (BCI) by using classifiers from machine learning technique. The BCI system consists of two main steps which are feature extraction and classification. The Fast Fourier Transform (FFT) features is extracted from the electroencephalography (EEG) signals to transform the signals into frequency domain. Due to the high dimensionality of data resulting from the feature extraction stage, the Linear Discriminant Analysis (LDA) is used to minimize the number of dimension by finding the feature subspace that optimizes class separability. Five classifiers: Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Naïve Bayes, Decision Tree and Logistic Regression are used in the study. The performance was tested by using Dataset 1 from BCI Competition IV which consists of imaginary hand and foot movement EEG data. As a result, SVM, Logistic Regression and Naïve Bayes classifier achieved the highest accuracy with 89.09% in AUC measurement.
Design of a cell selection mechanism to mitigate interference for cell-edge macro users in femto-macro heterogeneous network
Authors: Abdullah Shapina , Din Norashidah Md. , Elias Shamsul J. , Yoon Khang Adam Wong , Din Roshidi , Bakar Rosmadi
Published: June 2019

The Femto-Macro heterogeneous network is a promising solution to improve the network capacity and coverage in mobile network. However interference may rise due to femtocell deployment nearby to macro user equipment (MUE) within macrocell network coverage. Femtocell offers main priority in resource allocation to its subscribed femto user equipment (FUE) rather than unsubscribed MUE. MUEs will suffer severe interference when they are placed near or within the femtocell area range especially at the cell edge. This phenomenon occurs due to the distance is far from its serving macro base station (MBS) to receive good signal strength. This paper presents a design of cell selection scheme for cell-edge MUE to select an optimal femto base station (FBS) as its primary serving cell in physical resource block allocation. In this study, the proposed cell selection consists of four main elements: measuring the closest FBS distance, Signal to Interference-plus- Noise-Ratio (SINR), physical resource block (PRB) availability and node density level for the selected base station. The main goal is to ensure celledge MUE has priority fairly with FUE in physical resource block allocation per user bandwidth demand to mitigate interference. Hence, the cell-edge MUE has good experienced on receiving an adequate user data rate to improve higher network throughput.
FACTS device installation in transmission system using whale optimization algorithm
Authors: Shahbudin Irham Syafiq , Musirin Ismail , Suliman Saiful Izwan , Harun Afdallyna Fathiyah , Syed Mustaffa Sharifah Azma , Suyono Hadi , Md Ghani Nor Azura
Published: June 2019

As the world is progressing forward, the load demand in the power system has been continuously increasing day by day. This situation has forced the power system to operate under stress condition due to its limitation. Therefore, due to the stressed condition, the transmission losses faced higher increment with a lower minimum voltage. Theoretically, the installation of the Flexible AC Transmission System (FACTS) device can solve the problem experienced by the power system. This paper presents the Whale Optimization Algorithm for loss minimization using FACTS devices in the transmission system. Thyristor controlled series compensator (TCSC) is chosen for this study. In this study, WOA is developed to identify the optimal sizing of FACTS device for loss minimization in the power system. IEEE 30-bus RTS was used as the test system to validate the effectiveness of the proposed algorithm.
Knots timber detection and classification with C-Support Vector Machine
Authors: Muhammad Redzuan Fakhira Iwani , Yusoff Marina
Published: June 2019

Timber knots recognition is of prime importance to further determine the timber grade. The recognition is normally based on the human expert’s eyes in which can lead to some flaws based on human limitations and weaknesses. The use of X-ray can cause emits radiation and can be dangerous to the workers. This paper addresses the employment of computational methods for knot detection. A pre-processing and feature extraction methods include contrast stretching, median blur and thresholding, gray scale and local binary pattern were used. More than 400 datasets of knot images of the tropical timbers, namely Acacia and Hevea Brasiliensis have been tested using C-support vector machine as a knot classifier. The findings demonstrate different performances for three types of kernel. Linear kernel function outperformed both radial basis function and polynomial kernel functions for Acacia and Hevea Brasiliensis species. Both species classifications using linear kernel have managed to achieve a promising accuracy. Knots classification with the used of support vector machine has shown a promising result to improve the classifier and test with different types of tropical timbers.
Hand motion pattern recognition analysis of forearm muscle using MMG signals
Authors: R. Mohamad Ismail M. , Lam C. K. , Sundaraj K. , H. F. Rahiman M.
Published: June 2019

Surface Mechanomyography (MMG) is the recording of mechanical activity of muscle tissue. MMG measures the mechanical signal (vibration of muscle) that generated from the muscles during contraction or relaxation action. It is widely used in various fields such as medical diagnosis, rehabilitation purpose and engineering applications. The main purpose of this research is to identify the hand gesture movement via VMG sensor (TSD250A) and classify them using Linear Discriminant Analysis (LDA). There are four channels MMG signal placed into adjacent muscles which PL-FCU and ED-ECU. The features used to feed the classifier to determine accuracy are mean absolute value, standard deviation, variance and root mean square. Most of subjects gave similar range of MMG signal of extraction values because of the adjacent muscle. The average accuracy of LDA is approximately 87.50% for the eight subjects. The finding of the result shows, MMG signal of adjacent muscle can affect the classification accuracy of the classifier.